1. MSS Pathology
SECTION 3

2. Diseases of skeletal muscle

3. Diagnosis of muscle disorders
Clinical history: presence of weakness, cramps, irregular twitching, atrophy…etc
Exclude systemic disorder
EMG (electromyogram): a test in which the electrical activity in muscle is analyzed after being amplified, displayed, & recorded.
Blood test: CPK or CK level is an indicator of
muscle destruction
Muscle biopsy

4. Normal Skeletal Muscle & Motor Unit
The motor unit consists of:
Motor neuron in brain stem or spinal cord.
Peripheral axon.
Neuromuscular junction.
Skeletal muscle fiber.
2 functional types of muscle fibers:
Type I (slow twitch - aerobic).
Type II (fast twitch - anaerobic).

5. MUSCLE BIOPSY

6. Muscle biopsies are studied by applying various techniques to identify the enzymes in type I & type II fibers on a frozen section.
Normal ‘ CHECKERBOARD APPEARANCE

7. I II
ATPase

8. Muscle Disorders Muscular Dystrophies Neurogenic disorders
Inflammatory Myopathy
_____________________________________
Myotonic Syndromes
Congenital Myopathies
Metabolic e.g. glycogen storage diseases
Endocrinopathies e.g. Cushing’s Syndrome
Drug-induced
Neuromuscular junction disorders

9. 1- Muscular Dystrophy

10. MUSCLE DYSTROPHY: Primary disease of muscle
Several types, various inheritance
Start in childhood or adolescents, some late
Progressive degeneration of muscle fibers
Similar clinical & histological features, but differ in location & rate of progression

11. Types:
Duchenne muscle dystrophy
Becker muscle dystrophy
Limb Girdle dystrophy
Myotonic Dystrophy
Others

12. Duchenne Muscular Dystrophy (DMD)
Boys are affected.
Mostly X-linked inherited disease, female carrier
Rare sporadic mutations
Commonest & most severe
Starts at as 1 yr.- 5yrs., delayed walking, proximal weakness, death by age 20yrs.

13. Loss of function mutation (deletion) of
Pathogenesis:
Loss of function mutation (deletion) of
Dystrophin gene on short arm of Xp21
Dystrophin stabilizes muscle during contraction
Without dystrophin, sarcolemma are weak, tear & muscle shows splitting…etc
In DMD, Dystrophin is totally absent

14. Normal Dystrophin

15. DMD

17. 17

18. Morphology: Marked variation in muscle fiber size
Degenerative changes in scattered fibers: fiber splitting, loss of striations, necrosis …
Regenerative changes: basophilia, nuclear enlargement, prominent nucleoli
Endomysial fibrosis, few inflammatory cells
Later:myofiber loss & infiltration by fat
Abnormal dystrophin staining

20. Clinical picture: Boy born normal, but progressive muscle weakness.
Starts proximally, first in the pelvis, later shoulder
Characteristic ‘Pseudohypertrophy’ of leg muscles
High serum creatine kinase which later returns to normal
Cardiomyopathy
Death from respiratory insufficiency, lung infection, cardiac failure

21. Becker Muscular Dystrophy
Starts later
Milder
Less common
Same gene defect but Dystrophin is decreased in amount & has abnormal molecular weight
Cardiac disease may be present
Outcome is variable with a nearly normal
life span. 21

22. 2- Muscle Atrophy

23. Causes: Motor neuron disease (ALS), Polio… Peripheral neuropathy
Trauma
Patients with disuse atrophy when immobilized (Type II fibers)
Patients who receive glucocorticoids
Patients with hypercortisolism

24. Neurogenic “ Group Atrophy”
Muscular shrinkage secondary to deprivation of normal innervations
Initially all the muscle fibers in a motor neuron are affected

25. Later collateral sprouting, taken over by one nerve
Single type fiber  loss of normal mixture of Type 1 and Type 2
Called “GROUP ATROPHY “
Small angulated muscle fibers

26. © 2007 Elsevier

27. 3- Inflammatory Myopathies

28. Infection (myositis) - Bacterial - Viral:- Influenza, coxsackie, HIV
- Parasitic: Trichinella spiralis,
Cysticercosis

29. II. Noninfectious immune mediated myopathies
- Polymyositis
- Dermatomyositis
- Inclusion body myositis

30. Polymyositis & Dermatomyositis
Group of immunologically mediated muscle injury characterized by inflammation
May be associated with other disease
of autoimmune nature
Pathogenesis:
Antibody mediated tissue injury in dermatomyositis and cytotoxic T- cell injury in polymyositis.

31. Clinically:-
- Symmetric muscle weakness initially affecting large muscles of trunk, neck, limbs
- Associated skin rash of eyelids in dermatomyositis
- Dermatomyositis: Children (isolated), Adults (could be paraneoplastic)

32. Histology:- Infiltration by lymphocytes that surround muscle fibres:
PM: Endomysial.
DM: Paraseptal.
Inflammation around blood vessels – in DM
Degenerated and regenerated fibres.

33. A. Dermatomyositis. Note the rash affecting the eyelids.
B. Dermatomyositis. Muscle shows paraseptal/ perifascicular atrophy of muscle fibers and inflammation.
© 2007 Elsevier

34. 4- Toxic Myopathies

35. Thyrotoxic M. Myofiber necrosis & regeneration
Ethanol intoxication after heavy intake  myofiber swelling & necrosis
Various drugs, e.g. Statins

36. 5- Neuromuscular Junction Disorders

37. Myasthenia gravis
Acquired autoimmune disorder of neuro-muscular transmission
F>M, any age
AB against post-synaptic acetylcholine receptors in 85% of cases
Other autoimmune diseases
Abnormality in thymus: Thymic Hyperplasia in 65% or Thymoma in 20%...

