Bone pathology Flashcards
1
Q
Bone Intercellular Signals
A
Receptor Activator of NF-KappaB Ligand (RANKL)
- Expressed on Osteoblasts
- Upregulated by PTH, vitamin D3, some malignancies
- Binds to RANK (TNF family) on Osteoclasts and precursors to activate them
- Function inhibited by Osteoprotegrin (OPG); TNF family: binds to RANKL acting as a decoy preventing RANK-RANKL interaction.
- osteoporosis -> decr in OPG production
2
Q
A
Osteoporosis: Metabolic Bone Disease -> Abnormal bone modeling/remodeling
- *Gross:**
- widened Haversian canals in cortex
- compression fracture: Horizontal bone thinned out (red);
- Vertical bone thickened
- *Structural**
- distal radius -> Colle’s fractures
- femur and hip
- *Microscopic:**
- nl bone (left)
- osteoprosis (right)
- disappearance of trabecular bone aka spongy bone
EtioPathogenesis: Primary Osteoporosis
- Postmenopausal, 2, Aging, 3, Physical activity decr
- decr serum estrogen -> incr. IL-1, IL-6, and TNF -> incr RANK expression -> incr osteoclast activity and decr activity of osteoblasts
Etiopath of Secondary Osteoporosis
- Endocrine
- Hyperparathyroidism
- Hyperthyroidism, Diabetes Type I, Addison’s disease, Pituitary tumors, vit D allele variation
- Neoplasia: Carcinomatosis, multiple myeloma, paraneoplastic disease
- Gastrointestinal: Malnutrition, hepatic insufficiency, vitamin D or C deficiency, malabsorption
- Drugs: Chemotherapy, corticosteroids (nl serum Ca2+ levels), alcohol
- Immobilization
Dx: XRay & DEXA scan
3
Q
A
HyperPTH leading to 2o osteoporosis
- incr PTH -> osteoblast stim -> incr RANKL -> osteoclast activity
- Osteoclastic tunneling
- 2 types
Osteitis fibrosa cystica: Brown tumour (Gross image)
- microfractures -> neovascularisation, hemorrhages, giant cell-like tumours
- hemosiderin deposits
- ribs, diaphyses of long bones, fingers
- *Osteitis dissectans (microscopic image)**
- Osteoclastic tunneling
- splitting like railroid tracks
Etiology
Increased PTH resulting in increased osteoclast activity.
1° - adenoma – high Ca, low PO43-
2° - renal failure – low Ca, high PO43- (opposite levels vs 1o)
3° - initially secondary cause that turned primary due to cellular adaptive change
Sx: Stones, Bones, Moans
- Renal stones due to nephrocalcinosis
- Bone density decreased
- Psychiatric sx
- Groans: abdominal problems such as anorexia, constipation, and ulcers
- *C&C:**
- metastatic calcifications: kidney, lungs, and stomch
4
Q
Renal Osteodystrophy
A
- Chronic renal failure → hyperphosphatemia →
- Hypocalcemia → Secondary incr PTH
- Reason for Hypocalcemia
- Decreased vitamin D metabolism in kidney (inhibition of conversion of vitamin D to active metabolites by phosphate)
- Diminished intestinal absorption of vitamin D
- Iron and aluminum accumulation in bone (from dialysate) prevents further bone deposition
- incr PTH → incr Osteoclastic activity → incr Bone resorption
- decr Matrix mineralization (osteomalacia)
- Osteoporosis
- Growth retardation
5
Q
A
Vitamin D Deficiency: Osteomalacia & Rickets
- Defective mineralization of osteoid
- Malnutrition, malabsorption, receptor abnormalities, lack of sun exposure
- Under-mineralized matrix
- – Persistent hyaline cartilage
- – Fractures, skeletal deformity
- *Microscopic:** Abnormal mineralization
- mineralized osteiod (black)
- un-mineralized osteiod (pink)
- *Etiopath:**
- Vit D deficiency leading to diminished bone density
