1. PATHOLOGY of MUSCULOSKELETAL SYSTEM (Section 1) Dr. Mohammed Alorjani MD, EBP. 2015

2. Bone Cells  Bone forming: Osteoblasts Continuous Osteocytes REMODELING  Bone Digesting: Osteoclast precursors Functioning osteoclasts  Regulated by RANK-RANKL pathway & Osteoprotegerin (OPG)

4. Congenital & Developmental Conditions

5.  Inherited syndromes affecting bones Hurler syndrome (Mucopolysaccharidosis) Lysosomal storage disease Marfan syndrome: mutation in fibrillin gene required for structural integrity of connective tissue

6. A- DYSOSTOSES:  Localized developmental abnormalities of migration of mesenchymal cells – Mutated Homeobox Gene… May be sporadic or part of inherited syndromes Aplasia Supernumerary digits or ribs Abnormal fusion of skull bones, ribs…

7. B- SKELETAL DYSPLASIA:  Abnormalities in bone or cartilage formation, growth or maintenance  Due to mutations in signal transduction or in components of extracellular matrix  More diffuse effects

8. 1- Achondroplasia  AD - inhibited proliferation & function of growth plate → dwarfism (commonest form)  Activating point mutation in FGFR3 → inhibits cartilage proliferation → growth suppression.  Shortened proximal extremities, trunk of relatively normal length, enlarged head, Normal life span, intellect & reproduction.  Thanatophoric Dwarfism: Lethal - Small thorax

9. Achondroplasia

10. 2- Osteogenesis Imperfecta (Brittle Bone Disease)  Defective synthesis of type 1 collagen present in bones, joints, eyes, ears, skin and teeth.  Usually AD.  It has 4 major subtypes - different outcomes (Type 1 – NL life span, Type 2 fatal; #s).  Too little bone → bone fragility & fractures, blue sclerae, hearing defects, thin skull and dental abnormalities.  Can be diagnosed in-utero.

11. 3- Osteopetrosis (Marble bone disease)  Genetic, AD (Adult) or AR (Infantile; severe) → reduced bone resorption.  Impaired osteoclast function or formation.  Dense stone-like bone, liable to fracture. RESULT: Cranial nerve problems (compression). Decreased hematopoiesis → infections & HSM May benefit from bone marrow transplant

12. Acquired Diseases of Bone

13. 1- OSTEOPOROSIS: Progressive loss of bone mass  Normally osteoblast & osteoclast activity are in equilibrium  Maximum bone mass is in young adults up to 30 years. Later, osteoclast activity exceeds osteoblast activity  Result: Bone loss of 0.5%/year is normal  Governed by several factors e.g. vit. D, parathyroid hormone, level of estrogen…etc.

15. Osteoporosis continued:  Commonest Disorder of bone Localized Generalized  Primary or Secondary  Mostly affects spine & femoral neck  PRIMARY: Post-menapausal in women Senile in both sexes as an aging process

16.  SECONDARY: Endocrine disorders Carcinomatosis, multiple myeloma GIT disorders: malnutrition, malabsorption, obesity…etc Drugs: corticosteroids, anticoagulants, chemotherapy… etc. Others: immoblization, pulmonary disease, OI…etc.

17. Factors affecting bone resorption: Age-related changes: femoral neck… Hormonal factors: 50% of postmenopausal women develop #s. Physical activity: Magnitude of skeletal loading favored over number of load cycles Genetic factors: e.g. Vit. D Nutritional factors: Low dietary ca more common in adolescent girls…

18. Pathophysiology: Osteoclast Activation  Osteoclast precursors Active Osteoclasts  Receptor Activator Nuclear Factor κB  Receptor Activator Nuclear Factor Ligand RANK- RANKL M-CSF Osteoprotegerin OPG

19. PRIMARY Post-menapausal:  Several factors, including cytokines and hormones, stimulate the expression of RANKL  Estrogen deficiency is a significant cause of accelerated bone loss through the RANKL-RANK pathway  Binding of RANKL to RANK promotes osteoclast formation, function, and survival

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21. Morphology:  Thin bone trabeculae  Widely separated  Notable osteoclast activity  Normal mineral bone content  Most changes in weight bearing areas - vertebral bodies & femoral neck

22. Normal Osteoporosis

23. Clinical Picture:  Post-menapausal or senile  Often missed until fractures occur  Fractures: Lumbar & Thoracic & Head of femur  Diminished height  Kyphoscoliosis  Respiratory function  Pulmonary embolism

24. “I’ve lost six inches in height and none of my clothes fit me anymore.” Typical comments from people with osteoporosis

25. Diagnosis:  Plain X-ray only after 30-40% bone loss  Radiographic measurement bone density Quantitative CT & Absorptiometry  Laboratory biochemical markers of bone: Formation (alkaline phosphatase) Resorption (urinary calcium) Insensitive  Rarely, bone biopsy

26. Prevention & Treatment:  Calcium and Vitamin D dietary intake & supplements  Excercise  Antiresorptive Rx: e.g. Bisphosphonate & Estrogen replacement therapy ! CVS risk !  Osteoanabolic agents: e.g. PTH analogues.

