Bone, Joint And Soft Tissue

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

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B.

Resorb bone; not from progenitor bone cells  Multinucleated - monocytes 4. Chondrocytes  Forms and maintains cartilage 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

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cell adhesion/ cytokines/ calcium/ GF/ enzymes

C.

Minerals  provides hardness  mineralization dependent on PTH 1. Calcium – 90% 2. Phosphorus – 80%

D.

Blood vessels

Leu, brim, virns

Remodeling  Formation and resorption process  Constant process  Adjusment of the skeletal system to stress  Important for CA and PO4 balance

NON-NEOPLASTIC BONE PATHOLOGY 1 of 10

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro 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 structure proteins • Diseases associated with defects in folding and degradation of macromolecules • Disease associated with defects in metabolic pathways (enzymes/ion channels and transporters) • Diseases associated with decreased bone mass • Disease caused by osteoclasts dysfunction • Disease associated with abnormal mineral homeostasis • A. Malformations And Diseases Caused By Defects In Nuclear Proteins And Transcription Factors  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.

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C.

Disease Associated With Defects In Extracellular Structure Proteins i. Type I collagen diseases  Osteogenesis Imperfecta  group of phenotypically related disorders caused by deficiency in the synthesis of collagen type I  brittle bones / too little bone  marked cortical thinning and attenuation of trabeculae  4 sub types according to severity of mutation ii. Types 2, 10 11 collagen diseases  Hyaline cartilage

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

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” • • • • •

ii.

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

Thanatophoric dwarfism

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most common lethal form of dwarfism mutation in FGFR3 (missence /point mutation) diminished proliferation of chondrocytes and poor columnization in the zone of proliferation • • • • •

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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Short stature Chest wall abnormalities Malformed bones

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro

E.

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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.

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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 – metabolic bone disease  most common – senile / post menopausal osteoporosis  pathogenesis 1. age related changes • senile osteoporosis / low turn over variant 2. reduce physical activity 3. genetic factors • vitamin D receptor molecule 4. calcium nutrition status 5. hormonal influences • estrogen vs glucocorticoids

H.

Disease Associated With Abnormal Mineral Homeostasis i. Rickets and Osteomalacia  Accumulation of unmineralized bone matrix resulting from a diminished rate of mineralization  Causes:  Dietary deficiency in vitamin D  Defective bone mineralization  Congenital or acquired defects in vitamin D or phosphate metabolism  Malabsorption (most common cause in US)  Crohn’s disease  Celiac disease  Cholestatic liver disease  Biliary obstruction  Chronic pancreatitis

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro

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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 Hematoma ii.

iii.

Hyperparathyroidism  Increased bone resorption secondary to increased PTH  Classic pathologic change referred to as osteitis fibrosa cystica  Replacement of marrow by fibrous tissue  Numerous microfractures  Hemosiderin-laden macrophages  Eventually cystic degeneration and classic gross appearance referred to as “brown tumor”

Renal Osteodystrophy  Skeletal changes of chronic renal disease 1. increased osteoclastic bone resorption 2. delayed matrix mineralization 3. growth retardation 4. osteoporosis

Organization with neovascularization (2-3 days)

Pluripotential mesenchymal cells give rise to osteoblasts to synthesize woven bone Endochondral ossification

Intramembranous bone growth (7 days) Remodeling (months)

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: 1. Mechanical vascular interruption (fracture) 2. Corticosteroids 3. Thrombosis and ebolism 4. Vessel injury

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro 5. 6.

Increased intraosseos pressure with vascular compression Venous hypertension

OSTEOMYELITIS  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

BONE TUMORS AND TUMOR LIKE LESIONS

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I.

BONE FORMING TUMORS  Common feature is the production of bone by the 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  Little clinical significance and interfere with function

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)  Mutation in RB gene  Several subtypes according to the following:

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro • • • • •

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Anatomic portion Degree of differentiation Multicentricity Primary vs secondary Histologic variants

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4. II. CARTILAGE FORMING TUMORS  Characterized by the formation of hyaline or myxoid cartilage; fibrocartilage and elastic cartilage 1. Osteochondroma 2. Chondroma 3. Chrondroblastoma 4. Chondromyxoid fibroma 5. Chondrosarcoma 1.

2.