- Vit D deficiency in Adults from malnutrition, decr sun exposure, renal and liver disease
Sx Children: bowed legs, pigeon breast, frontal bossing, rachitic rosary
Sx Adults: weak bone, easily fractured
- *Dx:**
- low serum Ca2+ and phosphates
- High PTH and Alkaline phosphatase (due to activation of osteoblasts to calcify in basic env)
6
Q
Scurvy
A
Metabolic Bone Disease -> Abnormal matrix production
Etiopath: Vitamin C deficiency
Sx:
- Failed cross-linking of collagen
- Fragile capillaries and venules – Subperiosteal hemorrhages
- Defective osteoid synthesis – Microfractures
- Bony deformities
7
Q
A
Paget’s Disease: Metabolic Bone Disease -> Abnormal bone modeling/remodeling
X-Ray
- Remodelling is focal -> enlarges bone
- lytic and sclerotic areas; too much osteoclastic or osteoblastic activity (haywire)
Gross:
- affects flat and long bones
- weaker so easily fractured
- red due to hypervascularity
Microscopic:
- haphazard cement lines -> mosaic pattern
Etiology
- More common in Caucasians
- Virally induced [Paramyxovirus (measles, RSV) - nucleocapsid antigens identified in osteoclasts) (Paramyxovirus- slow virus disease)
- Genetic predisposition: p62 mutation
- Enlarges in any bone -> larger hats
Pathogenesis
- localized (does not involve entire skeleton)
- defect in signalling bw osteoblasts and osteoclasts
- Virus stimulates IL-6
- IL-6 & M-CSF -> Activate osteoclasts
- Osteoclasts hyperresponsive to RANKL & vit. D
- p62 incr RANK/RANKL SIGNALLING incr Osteoclasts
- 3 Disease of stages -> sclerotic bone
- Osteolytic Stage: Osteoclastic activity- patchy, florid
- Mixed Lytic and Blastic Stage: Predominently Osteoblastic
- Osteosclerotic (burnt-out) Stage: End stage: incr bone mass; mosaic pattern
Sx: often Asx and incidental finding
- increasing hat size
- lion-like face
Diagnosis:
- X-ray: May be monostotic or polyostotic (multiple bones)
- ↑Serum Alkaline Phosphatase
- ↑ Urinary Hydroxyproline
- nl serum Ca2+ and phosphate
C&C:
- Deformities – Pain (compressed nerves)
- Fracture/Microfractures -> Pain
- Degenerative Joint Disease -> Pain
- hearing difficulties if ossicles affected
- Rarely:
- High-Output cardiac failure (osteoblastic phase) due to AV malformations from bone remodeling leading to shunting
- 2o osteosarcoma
8
Q
Achondroplasia
A
Achondroplasia aka disportionate dwarfism
- bow leg
- Shortened limbs and ribs
- Normal head, IQ, reproductive system and life expectancy
- *Etiopath:**
- AD FGFR3 mutation leading to constituitively active FGFR3 signaling lead to decr endocondral ossification (cartilage development)
- sporadic mutation commonly
- Disordered proliferation of chondrocytes in cartilage anlage and growth plate
- – decr Proliferation
- – decr hypertrophy
- – Incomplete endochondral ossification
- *Dx**
- clinical presentation
- prenatal US measurements
C&C: gibbus deformity
9
Q
A
Osteogenesis Imperfecta
X-ray: every bone has fractures (hyperdense areas showing callous formations)
Etiopath:
- deficiencies in type I collagen synthesis due to AD COL1A1 and COL1A2 mutations
- Most commonly recognized congenital disease affecting collagen production
- Multiple clinicopathological subtypes
Sx:
- Involves bone matrix and other connective tissues with type 1 collagen: joints, eyes (blue sclera), skin, ears, teeth
- blue sclera due defective collagen in eyes -> shows the choroidal vv
10
Q
Ehler-Danlos Syndrome