28. 2- RICKETS / OSTEOMALACIA:  Decrease in vitamin D intake or metabolism  excess of unmineralized bone matrix.  Normally almost 100% of bone is mineralized, whereas in these conditions, mineralization may be < 20%.  Histology: thick unmineralized osteoid around more mineralized bone trabeculae  Weak bones  Bone deformities & Fractures

29. Normal MineralizationUnmineralized osteoid

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31. 3- HYPERPARATHYROIDISM:  Primary or Secondary  parathormone osteoclast activation  bone resorption  ↑ calcium  Result: Bone cyst in any site BROWN tumor/OSTEITIS FIBROSA CYSTICA in which there are osteoclasts, giant cells, hemosiderin & fibrovascular background Fractures & Deformities

34. 4- PAGET’S DISEASE of BONE (Osteitis Deformans)  Paget disease is a polyostotic or monostotic disorder of bone remodeling, in middle age  Disordered osteoclast hyperactivity with osteoblast activity  increased bone mass  Disorganized mosaic of bone - weaker bone, larger, less compact, more vascular,  Cause: Viral, genetic (SQSTM1 gene!), inflammatory disorder !!

35.  Three phases of development: Primary phase of osteoclastic activity, bone loss & hypervascularity. Phase of mixed osteoclastic & osteoblastic activity. Late osteosclerotic phase with formation of dense mineralized bone.

36. Pathology:  Focal replacement of the bone marrow by loose vascular connective tissue  Bone trabeculae are lined by huge osteoclasts.  Osteoblastic proliferation with concomitant bone resorption & new bone formation.  Irregular woven bone deposition with bone thickening (mosaic pattern).

39. Clinical Picture:  Often asymptomatic & discovered incidentally.  Alkaline phosphatase, serum calcium & phosphate normal  Deformities: Lower limbs  Bowing of the legs. Skull deformed & enlarged  headache

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41. Complications:  Nerve compression  deafness, visual disturbances  Increased vascularity in bone marrow leads to arteriovenous shunting  may lead to high output heart failure.  Osteosarcoma may develop (1%)  Prognosis good unless complications occur

42. Inflammatory Conditions

43. OSTEOMYELITIS

44. Osteomyelitis  Inflammation of the bone and the marrow cavity.  Usually blood-borne infection  Most serious types are: Pyogenic osteomyelitis. Tuberculous osteomyelitis. Syphilitic osteomyelitis.

45. Pyogenic Osteomyelitis  Caused by pyogenic bacteria: - Staph. Aureus, E. coli & Gp B Strep. (neonates), Salmonella (Sickle), mixed infection  Sources: 1- Hematogenous * 2- Direct extension 3- Direct trauma - !mixed 4- Iatrogenic  Mainly affects the metaphysis.  Infants: Epiphyseal infection joint

46. Clinical picture & Diagnosis:  Acute: Fever, bone pain,leukocytosis,BMR  Chronic : Low grade fever, pain, abscess, discharging sinuses Diagnosis: X-ray: Destructive lytic lesion with new bone formation Blood & sinus discharge culture Treatment: Appropriate antibiotic & surgical debridement

47. Pathology:  Acute, subacute, chronic stages  Neutrophil infiltration, early bone necrosis (Sequestrum)  Spread to periosteum  subperiosteal abscess  rupture into soft tissue  draining sinus  Chronic: plasma cells & lymphocytes, reactive new bone (involucrum), abscess (Brodie’s Abscess)

48. sequestrum involucrum Osteomyelitis

50. Complications:  Pathological fracture.  Septic arthritis.  Bacteremia & septicemia.  Endocarditis.  Amyloidosis.  Chronic skin sinus  Squamous cell carcinoma of the skin.

51. Tuberculous Osteomyelitis  May follow pulmonary or GIT tuberculosis.  Most common in immunosuppressed  Hematogenous or direct from nearby focus  May be solitary or multicentric.  Long bones & vertebrae most affected  Pathology: caseating granulomatous reaction destroying bone

52. Pott Disease  Tuberculous osteomyelitis affecting the vertebrae → KYPHOSIS,SCOLIOSIS ( Hunchback)  May drain into soft tissue & adjacent psoas muscle  PSOAS ABSCESS  Therapy: Antituberculous therapy, but difficult to treat.

