Gen Pathology (Dra.

Tesoro)

Bone, Joint and Soft Tissue

26 January 2008

BONE, JOINT AND SOFT TISSUE

Composition of Bone
A. Cells
1. Osteoblasts (3 months)
 Forms and mineralizes bone
 Produces ALP
2. Osteocytes
 Inactive osteoblasts
3. Osteoclasts
 Resorb bone; not from progenitor bone cells
 Multinucleated - monocytes
4. Chondrocytes
 Forms and maintains cartilage
B. Organic matrix
1. collagen fibers
 1-95% of matrix
osteiod
 not mineralized
 hydroxyproline
 two types:
1. woven – at growth plates, resist pressure
better
2. lamellar – harder/ can’t accept shock
proteoglycans
 cell adhesion/ cytokines/ calcium/ GF/
enzymes Remodeling
C. Minerals  Formation and resorption process
 provides hardness  Constant process
 mineralization dependent on PTH  Adjusment of the skeletal system to stress
1. Calcium – 90%  Important for CA and PO4 balance
2. Phosphorus – 80%

D. Blood vessels

NON-NEOPLASTIC BONE PATHOLOGY

Leu, brim, virns 1 of 10
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Developmental/Genetic And Acquired Abnormalities In

Bone Cells Matrix And Structures
• Malformations and diseases caused by defects in
nuclear proteins and transcription factors
• Disease caused by defects in hormones and signal
transduction mechanisms
• Disease associated with defects in extracellular C. Disease Associated With Defects In Extracellular
structure proteins Structure Proteins
• Diseases associated with defects in folding and i. Type I collagen diseases
degradation of macromolecules  Osteogenesis Imperfecta
• Disease associated with defects in metabolic pathways  group of phenotypically related disorders caused by
(enzymes/ion channels and transporters) deficiency in the synthesis of collagen type I
• Diseases associated with decreased bone mass  brittle bones / too little bone
• Disease caused by osteoclasts dysfunction  marked cortical thinning and attenuation of
• Disease associated with abnormal mineral homeostasis trabeculae
•  4 sub types according to severity of mutation
A. Malformations And Diseases Caused By Defects In ii. Types 2, 10 11 collagen diseases
Nuclear Proteins And Transcription Factors  Hyaline cartilage
 Dysostoses:
• Developmental anomaly due to localized
disorder of migration/condensation of the
mesenchymal cells
• Uncommon
• Genetic alteration that affects transcription
factors
• Homeobox genes (HOXD-13)
 Syndactyly
 Supernumerary digits
 Craniorachischisis

B. Disease Caused By Defects In Hormones And Signal

Transduction Mechanisms
i. Achondroplasia
 most common disease of the growth plate
 most common cause of dwarfism
 defect in the paracrine cell signaling resulting in the
reduction in the proliferation of chondrocytes in the
growth plates
 “without cartilage formation”

• Autosomal dominant
• Shortened proximal extremities
• Trunk has normal length
• Enlarged head with bulging
forehead and conspicous
depresion of the root of the nose
• Not associated with longevity,
intelligence and reproductive
status
ii. Thanatophoric dwarfism
 most common lethal form of dwarfism
 mutation in FGFR3 (missence /point mutation)
 diminished proliferation of chondrocytes and
poor columnization in the zone of proliferation
D. Diseases Associated With Defects In Folding And
Degradation Of Macromolecules
i. Mucopolysaccharidoses
 group of lysosomal storage diseases
 deficiencies in enzymes that degrade heparan
sulfate/ dermatan sulfate/ keratan sulfate
 acid hydrolases
 Abnormalities in hyaline cartilage: cartilage anlage,
growth plates, costal cartilages & articular surfaces
• Short stature
• Chest wall abnormalities
• Malformed bones

