Musculoskeletal Pathology

1. Musculoskeletal Pathology Assoc. Professor Jan Laco, MD, PhD

2. Bone diseases 1. Metabolic bone diseases • Osteoporosis • Osteomalacia and rickets • Fibrous osteodystrophy • Renal osteopathy • Paget’s disease 2. Fractures 3. Inflammations • Osteomyelitis • Tuberculous osteomyelitis 4. Tumours • Primary • Secondary (metastatic)

3. Osteoporosis • = absolute decline in the bone mass (bone atrophy) • minimal trauma fractures pathogenesis • excessive amount of osteoclastic resorption • impairment of osteoblast-mediated bone formation • both Type I osteoporosis (postmenopausal): • increased rate of bone resorption (estrogen loss   in number + activity of osteoclasts) Type II osteoporosis (senile, over 70 Y): • impairment of bone formation (failure to fill the normal-sized resorption cavities with new bone)

4. Osteoporosis Secondary osteoporosis (other disorders + drugs) • Cushing’s syndrome • Hyperthyreoidism • Hypogonadism (early oophorectomy) • Malnutrition, subtotal gastrectomy • Immobilisation, hemiplegia, paraplegia • Glucocorticoids Morphology: • thinning of individual trabecula x mineralisation is normal Clinical features: • hip fractures • compressive fractures of vertebral bodies – kyphosis • fractures of distal radius (Colles’ fracture)

5. Osteomalacia and Rickets Defective mineralisation of osteoid matrix Lack of vitamin D • low dietary intake, lack of sunlight, small gut malabsorption • chronic liver and/or renal diseases (impaired hydroxylation of vitamin Dprecursors) Hypophosphataemia (resistance to treatment with vitamin D) • hereditary (abnormality of phosphate transport by renal tubular epithelium) • tumor-associated (effect of certain mesenchymal neoplasms)

6. Osteomalacia and Rickets Osteomalacia- adults with closed epiphyses • amount of osteoid (>20% of trabecular surface) •NO bone loss • deformities • kyphoscoliosis, contracted pelvis, limb curvature, fractures Rickets- young individuals, epiphyses are not closed • disturbance of endochondral ossification + failure of matrix mineralisation • deformities • craniotabes rhachitica • caput quadratum (frontal and parietal bossing) • bulging of the costochondral junctions (“rickety rosary“)

7. Fibrous osteodystrophy = osteitis fibrosa cystica generalisata von Recklinghausen • pathogenesis severe hyperparathyreoidism (esp. primary)  PTH   osteoclastic resorption of bone Mi: outline of bony trabeculae shows deep indentations filledwith numerous osteoclasts and connective tissue • severe cases  brown tumors (a misnomer) = areas in which trabecular bone has been completely eroded away and replaced by vascular fibrous tissue with many osteoclasts and hemosiderin depositions (brown color) • clinical features: bone pain, pathological fractures, hypercalcaemia Rare in jaws

8. Paget’s disease of bone • = osteitis deformans • Sir James Paget (1882) • enlargement + deformities of bones • >45 years • one bone x many bones • sites:skull, pelvis, spine • etiology ??? (viral infection)

9. Paget’s disease of bone • Gross: • bones enlarged and thickened (thick calvarium) and softer (deformities – bowing of lower limbs) • skull deformities (narrowing of foramina of cranial nerves - neuropathies, deafness) • Micro: • episodes of bone resorption + subsequent reparation • 1. osteolytic phase – prominent osteoclastic resorption, giant multinucleated osteoclasts • 2. mixed / osteoblastic phase – continuing resorption and osteoblastic new bone formation • 3. osteosclerotic or burned-out phase – large irregular trabeculae with mosaic-like appearance due to numerous cement lines !!! greater risk of developing osteosarcoma !!!