A
- Hetrogenous group of CT disorders, recently classified in diff types
- lysyl hydroxylase def. or collagen synthesis dysfunction
Sx:
- Hyperextensibility of skin, easy bruising, hypermobile joints,
- Aortic dissection;
- blue sclerae may be present
- Bone is osteopenic, kyphoscoliosis, spondolisthesis
11
Q
Marfan’s Syndrome
A
Heterogeneous group of inherited (AD) CT disorder affecting bones, heart, aorta and eyes
Etiopath: Mutation in locus of fibrillin gene on chromosome 15
Sx:
- Usually tall with exceptionally long extremities, and long tapering fingers and toes
- Hyperflexible joints, kyphosis, scoliosis, pectus excavatum
- Eyes: subluxation of lens – ectopia lentis
- CVS: Mitral valve prolapse, Aortic dilatation due to cystic medial necrosis – AR; Aortic dissection, dissection also common in kidney and coronary aa
12
Q
Acute osteomyelitis
A
Xray: mix lytic and sclerotic areas in bone
- *Microscopic:**
- pus and necrotic debris
- enlarged Haversian canals
Acute osteomyeltis features
- Usually Bacterial but No organism isolated in 50%.
- S. aureus (80-90%) – receptors for bone matrix components e.g. collagen
- Gram -ve rods (E. coli, Klebsiella, Pseudomonas) – Genitourinary (GU infection), IV drug abuse
- Mixed bacterial (direct inoculation)
- H. influenza (neonates)
- GBS (neonates)
- Salmonella (sickle cell disease)
Epidemiology
- Young, growing children
- Adults (> 50 years)
- Gender M:F = 2:1
- Typical presentation: young boy presenting w hot, swollen leg
- Acute Osteomyelitis is worse in infants and young children
- Location
- Long tubular bones (femur, tibia, humerus)
- Vertebral bodies
- Predisposing factors: catheter, trauma, infection, underlying disease, IV drug abuse
Pathogenesis
- Acute inflammation
- Bone necrosis
- Subperiosteal abscess
- Progressive ischemia leads to segmental bone necrosis (sequestrum) surrounded by viable new bone (involucrum) formation
- Draining sinus tracts
- Extension into joint space
Sx:
- bone pain w fever and leukoctyosis
- lytic focus surrounded by sclerosis on XRay
Dx: Blood culture
Rx
- Treat early
- IV antibiotics 4-6 weeks
- Exception: Children with hematogenous spread
- Oral therapy if organism is susceptible
- Good compliance
- Rapid response
- Exception: Children with hematogenous spread
- Consider surgical debridement
13
Q
A
Osteopetrosis (stone-like bones) aka marble bone disease
X-rays: Bones lack medullary canal
- Increased bone density (hyperdense on Xray)
- Bulbous misshapen (distorted) ends of long bones -> ERLENMEYER’S FLASK DEFORMITY
- Diffuse symmetrical skeletal sclerosis
Microscopic: Medullary cavity abnormally filled with primary spongiosa and no hematopoietic elements
Etiopath:
- defective osteoclast-mediated bone resorption.
- Several variants with the most common
- AD adult form with mild clinical manifestations,
- AR infantile, with a severe/lethal phenotype
- Can arise due to:
- Brittle bone disease
- Dysfunction of 1. Carbonic Anhydrase (CA II), 2. Proton pump, 3. Chloride channel
- Inability of osteoclasts to degrade pre-existing cartilage and bone.
- Persistence of cartilage anlage (primary spongiosum) in medullary cavity.
- Progressive deposition of bone on pre- existing matrix without osteoclastic activity (or without osteoclasts)
Sx:
- Bones are abnormally brittle and fracture
- Structural changes in spine -> more bone to disc material.