• Micromelic shortening of the limbs

• Frontal bossing with relative
macrocephaly
• Small chest cavity
• Bell shaped abdomen
• Die due to respiratory
insufficiency
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E. Disease Associated With Defects In Metabolic
Pathways (Enzymes/Ion Channels And Transporters)
i. Osteopetrosis
 rare genetic diseases
 reduced osteoclasts bone resorption. Resulting in
diffuse symmetric skeletal sclerosis
 stone like quality of the bones which are
abnormally brittle and fractures like a chalk
 marble bone disease / albers schonberg disease
 deficient osteoclast activity
G.
• Bone lack medullary canal
• Ends of long bones are bulbous
and misshapen
• No room for bone marrow
• Fracture anemia and
hydrocephaly
]
Disease Caused By Osteoclasts Dysfunction
i. Paget’s Disease / Osteitis Deformans
 Initial osteoclastic activity due to defective
remodeling followed by disorganized hyperplastic
bone formation
 3 phases
1. osteolytic stage
2. osteoclastic-osteoblastic stage
3. osteosclerotic stage
 Etiology uncertain (viral infection?)
 M > F / Most patients > 55 years
 Most commonly involves lumbosacral spine, pelvis
and skull; very rare in ribs / Usually polyostotic
 Pain

Complications:
• Fractures
• Degenerative arthritis
• Bone tumors
(osteosarcoma,
fibrosarcoma,
chondrosarcoma and GCT)
• High-output cardiac failure
Mosaic pattern

F. Diseases Associated With Decreased Bone Mass

i. Osteoporosis
 increased porosity of the skeleton resulting in
reduced bone mass
 predispose the bone to fracture
 localized – disused osteoporosis vs generalized – H. Disease Associated With Abnormal Mineral
metabolic bone disease Homeostasis
 most common – senile / post menopausal i. Rickets and Osteomalacia
osteoporosis  Accumulation of unmineralized bone matrix
 pathogenesis resulting from a diminished rate of mineralization
1. age related changes  Causes:
• senile osteoporosis / low turn over  Dietary deficiency in vitamin D
variant  Defective bone mineralization
2. reduce physical activity  Congenital or acquired defects in vitamin D
3. genetic factors or phosphate metabolism
• vitamin D receptor molecule  Malabsorption (most common cause in US)
4. calcium nutrition status  Crohn’s disease
5. hormonal influences  Celiac disease
• estrogen vs glucocorticoids  Cholestatic liver disease
 Biliary obstruction
 Chronic pancreatitis
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FRACTURES
 Most common pathologic condition of bones
1. traumatic
2. non traumatic
 Classification
1. complete(break na break ang bone) vs incomplete
2. simple (close) vs compound (penetrate skin)
3. comminuted(several pieces)vs displaced(not aligned)
4. pathologic (w/ dse) and stress (due to trauma)

Bone Fractures
Organization with
Hematoma neovascularization
(2-3 days)
ii. Hyperparathyroidism
 Increased bone resorption secondary to increased
PTH Pluripotential mesenchymal
 Classic pathologic change referred to as osteitis Intramembranous
cells give rise to osteoblasts to
fibrosa cystica bone growth (7
synthesize woven bone
 Replacement of marrow by fibrous tissue days)
 Numerous microfractures
 Hemosiderin-laden macrophages Endochondral Remodeling (months)
 Eventually cystic degeneration and classic ossification
gross appearance referred to as “brown
tumor”
Lamellar bone

OSTEONECROSIS / AVASCULAR NECROSIS

 Relatively common event
 Occurs in the medullary cavity of the metaphysis and
diaphysis and the subchondral regions of the epiphysis
 Results from ischemia
 Mechanisms:
iii. Renal Osteodystrophy
1. Mechanical vascular interruption (fracture)
 Skeletal changes of chronic renal disease
2. Corticosteroids
1. increased osteoclastic bone resorption
3. Thrombosis and ebolism
2. delayed matrix mineralization
4. Vessel injury
3. growth retardation
4. osteoporosis
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5. Increased intraosseos pressure with vascular I. BONE FORMING TUMORS

compression  Common feature is the production of bone by the
6. Venous hypertension neoplastic cells
 Woven trabeculae (except osteoma) and variably
mineralized
1. Osteoma
2. Osteoid osteoma / osteoblastoma
3. Osteosarcoma