10. Fractures = breaks in continuity of bone • infraction = incomplete fracture • pathological fracture: • bone disease (osteoporosis, cysts, tumours) minor trauma or spontaneously fracture • Fracture healing: hematoma between ends of bone + necrosis of BM  organization of hematoma - granulation tissue  connection of bone ends by fibrous tissue (fibrous callus) woven bone + cartilage in fibrous tissue  provisional callus remodelling to mature lamellar bone  definite callus • Impaired fracture healing • infection, poor immobilization, non-vital bone ends • exuberant callus  pseudo-arthrosis

11. Osteomyelitis = infective inflammation of bone(Staphylococci, Streptococci...) • infection way: • directly (open fractures, operations) • hematogeneously • pathogenesis • acute pyogenic inflammation of BM  rise of interstitial pressure   blood supply ischaemic necrosis • inflammation subperiosteal space (subperiosteal abscess)periosteal blood vessels shear off ischemic necrosis • perforation of periosteum soft tissues and skin - sinus track, portions of dead bone can be discharged onto the skin • adults • sites: mandible (periapical infection, fracture) • complications • sepsis, amyloidosis, pyogenic arthritis, skin squamous carcinoma

12. Tuberculous osteomyelitis • children, blood-borne infection • long bones, vertebrae • bone destruction + granulomatous lesion with caseation • Tuberculosis of the spine (Pott’s disease) • sharp anterior angulation of the spine (kyphosis) • caseation may spread to the paravertebral soft tissues and track down along the psoas muscle to form an inguinal subcutaneous mass

13. Bone metastases • Much more common than primary bone tumours • Usually multiple • Osteolytic (bone destruction) • Osteoplastic (reactive bone formation) – prostatic carcinoma • Tumors • prostatic carcinoma, breast carcinoma, renal cell carcinoma, carcinoma of stomach, thyroid carcinoma

14. 1. Bone-forming tumours Osteoma Osteoid osteoma Osteoblastoma Osteosarcoma 2. Cartilage-forming tumours Osteochondroma Chondroma Chondrosarcoma 3. Other tumours Giant cell tumor of bone Ewing’s sarcoma 4. Tumour-like lesions Fibrous dysplasia Bone cysts Primary bone tumours – classificationless common, usually solitarydiagnosis: microscopy + age + site + RTG

15. Osteoma • benign lesion, rather hamartoma • formation of dense mature lamellar bone • sites:skull, facial bones, paranasal sinuses, orbit, torus palatinus et mandibularis • may cause mechanical problems • ! component of Gardner’s colonic polyposis syndrome

16. Osteoid osteoma • benign osteoblastic lesion • severe pain • young people (5-24 years), male predominance • site: long bones (femur, tibia), ends of the shafts • RTG • small radiolucent area + radio-opaque rim of reactive bone • Microscopic features: • small central area (nidus)<1cm + zone of dense sclerotic bone (reaction to the nidus) • nidus- interlacing bands of osteoid in haphazard fashion • osteoid surrounded by normal osteoblasts • vascular fibrous tissue in spaces between trabeculae

17. Osteosarcoma • most common primary malignant neoplasm of bone • peak 10-25 Y, (elderly people - Paget’s disease), males • site: metaphyseal region of the long bones • lower end of femur, upper end of tibia, upper end of humerus, mandible • from medullary cavity invasion of cortical boneelevate periosteum (RTG sign - Codman’s triangle) soft tissues • microscopy: • identification of bone or osteoid formation by the tumour cells • irregular “ lace-like“ osteoid trabeculae surrounded by atypical malignant osteoblasts • malignant cartilage and sarcomatous spindle cell stroma also present •    malignant with poor prognosis, metastases to lungs

18. Parosteal osteosarcoma • variant of osteosarcoma in older people • juxtacortical position of metaphyseal region • forms large lobulated mass tending to encircle the shaft • very slow growth • microscopic features • well-formed bone and osteoid + spindle cell stroma with only scanty cytological signs of malignancy • very good prognosis with adequate resection