- Thickening of skull -> narrowing of foramina
- Hepatosplenomegaly from extramedullary hematopoiesis (EMH) & pancytopenia
- vision and hearing impairments
- hydrocephalus
- Renal Tubular Acidosis (RTA) due to CA deficiency
C&C
- Cranial n. palsies due to nerve compression (carpal tunnel and cranial nerve deficits ex. Bell’s palsy, hearing and vision loss)
- Pancytopenia due spongiosa taking over medulla and decreasing hematopoietic cells.
- Recurrent infections due to reduced marrow size.
14
Q
Chronic Osteomyelitis
A
5-25% of Acute Osteomyelitis do not resolve -> Chronic Osteomyelitis
- – Delay in diagnosis
- – Inappropriate treatment:
- Inappropriate antibiotics
- Therapy is too short
- – Inadequate surgical debridement – extensive necrosis
- – Underlying medical condition (eg. diabetes)
Pathogenesis:
- – Chronic inflammation
- – Resorption of dead bone
- – Deposition of woven bone
C&C
- Brodie abscess: Intracortical abscess
- Sclerosing OM of Garré: Jaw - extensive new bone obscuring the underlying bone
- Recurrent acute exacerbations
- Pathologic fracture
- Secondary amyloidosis
- Endocarditis
- Sepsis
- Septic Arthritis
- Rarely, malignant complications
- – Squamous cell carcinoma of fistula tract
- – Sarcoma of infected bone
15
Q
A
Tb osteomyelitis (Pott’s fracture)
Morphology:
- caseous granulomatous inflammation instead of abscess (other bacterial)
- destruction of vertebrae and IV
- can also affect hips and knees
Etiopath:
- 1-3% of patients with pulmonary TB
- Immunocompetent or compromised
- Location: Spine (Pott’s spine) > knees > hips
- Burrowing abscesses with caseating granulomas and calcification
Skeletal Tb
- Very Destructive
- Spreads through medullary cavity causing extensive caseous necrosis
- Extends thru IV discs involving multiple bones
- Difficult to control
C&C:
- kyphosis -> Gibbus deformity
- spinal cord compression
16
Q
A
Osteoarthritis: non-inflammatory arthritis
Morphology
Xray:
- Changes in Wt. bearing cartilage & bones
- Arrows indicate osteophytes; Repair response: Fibrocartilage grows over articular cartilage from periphery → Osteophytes
- Radio-lucent = subchondral sclerosis
- Radio-dense area = subchondral cysts (synovial fluid forced into subchondral microfractures in a ball-valve manner)
Microscopic: Fibrillation & Vertical Cracking indicating joint degeneration
- Eburnation & erosion
- cartilage thinning
- exposure of subchondral bone and remodelling
- ivory appearance of bone
- Arrows 1: eburnation
- Arrows 2: subencondral cysts
- Arrows 3: nl/what it should look like
Primary
– Aging phenomenon; Most common form of arthritis
– Oligoarticular: hands, hips, knees, metatarsophalangeal joints
– 80-95% of people over 65 years
- Risk factors
- Female sex
- Obesity
- Hereditary
Secondary
– Younger patients
– Predisposition
- Diabetes
- Hemachromatosis
- Ochronosis: alkaptonuria due to Homogentisate oxidase def.; exam q
- Obesity
- Congenital deformity
– Polyarticular
– Severe
- Risk factors
- – Trauma
- – Neuromuscular dysfunction
- – Metabolic disorders
Etiology
- Changes in components of articular cartilage
- – Altered proteoglycans
- – Diminished pliability of collagen
- Changes in chondrocytes
- – IL-1 and TNF-a break down matrix
- – Inhibit type II collagen synthesis
- Other changes: Non-inflammatory with some signs of signalling from:
- – Proinflammatory cytokines
- – Inflammatory cells
Pathogenesis