1. OSTEOMA
 Bosselated, round to oval sessile tumors that project
from the subperiosteal or endosteal surfaces of the
cortex
 Skull and facial bone
 Gardnes syndrome
 Composed of woven and lamellar bone
 Reactive bone induced by infection, trauma or
hemangioma
OSTEOMYELITIS  Little clinical significance and interfere with function
 Inflammation of the bone and commonly implies
infections
 Bacterial infection of bone
 Coagulase-positive Staph (80-90% of cases)
 Klebsiella
 Pseudomonas (“tennis shoe” osteo)
 Neisseria
 Salmonella (SCD)
 TB
 50% of cases no pathologic organisms are isolated
 Local, exogenous or hematogenous infection
 Dead bone (“sequestrum”) is surrounded by new bone
formation (“involucrum”)
 Chronic osteomyelitis often requires surgery
 Tuberculous osteomyelitis – Pott disease
 Skeletal syphilis
2. OSTEOID OSTEOMA / OSTEOBLASTOMA
 Benign tumors with identical histologic patterns but
differ in size, site of origin and symptoms
 Osteoid Osteoma
• < 2 cm
• 10-20 y/o
• Appendicular bone / cortex
• Painful lesion (PGE) nocturnal – aspirin
 Osteoblastoma
• Spine
• Dull pain, achy - not responsive to salicylates
• No marked bony reaction

3. OSTEOSARCOMA
 Malignant mesenchymal neoplasm in which the cell
produce bone matrix
 20% of primary bone tumors
 Bimodal age distribution (<20/75% - elderly)
 Metaphyseal region of long bones (knee)
BONE TUMORS AND TUMOR LIKE LESIONS  Mutation in RB gene
 Several subtypes according to the following:
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• Anatomic portion  Epiphyses / apophyses

• Degree of differentiation  Painful
• Multicentricity  Polyhedral chondroblasts
• Primary vs secondary
• Histologic variants

4. CHONDROSARCOMA
II. CARTILAGE FORMING TUMORS  Group of tumors with a broad spectrum of clinical and
 Characterized by the formation of hyaline or myxoid pathologic findings
cartilage; fibrocartilage and elastic cartilage  Production of neoplastic cartilage
1. Osteochondroma  Second most common primary bone tumor
2. Chondroma  40 y/o / women
3. Chrondroblastoma
4. Chondromyxoid fibroma
5. Chondrosarcoma

1. OSTEOCHONDROMA
 Exostosis
 Benign cartilage capped out growth that is attached to
the to the underlying skeleton by a bony stalk

III. FIBROUS AND FIBRO-OSSEOUS TUMORS

 Non-neoplastic condition
 Monostotic variety
• Older children and young adults
• May involve rib, femur, tibia and skull
 Polyostotic variety
• Unilateral distribution associated with endocrine
dysfunction, precocious puberty in females and
2. CHONDROMA areas of cutaneous hyperpigmentation (McCune-
 Benign lesion of hyaline cartilage that arises with in the Albright syndrome)
medullary cavity – Enchondroma  May be complicated by malignancy
 Intraosseous cartilage – 20-50 y/o • Osteosarcoma, chondrosarcoma and MFH
 Ollier’s disease vs Maffuci syndrome  Treat with surgical curettage and repair of fractures

• Misshapen bony trabeculae

interspersed with fibrous tissue
• Woven bone NEVER is
transformed to lamellar bone

3. CHONDROBLASTOMA 1. FIBROUS CORTICAL DEFECT / NONOSSIFYING

 Rare benign tumor – 1 % of primary tumors FIBROMA
 Young/ male /knee  Fibrous Cortical Defect
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• extremely common  women than men