19. Osteochondroma (exostosis) • very common, hamartoma ? • young people, males • site: long bones (femur, tibia, humerus), metaphyses, mandible (condylar and coronoid process) • Grossly • pedunculated or sessile lesions - bone + cap of cartilage • Micro: • ordered columnar arrangement of chondrocytes and zone of endochondral ossification (as in epiphyseal growth plate) • Osteochondromatosis • multiple osteochondromas, some risk of malignant transformation (secondary chondrosarcoma)

20. Chondroma • benign tumour - mature hyaline cartilage • children, adolescents and young adults • site: medullary cavity of small bones of hands and feet(enchondroma), maxilla (rare) • Ollier’s disease (multiple chondromas) • RTG • radiolucent lesion expanding and thinning cortical bone • Micro • lobules of mature hyaline cartilage

21. Chondrosarcoma • malignant cartilaginous tumor • primary (de novo) x secondary (malignant transformation of benign cartilaginous tumors – osteochondroma) • middle aged and elderly (primary chondrosarcoma), younger age group (secondary chondrosarcoma), M : F - 3:2 • site: central skeleton (ribs, pelvis, proximal end of femur and humerus), anterior maxilla • RTG • aggressive growth, destruction of cortical bone and extension into the soft tissues • Micro • cartilaginous tissue with high cellularity, cytologic atypia of chondrocytes, binucleated cells, mitotic activity, necrosis • differential diagnosis low-grade chondrosarcoma x chondroma • histological picture + clinical and radiological features!!!

22. Giant cell tumor of bone • peak 3rddecade • site: long bone epiphyses • RTG • lytic and radiolucent lesion • Gross • brown with grey and red areas (fibrosis and hemorrhage) • Micro • stromal mononuclear cells + multinuclear giant cells ~osteoclasts • locally aggressive, may recur locally, malignant change in about 10% of cases (metastases)

23. Ewing’s sarcoma • group of primitive neuroectodermal tumours (PNET) • peak 5-20 years, males • site: most often long bones and pelvis, mandible (body) • RTG • lytic destruction of the bone • Gross • grayish white, focal necrosis and haemorrhage • Micro • small uniform round cells with glycogen (PAS +) • clinical features: pain and swelling • very aggressive tumor with poor prognosis • metastatic spread to lungs and other bones

24. Fibrous dysplasia • non-neoplastic condition • children and adolescents • site: ribs, femur, tibia, maxilla, mandibula, humerus • monostotic x polyostotic form • micro • well-demarcated localized area of bone replaced by fibrous tissue with spicules of woven bone of fish-hook or Chinese letters shape • McCune-Albright´s syndrome = polyostotic FD + skin pigmentation + precocious puberty

25. Bone cysts • Solitary bone cyst • unicameral cavity lined by smooth fibrous membrane • mandible • Aneurysmal bone cyst • multiple spaces filled with red blood cells separated by thin fibrous septa with numerous osteoclasts • rare in jaws

26. 1. Congenital defects Dysplasia coxae congenita 2. Trauma 3. Degenerative diseases Osteoarthritis 4. Inflammation Infective arthritis Lyme disease Tuberculous arthritis Rheumatoid arthritis Gout 5. Tumours Pigmented villonodular synovitis Joint diseases

27. Dysplasia coxae congenita • autosomal recessive disorder • hypoplasia of hip joint with congenital subluxation or luxation • untreated may lead to early secondary osteoarthritis

28. Trauma • disruption of synovial membrane – bleeding into joint cavity (hemarthros) • organization of hematoma fibrous adhesions limiting joint movements or ankylosis (join space replaced by metaplastic bone) • hemarthros often complicates disorders of coagulation (hemophilia)

29. Osteoarthritis • most common of joint diseases (14% of adults) • breakdown of the articular cartilage • weight-bearing joints • hip, knee, intervertebral joints, TMJ (asymptomatic) • clinical features • pain, joint deformity, limitation of movement, crepitus (creaking sound heard on movement of the joint) • RTG • narrowing of joint space • Two main groups: • primary OA: no known associated condition • secondary OA: known associated event or disease causally related to OA (congenital disorders, inflammation, trauma)