- Degenerative disease of cartilage (chondrocytes and matrix) but NO JOINT FUSION; Central destruction
- – Direct injury
- – decr Synthesis
- – incr Enzymatic breakdown:
- MMP breakdown Proteoglycans (PG) (stromelysins) & collagen (collagenases)
- Metalloproteinases are regulated by cytokines (IL-1 and TNF)
- Genetic predisposition (cartilage abnormalities) -?collagen genes mutations
- Injury & repair of the subchondral bone and/or synovium (secondary to cartilage degeneration) leading to:
- Chondrocyte proliferation- “cloning”
- incr water related to decr proteoglycan content (chondromalacia- softening)
- Type II collagen: decr synthesis and incr breakdown
Sx:
- 1st Carpometacarpal joint – most commonly affected joint in hand (subluxation, ”squaring”)
- Haberden’s nodes - DIP
- Bouchards’s nodes – PIP
- Unilateral (typically) but can be bilateral
C&C:
- spinal stenosis
- cervical spondylsis
17
Q
A
Rheumatoid Arthritis
Morphology:
Clinical and Xray
- Joint space - narrowed with pannus (fibrosing ankylosis)
- Eventually ossifies (bony ankylosis)
- Inflammation of adjacent tendons, ligaments, and muscle
Microscopic
- Papillary Synovial Hyperplasia
- Bulbous fronds
- synovium filled with inflammatory cells (lymphocytes, macrophages) and rice bodies made of fibrin and neutrophils (slide 15 not shown)
- Pannus formation: overgrowth of synovium (below); pannus fibrosis -> bone metastasis -> fusion of joints -> ankylosis
Xray: showing ankylosis
Etiology
- polyarthritis: pain, inflammation, swelling, autoimmune destruction (auto-Ab RF, ACPA)
- Prevalence estimated at ~0.5 - 1%
- Female:male ratio = 2.5:1
- Genetic predisposition assoc HLA-DR4 locus
- Environmental triggers: smoking, infections (EBV, E. coli), stress
Pathogenesis
- Subarticular Osteoporosis; Peripheral destruction
- Incr Osteoclastic activity (due to incr RANKL produced by activated T cells and synovial fibroblasts) -> Subchondral cysts, Osteoporosis (localized and systemic)
- Activation of macrophages & B-cells
- Antibodies against self-antigens in the joint (Autoantibodies = Rheumatoid Factor)
IgM directed against IgG (IgG bind the Fc portions of IgG)
- Inflammation, cytokines, TNF, antibodies –> destruction of joint
Sx
- Symmetrical arthritis, typically of the hands and feet, also often involving ankles, knees, wrists, elbows and shoulders
- MCP & PIP but NOT DIP
- knees involved but NOT hip
- Z-deformity of thumb
- ulnar deviation of digits due to myofibroblasts contraction (part of pannus)
- thenar atrophy from CTS
- Swan-neck deformity
- Boutonniere deformity
- Joint destruction occurs early and is a marker for disease progression
- Rheumatoid nodules (25% of Pt) characterized by central area of necrosis w epithelioid histiocytes
- Skin subject to pressure - ulnar aspect of forearm, occiput, lumbosacral area
- Non-tender firm nodule in subcutaneous fat
- Also develop in Joints, Tendons, Soft Tissue, Lung, Heart (peri-, myo-, endocardium), Aorta, Spleen, Viscera
- fever, malaise, weight loss, and myalgias
Assoc disorders
- Soft tissue- Rheumatoid nodules
- Lung involvement
- Vasculitis
- Uveitis: Usually in juvenile RA
- incr risk of lymphoma
Dx
- X-ray
- anti-CCP Ab
- anti-RF Ab
C&C
- RA is a systemic disease w a course of symmetric arthritis and Chronic papillary synovitis
- End-stage lung disease
- Vasculitis & its complications