Epiphyses / apophyses Painful Polyhedral chondroblasts

CHONDROSARCOMA  Group of tumors with a broad spectrum of clinical and pathologic findings  Production of neoplastic cartilage  Second most common primary bone tumor  40 y/o / women

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

CHONDROMA  Benign lesion of hyaline cartilage that arises with in the medullary cavity – Enchondroma  Intraosseous cartilage – 20-50 y/o  Ollier’s disease vs Maffuci syndrome

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 areas of cutaneous hyperpigmentation (McCuneAlbright syndrome)  May be complicated by malignancy • Osteosarcoma, chondrosarcoma and MFH  Treat with surgical curettage and repair of fractures • •

3.

CHONDROBLASTOMA  Rare benign tumor – 1 % of primary tumors  Young/ male /knee

1.

Misshapen bony trabeculae interspersed with fibrous tissue Woven bone NEVER is transformed to lamellar bone

FIBROUS CORTICAL DEFECT / NONOSSIFYING FIBROMA  Fibrous Cortical Defect

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro

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2.

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• extremely common • 30-50% <2 years old • Developmental defect • Metaphysis of long bones lower extremities Nonossifying Fibroma • >5-6 cm • Adolescence • Spontaneous resolution

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IV. MISCELLANEOUS TUMORS

2.

most common primary bone lesions in the distal phalanx

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.

1.

women than men long bones, most often the distal femur, proximal tibia, and distal radius

EWING SARCOMA AND PNET  Ewing's sarcoma is a highly malignant tumor (small round cell)  A type of peripheral primitive neuroectodermal tumor (PNET)  Translocation of t(11;22)(q24;q12)  Lower extremity more than the upper extremity, but any long tubular bone may be affected  Most common sites are the metaphysis and diaphysis of the femur followed by the tibia and humerus.  First and second decade but may affect persons from age 2 to 8 – second most common malignant tumor of the bone in children  Whites more than blacks and Asians  Male to female is 3:2.

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

METASTATIC DISEASE  Most common form of skeletal malignancy a. Direct extension b. Lymphatic c. Hematogenous d. Intraspinal seeding  Adults 75% • prostate • breast • Kidney • lung PATHOLOGY OF JOINTS AND SYNOVIAL MEMBRANES     

1.

Osteoarthritis Rheumatoid arthritis Spondyloarthropathies Gout Pseudogout

OSTEOARTHRITIS  Most common form of joint disease  Slowly progressive  Degenerative joint disease  Elderly or status post trauma  Cartilage attrition may be due to IL-1

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro

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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

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro • • 4.

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Post-venereal Urethritis, conjunctivitis and seronegative polyarthritis

GOUT  Common end point of a group of disorders that produce hyperuricemia  Endogenous crystals • Monosodium urate (gout) • Calcium pyrophosphate dihydrate • Calcium phosphate (pseudo gout) i. Acute arthritis • Crystallization of urates ii. Chronic arthritis • Tophi  Contributing factors: • Age • Genetic predisposition • Alcohol • Obese • Drugs • Lead

IV. SMOOTH MUSCLE TUMOURS V. PERICYTIC (PERIVASCULAR) TUMOURS VI. SKELETAL MUSCLE TUMOURS VII.VASCULAR TUMOURS VIII.CHONDRO-OSSEOUS TUMOURS IX. TUMOURS OF UNCERTAIN DIFFERENTIATION 

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Introduction • Majority are benign • <1% are malignant, but are life threatening • >50 histologic subtypes • Careful physical examination and radiographic evaluation to valuate size, depth, location of the mass, along with signs of neurovascular involvement are essential for the designing the best therapeutic approach. Epidemiology • ratio of benign vs sarcoma 100:1 • benign soft tissue annual clinical incidence 3000/mil • sarcoma annual clinical incidence 30/mil • no significant geographic differences • 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

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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 WHO CLASSIFICATION I. ADIPOCYTIC TUMOURS II. FIBROBLASTIC/MYOFIBROBLASTIC TUMOURS III. FIBROHISTIOCYTIC TUMOURS

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Etiology • the etiology of most benign and malignant soft tissue tumours is unknown • Majority seems to arise de novo • Possible etiologies:

Gen Pathology – Bone, Joint & Soft Tissues by Dra Tesoro

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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

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SYNOVIAL SARCOMA - BIPHASIC

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