30. Osteoarthritis • Morphology: • erosive changes of joint cartilage (“fibrillation“) + flaking off of small portions of cartilage • complete loss of cartilage – polishing of the denuded bone (smooth ivory-like surface) • thickening of subchondral bone plate, synovial fluid under pressure may enter into small defects in the bone – forming of subchondral pseudocysts • bony outgrowths at the margins of the articular cartilage (osteophytes)

31. Infective arthritis • bacteria (St. aureus, N. gonorrhoeae) • routes of infection: • blood spread (most common) • direct penetration (trauma) • direct spread (osteomyelitis) • morphology • hyperemia + acute inflammatory infiltrate in synovial membrane, exudate accumulation in the joint cavity (pyarthros) • lysosomal enzymes released from neutrophils may cause severe damage of the articular cartilage – secondary osteoarthritis

32. Lyme disease • spirochaete Borrelia burgdorferi transmitted to humans via tick bites • skin + nervous system + heart + joints • 3 clinical stages: • stage I: • macular skin lesion (erythema migrans) + low-grade fever, headache, arthralgia, muscle pain, LNpathy • stage II: bloodstream dissemination of borrelia • nervous system (meningitis, meningoencephalitis, neuritis) • heart (atrioventricular block, pericarditis) • stage III: • chronic disease (months to years after initial infection) • arthritis(large joints, similar to rheumatoid arthritis) • nervous system (encephalopathy) • skin (acrodermatitis chronica atrophicans Herxheimer)

33. Tuberculous arthritis • children • associated with infection (haematogeneous dissemination) • site: knee, hip, elbow and ankle • clinical features • insidious development of pain, swelling and limitation of movement, other signs of inflammation mild or absent • Micro • synovial hyperplasia, tuberculous granulomas in 90% of cases

34. Rheumatoid arthritis • common multisystem autoimmune disease • 3x commonly in premenopausal women as in males • site: small joints of the hands and feet, knees, hips, involvement frequentlysymmetrical, TMJ - minor symptoms • rheumatoid factors (IgM directed against Fc´ portion of IgG) positive in 95% pts.

35. Rheumatoid arthritis • inflammatory hyperplasia of synovial membrane with increased vascularity, cellularity and synovial fluid production • inflammatory infiltrate(lymphocytes, plasma cells,lymphoid follicles • proliferation of inflammed hypervascular granulation tissue termed pannusdegradation of underlying articular cartilagefibrous adhesions limit joint movement, formation of metaplastic bone (ankylosis) • deformities of joints (ulnar deviation of fingers) • periarticular rheumatoid nodules in 30% • central area of fibrinoid necrosis + macrophages and fibroblasts arranged in a palisaded fashion) • complication: secondary amyloidosis

36. Variants of RA • Juvenile rheumatoid arthritis (JRA): < 16 Y • large joints predominantly involved, RFs often negative • Still’s disease (systemic JRA) • fever, leucocytosis, enlargement of liver, spleen and lymph nodes • Felty’s syndrome: RA + splenomegaly + neutropenia

37. Gout • disorder of purine metabolism leading to hyperuricaemia • peak 30 – 60 Y, males • deposition of monosodium urate crystals in articular cartilage, synovial membrane and periarticular soft tissues (tophi, tophaceous gout) • clinical features: • acute gouty arthritis: metatarsophalangeal joint of the big toe (70%), ankle, knee, wrist, elbow joint is red, hot, swollen, very painful and tender • chronic gouty arthritis: follows recurrent episodes of acute gouty arthritis, progressive erosion of cartilage and bone – limited joint function • Micro • deposits of urate crystals + inflammatory infiltrate + foreign body-type giant cells