- – Myocardial infarction, cerebrovascular disease, renal failure, pleural effusions, mesenteric and intestinal infarction, gangrene
- Systemic amyloidosis
- Anemia of chronic disease
- Baker cysts behind knee
- Iatrogenic effects of Tx- Immunosuppression
- Life Expectancy decr by 3-7 yrs
26
Q
A
Osteosarcoma
Xray (below): sunburst appearance
Gross image (below):
- Codman’s triangle
- white spots: osteoid tissue replacing marrow
Microscopic:
- immature un-mineralized bone surrounded by neoplastic cells
- large pleiomorphic cells
Epidemiology
Most common bone sarcoma (20%)
– Bimodal age distribution
- Elderly (Paget’s, radiation)
- Children, young adults
– Location
- Metaphyseal (long bones) in youth; typically around knee where most of the proliferative growth plates occur
- Flat bones in elderly: more in pelvis
Etiopath
- Anatomic location
- – Intramedullary (usually low grade) – Intracortical (high grade)
- – Juxtacortical (low or high grade)
- Grade
- – Grade 1: mild cytologic atypia
- – Grade 2: intermediate cytologic atypia
- – Grade 3: high grade, pleomorphic cytological atypia
- Osteoblastic, chondroblastic, fibroblastic histology
- Hereditary tumours:
- germline p53 mutations (Li-Fraumeni)
- hereditary Rb
- Sporadic
- – P53 mutations
- – MDM2 (inactivates apoptotic capacity of p53)
- – Rb mutations are rare
28
Q
A
Enchondroma
XRay:
- circumscribed lesion with punctate ?lytic areas
- radio-lucent in medulla: un-mineralized bone; characteristic of disease
- Sign: O-sign
Etiopath
- Benign: Hyaline and myxoid cartilage
- Metaphyseal and diaphyseal
- Medullary cavity
- May erode (but not invade) cortex
- Present with pathologic fracture
- Solitary or syndromic (Ollier’s or Mafucci’s disease)
- May give rise to chondrosarcoma; Malignant Transformation!
Sx:
- Nodules on distal extremities, non-invasive nodules of cartilage (unmineralized).
- May be surrounded by erythema and hemangiomas.
Assoc conditions
- Multiple Enchondromatosis
- Ollier’s Disease
- – Disfiguring
- – 20% develop chondrosarcoma
- Mafucci’s Disease
- – Enchondromas and soft tissue vascular tumors such as hamangioma
- – 20% develop chondrosarcoma
- – 100% develop another extraskeletal malignancy: ovarian carcinoma, brain glioma, lung carcinoma
- Ollier’s Disease
30
Q
A
Chondrosarcoma
Gross: arrow points at mass at metaphysis
Microscopic: glassy blue matrix w chondrocytes -> cartilage disease (too cellular)
Etiopath:
- Typically occurs in older adults
- Pelvis, humerus, proximal femur (rare in hands and feet)
- May arise in enchondroma (low grade)
- Low grade (1/3) do not metastasize, but may recur and dedifferentiate
- High grade metastasize
- Hematogenous spread: lung & liver
31
Q
A
Giant Cell Tumor of Bone
Xray: well circumscribed radiolucent area showing expanding lytic lesion (sometimes soapy bubble)
Microscopic: stromal cell (w RANKL) recruiting osteoclastic giant cells (w RANK)
Etiopath:
- Benign locally aggressive tumor
- 4-5% of all primary bone tumors
- Age 20-40 yrs
- Epiphysis
- End of long bones
Sx: pain in distal femur or proximal tibia
C&C: spread to lungs (2%)
32
Q
Ewing’s Sarcoma & Primitive Neuroectodermal Tumor (PNET)
A
- Family of small blue cell tumors with a characteristic t(11;22) and t(21;22)
- arises from neuroectoderm
- 6-10% of all primary malignant bone tm.
- Age: youngest among malignant bone tm
-
Diaphysis of long bones
- grows from medullary cavity
- onion-skin appearance
- Prognosis: dismal, improves by chemo