• 30-50% <2 years old  long bones, most often the distal femur, proximal tibia,
• Developmental defect and distal radius
• Metaphysis of long bones lower extremities
 Nonossifying Fibroma  most common primary bone lesions in the distal
• >5-6 cm phalanx
• Adolescence
• Spontaneous resolution

2. FIBROSARCOMA / MALIGNANT FIBROUS

HISTIOCYTOMA
 Fibroblastic collagen producing sarcoma of the bone
 Overlapping clinical, radiological and pathologic features
 Any age/ equal sex distribution
 Enlarging painful masses
 Metaphysis of long bones and flat bones of the pelvis

3. METASTATIC DISEASE
 Most common form of skeletal malignancy
a. Direct extension
b. Lymphatic
c. Hematogenous
d. Intraspinal seeding
 Adults 75%
• prostate
• breast
• Kidney
• lung
IV. MISCELLANEOUS TUMORS
PATHOLOGY OF JOINTS AND SYNOVIAL MEMBRANES
1. EWING SARCOMA AND PNET
 Ewing's sarcoma is a highly malignant tumor (small  Osteoarthritis
round cell)  Rheumatoid arthritis
 A type of peripheral primitive neuroectodermal tumor  Spondyloarthropathies
(PNET)  Gout
 Translocation of t(11;22)(q24;q12)  Pseudogout
 Lower extremity more than the upper extremity, but
any long tubular bone may be affected 1. OSTEOARTHRITIS
 Most common sites are the metaphysis and diaphysis of  Most common form of joint disease
the femur followed by the tibia and humerus.  Slowly progressive
 First and second decade but may affect persons from  Degenerative joint disease
age 2 to 8 – second most common malignant tumor of  Elderly or status post trauma
the bone in children  Cartilage attrition may be due to IL-1
 Whites more than blacks and Asians
 Male to female is 3:2.

2. GIANT CELL TUMOR

 Giant cell tumor of bone is a benign lesion that is a
usually solitary and locally aggressive. It is believed by
some to be potentially malignant
 numerous multinucleated giant cells
 Giant cell tumor accounts for 5 to 9 percent of all
primary bony tumors and may be the most common
bone tumor in the young adults aged 25 to 40
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 Rheumatoid Factor
• Positive in 70-80% of patients with classic RA
• Autoantibodies of IgM, IgG or IgA class that
react with Fc region of IgG
• Not specific for RA
• Circulating complexes bind complement
 Synovial hyperplasia driven by IL-1

Rheumatoid nodules are present in 25% of patients

2. RHEUMATOID ARTHRITIS
 Chronic systemic disease of unknown etiology
 Joints of hands and feet nearly always involved; may
involve elbows, knees, ankles, hips, spine and TMJ
 F > M (3:1)
 4th to 6th decade
 Prevalence 0.5 – 1%
 Strongly associated with HLA-DR4 and several non-MHC
genes 3. SPONDYLOARTHROPATHIES
 Ankylosing spondylitis
• Rheumatoid spondylitis/ Marie-Strumpell
disease
• HLA-B27
• Vertebral column and sacro-iliac joints
 Reiter syndrome
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• Post-venereal IV. SMOOTH MUSCLE TUMOURS