38. Pigmented villonodular synovitis • benign tumor rather than inflammatory condition • site: knee joint (80%) • clinical symptoms: mild pain, swelling, tenderness • Gross • brown-coloured thickened synovium thrown into small villous folds • Micro • diffuse proliferation of mononuclear cells with osteoclast-like multinuclear giant cells and depositions of haemosiderin

39. Diseases of tendons, tendon sheaths and bursae • 1. Degenerative ganglion • 2. Inflammatory tendovaginitis bursitis

40. Ganglion • area of myxoid degeneration of connective tissue of tendon sheath • on extensor surfaces of hand and feet • Morphology: thin walled pseudocyst containing mucoid fluid

41. Tendovaginitis • = inflammation of tendon sheath • purulent, rheumatoid (serofibrinous), tuberculous • Tendovaginitis stenosans (deQuervain) = stenosis of tendon sheath by accumulation of fibrocartilaginous tissue – discontinual movement of affected finger (digitus saltans)

42. Bursitis • bursae around shoulder, elbow and knee • acute bursitis (mechanical overload) • serofibrinous exudate • chronic bursitis (repeated traumatisation) • fibrous thickening of wall, hyperplasia of synovial lining and fibrin deposits

43. Diseases of skeletal muscle • Muscle atrophy • Muscle dystrophy • Myasthenia gravis • Inflammatory disorders (myositis)

44. Muscle atrophy • Generalized: malnutrition, hypopituitarism, immobilisation • Localized: immobilisation of one limb, denervation (trauma, neuritis, poliomyelitis) • Microscopic features: decrease in size of muscle fibers

45. Muscle dystrophy • heterogeneous group of genetically determined disorders • spontaneous progressive degeneration of muscle fibers • Micro • different size of muscle fibers (combination of atrophy and hypertrophy) • degenerative changes (fragmentation of the sarcoplasma, necrosis) • regeneration (cells with basophilic cytoplasm and more nuclei), fibrosis, later lipomatosis

46. Muscle dystrophy Duchenne-type dystrophy: • X-linked recessive disorder – males affected only • lack of dystrophin • early childhood (5 years) • pelvifemoral groups of muscles affected earliest (frequent falls, gait disturbances, difficulty in rising) • progress to other muscle groups (wheelchair bound at 10 to 12 Y) • death at 20 Y (respiratory difficulties, pneumonia) Becker-type dystrophy: • much milder clinical picture • dystrophin is abnormal

47. Myasthenia gravis • acquired autoimmune disorder • Ab bind to acetylcholine receptors on motor endplate – defect of neuromuscular transmission • association with hyperplasia of thymus in 60% and with thymoma in 20% • Clinical features • abnormal muscle fatiguability, muscle weakness (eyelids) • respiratory muscles may be severely affected • Microscopic features: no light-microscopic abnormalities

48. Myositis = inflammation of muscles • Myositis ossificans • tumor-like lesion preceded by trauma • central area of plumpfibroblasts surrounded by zone of immature woven and mature lamellar bone • must be distinguished from extraskeletal osteosarcoma

49. Soft tissue tumors • in non-skeletal mesodermal tissues such as adipose tissue, fibrous tissue, muscle, blood vessels and peripheral nerves • benign • intermediate: locally aggressive x rarely metastasizing • malignant • from primitive mesenchymal stem cells • classification according to their differentiation lines (e.g. liposarcoma is not a tumor arising from lipoblast but exhibiting lipoblastic differentiation)

50. Fibrohistiocytic tumors Benign fibrous histiocytoma Malignant fibrous histiocytoma Vascular tumors Hemangioma Angiosarcoma Tumors of peripheral nerves Schwannoma Neurofibroma Malignant peripheral nerve sheath tumor Tumors of uncertain origin Synovial sarcoma Classification of soft tissue tumors Lipomatous tumors Lipoma Liposarcoma Smooth muscle tumors Leiomyoma Leiomyosarcoma Skeletal muscle tumors Rhabdomyoma Rhabdomyosarcoma Fibroblastic tumors Nodular fasciitis Fibromatoses Fibrosarcoma