54. JOINTS

55.  1- Infectious arthritis: Septic- Acute: Staph., Strep., Gonococci…etc Any joint, inflammation with suppuration. Heals with antibiotics, or fibrosis & calcification Tuberculous: Complication of pulmonary or miliary TB Granulomatous inflammation with caseation. Destruction of cartilage & deformity. More common in children & in spine Inflammatory Disorders:

56.  2- Rheumatoid Arthritis : F>M, middle age, ? Etiology Autoimmune process Tcell & macrophage reactions in genetically predisposed  TNF  tissue damage & synovial proliferation Role of anti-CCP Abs Systemic disease with involvement of small joints of hands & feet, mainly proximal interphalyngeal joints. Later any joint Stiff swollen red joints, later deformity, & fusion of joints(ANKYLOSIS)

57. Pathology: Acute & chronic inflammatory cells, lymphoid follicles in hypertrophied synovium, extends into joint Later, synovium + inflammatory cells  ‘PANNUS’  fibrosis  Joint destruction ‘Rheumatoid nodules’ in joints & soft tissue ----------------------------------------------------- Serological tests : Hypergammaglbulinemia Rheumatoid Factor Positive (IgM or IgA autoAB that bind to Fc portion of self IgG  immune complexes deposited throughout the body…

59. Rheumatoid nodule

61. RA - Clinical Features: 1.Severe joint pain and morning stiffness. 2.Arthritis in 3 or more joint areas. 3.Arthritis of small hand joints. 4.Symmetric arthritis. 5.Rheumatoid nodules. 6.Serum rheumatoid factor. 7.Typical radiographic changes At least 4 features for diagnosis.

62. Degenerative & Metabolic Diseases

63. 1- Osteoarthritis Commonest type. Both sexes. Primary degenerative disease of cartilage: >65 yrs. Secondary in younger patients:  trauma, obesity, bone deformity… Genetic causes Hips, Knees, Hands & Intervertebral joints → Swelling & decreased mobility

64. Pathology: Proliferation & disorganization of chondrocytes, water, proteoglycans & type II collagen  Fibrillation/Cracking of matrix superficially  Chondromalacia Loss of cartilage  Exposed smooth subchondral hard bone (Bone eburnation) Minor fractures  Loose cartilage bodies ’Joint mice’ in joint space Gaps filled by synovial cysts & bony outgrowths ‘osteophytes’. Occasional fibrous Pannus.

65. Severe osteoarthritis with small islands of residual articular cartilage next to exposed subchondral bone. 1, Eburnated articular surface. 2, Subchondral cyst. 3, Residual articular cartilage.

67. Clinical:  Morning stiffness  Pain & swelling in joints  Progressive deformity in joints, but no ankylosis  Spinal root compression due to involvement of vertebra by osteophytes  Treatment: Analgesics, Joint replacement

68. 2- Gout: Accumulation of Uric Acid in soft tissue & joints  acute arthritis  chronic arthritis & renal complications Primary (90%) is unknown  Middle aged men with high uric acid level Secondary:  High nucleic acid turnover; e.g. leukemia  Renal failure  Inborn error of metabolism; e.g. Lesch- Nyhan syndrome

69. Pathology: Repeated attacks of ACUTE ARTHRITIS in small joints, with deposition of MONOSODIUM URATE crystals  severe inflammation Repeated attacks  ” Tophi”  Tophi are foci of urate crystals surrounded by inflammation with foreign body giant cell reaction. Chronic Tophaceous arthritis with joint destruction & deformity. Gouty nephropathy: calculi, pyelonephritis

70. Tophus in Gout

72. 3- Pseudogout (chondrocalcinosis) Deposition of calcium pyrophosphate with similar pathology to gout Over the age of 50, often less severe Acute, subacute, or chronic arthritis of knees, wrists, elbows, shoulders, and ankles. Cause? Some cases are inherited

73. Tumors & Tumor–Like Lesions in Joints  Ganglion: Small cyst near tendon or joint, most around wrist, symptomless  Synovial cyst: Herniation of synovium through joint capsule at popliteal fossa ( Baker’s cyst)

74. Pigmented Villo-nodular Tenosynovitis & Giant Cell Tumor of Tendon Sheath  PVNS mainly around knee, benign but may be large & aggressive  GCT smaller, painless nodule & around tendon  Cause ? Neoplasm ?  Both have similar morphology: spindle cells, histiocytes, pigment ….