• Urethritis, conjunctivitis and seronegative V. PERICYTIC (PERIVASCULAR) TUMOURS
polyarthritis VI. SKELETAL MUSCLE TUMOURS
VII.VASCULAR TUMOURS
4. GOUT VIII.CHONDRO-OSSEOUS TUMOURS
 Common end point of a group of disorders that produce IX. TUMOURS OF UNCERTAIN DIFFERENTIATION
hyperuricemia
 Endogenous crystals  Introduction
• Monosodium urate (gout) • Majority are benign
• Calcium pyrophosphate dihydrate • <1% are malignant, but are life threatening
• Calcium phosphate (pseudo gout) • >50 histologic subtypes
i. Acute arthritis • Careful physical examination and radiographic
• Crystallization of urates evaluation to valuate size, depth, location of the mass,
ii. Chronic arthritis along with signs of neurovascular involvement are
• Tophi essential for the designing the best therapeutic
 Contributing factors: approach.
• Age  Epidemiology
• Genetic predisposition • ratio of benign vs sarcoma 100:1
• Alcohol • benign soft tissue annual clinical incidence 3000/mil
• Obese • sarcoma annual clinical incidence 30/mil
• Drugs • no significant geographic differences
• Lead • Benign soft tissue tumours
-1/3 lipoma
-1/3 fibrohistiocytic and fibrous tumours
- 10% vascular tumours
-5% nerve sheath tumours
• 99% are superficial
• 95% are <5cm in diameter
• There is a relationship between type of tumours,
symptoms, location and patient’s age and gender
 LIPOMA – painless, rare n hand, lower leg and foot
and very uncommon in children
 Multiple ANGIOLIPOMA – painful, in young men
 ANGIOLEIOMYOMA – painful, lower leg , middle
aged women
 VASCULAR TUMOURS (1/2) – younger than 20 y.o.

• Soft Tissue Sarcomas

- may occur any where
 ¾ extremities (thigh)
 10% trunk wall and retroperitoneum
- slight male predominance
- more common in increasing age (median age 65y.o.)
- size:
 Extremities/trunk wall tumours
 1/3 superficial with a median diamter
of 5cm
 2/3 deep seated with median
diameter of 9cm
 Retroperitoneal tumours large on diagnosis
1/10 have metastasis (most common lung)
 1/3 die because of the tumour
-¾ are high garde pleomorphic (MFH-like), liposacroma,
synovial sarcoma, and Malignant peripheral nerve
sheath tumours
- ¾ are highly malignant (grade 3-4)
- age: vary/type
 Embryonal rhabdomyosarcoma - exclusive in
children
 Synovial sarcoma – young adults
 Pleomorphic high grade
sarcoma/lipsarcoma/leiomyosarcoma – elderly
SOFT TISSUE TUMORS
 Etiology
• the etiology of most benign and malignant soft tissue
WHO CLASSIFICATION
tumours is unknown
I. ADIPOCYTIC TUMOURS
• Majority seems to arise de novo
II. FIBROBLASTIC/MYOFIBROBLASTIC TUMOURS
• Possible etiologies:
III. FIBROHISTIOCYTIC TUMOURS
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1. Chemical carcinogens
 phenoxyacetic herbicides/chlorophenol and
their contaminants in agriculture and forestry
work
 Different findings in herbicides is the use of
different dioxin contaminants
2. Radiation
 Incidence of post –radiation sarcoma ranges
from 1,000-1%
 Most are breast cancer patients
 Risk increases with dose: <50Gy/10 years
median time
 MFH – highly malignant
 Germ line mutation of retinoblastoma gene
(RB1) have an elevated risk of developing
post-irradiation sarcomas, usually
osteosarcomas
3. Viral infection and immunodeficiency
4. Genetic susceptibility
 Human Herpes virus 8 – Kaposi sarcoma and
the clinical course is dependent on the immune
status of the patient
 Epstein-Barr virus is associated with smooth
muscle tumours in patients with
immunedeficiency
 Stewart-Treves syndrome: angiosarcoma in
chronic lyphoedema, particularly after radical
mastectomy, has by some authors been
attributed to regional acquired
immunodeficiency
 LIPOMA
 LIPOSARCOMA - LIPOBLASTS
 FIBROSARCOMA – HERRING BONE PATTERN
 MALIGNANT FIBROUS HISTIOCYTOMA – STORIFORM
PATTERN
 RHABDOMYOSARCOMA – STRAP CELLS
 LEIOMYOMA
 LEIOMYOSARCOMA
 SYNOVIAL SARCOMA - BIPHASIC