38. Acquired autoimmune disorder of neuro-muscular transmission
Muscle weakness, Pitosis & diplopia, dysarthria & dysphagia, fatigable weakness
Classically diurnal variation in strength, i.e. best in morning, worse as the day progresses
Histology of muscle is normal
Thymectomy may help the patient

39. Lambert-Eaton Syndrome
Very similar to M. Gravis
Autoantibodies that inhibit function of presynaptic Calcium channels at neuro-muscular junction
Improvement after continuous stimulation
but later deterioration
Paraneoplastic e.g. with SCLCa

40. Soft Tissue Tumors

41. General Characteristics:
Classified according to tissue of origin,
sometimes unknown, Any age.
Present as an enlarging mass
May be part of inherited syndromes:
Neurofibromatosis, type I
Li-Fraumeni Syndrome & others
Some have specific gene lesions
Malignant tumors arise ‘de nove’ or after
recurrent “Benign” tumors → SARCOMA

42. SOFT TISSUE TUMORS: Adipose tissue: Lipoma –Liposarcoma
Fibrous tissue: Fibroma-Fibrosarcoma
Fibrohistiocytic tumors.
Smooth muscle:
Leiomyoma - Leiomyosarcoma
Skeletal muscle:
Rhabdomyoma - Rhabdomyosarcoma
Vascular tumors:
Hemangioma - Angiosarcoma
Peripheral nerve sheath tumors.
Tumors of unknown exact cell of origin.

43. Grade I (Low grade) may recur but rarely metastasizes
Malignant soft tissue tumors are graded according to differentiation, mitoses and necrosis into grade I – III
Grade I (Low grade) may recur but rarely metastasizes
The prognosis depends on
Type
Grade
Stage: Tumors <=5cm – Mets rate: 30%
Location: superficial - better

44. Tumors of Adipose tissue
Lipoma:
Commonest of soft tissue tumors
Most in subcutaneous tissue
Single or multiple, may be familial
No malignant transformation
Grossly: Circumscribed yellow mass
Histologically: Mature fatty tissue
Many histological variants.

45. Liposarcoma Adults: 40-60 yrs Deep soft tissue & retroperitoneum
Grossly: Large yellow glistening mass
Histologically:
Low grade: Well differentiated (Amp. 12q, MDM2 gene) & Myxoid type (t(12;16))
High grade: Round & Pleomorphic
Diagnosis depends on identification of lipoblasts
Prognosis depends on type & site

48. Fibrous Tumors & Reactive Proliferations

49. 1- Nodular fasciitis
Reactive fibroblastic proliferation frequently misdiagnosed as sarcoma.
Mostly affects young adults and presents as rapidly enlarging sometimes painful mass.
Location: Upper extremity and trunk.
Many have history of local trauma.
Self-limiting.
Similar reactive lesion in muscle is Myositis Ossificans, contains bone

50. Morphology
Grossly: Unencapsulated < 3 cm mass in subcutaneous tissue, muscle or fascia.
Micro: immature appearing fibroblasts with high mitoses but no atypia, set in myxoid background.

51. 2- Fibromatosis A group of fibroblastic proliferation
Grow in infiltrative fashion
Recur after surgical excision but do not metastasize.
Various age groups
Various types

52. Two types:
A. Superficial:- palmar (Dupuytren’s
contracture, can occur in the penis
B. Deep called desmoid tumors that arise in the abdominal wall, muscles of the trunk and extremities, within abdomen - these tend to be more aggressive. Single or multiple.
Gardner syndrome; APC/B-Catenin

53. Desmoid Tumor

54. Dupuytren’s contracture

55. 3-Fibrosarcoma Mostly affects adults.
Sites: Deep tissues of thighs, knees and retroperitoneum.
They tend to grow slowly.
Gross: solitary, infiltrative or well-circumscribed.
Micro: Fasicles of fibroblasts arranged in herringbone appearance
Recurrence and metastatic rates depend on the grade.

56. 56

57. Fibrosarcoma / Herringbone appearance

58. Fibrohistiocytic Tumors
Several types
Benign & malignant
Most are in adults
Superficial usually benign
Deep often malignant, larger, highly pleomorphic, metastasizing.
Treatment by excision

59. Benign Fibrous Histiocytoma (Dermatofibroma):
Common tumor
Circumscribed tumor in dermis or sucutaneous tissue < 1 cm.
Histology: Spindle cells & histiocytes
Dermatofibrosarcoma Protruberance:
As above, but larger, deeper
Mitoses present, CD34 positive
Recurs after excision
Pleomorphic undifferentiated sarcoma.

60. Tumors of Smooth Muscle:
Benign: Leiomyoma, mainly uterine
but could arise from vascular smooth muscle
Malignant: Leiomyosarcoma (10-20% of STS)
- uterus or soft tissue.
Superficial skin – better prognosis - Large – deep in extremities or in retroperitoneum.

61. Tumors of Skeletal Muscle Almost all are malignant

62. Rhabdomyosarcoma: adolescents & young adults.
Commonest sarcoma of children,
adolescents & young adults.
Chromosomal translocation t(2;13) produces a fusion gene PAX3-FKHR controlling muscle differentiation (alveolar variant)
Sites: Soft tissue, head & neck, genito-urinary tract
Aggressive tumor

63. Types:
Embryonal: most common type mainly in head & neck, genitourinary & retroperitoneum.
Alveolar: in extremities of adolescents.
Pleomorphic: in soft tissues of adults.
+ve for: Desmin, Myogenin & MYOD-1.
Diagnostic cell is the Rhabdomyoblast which is Tadpole or Strap cell
Prognosis worsens: embryonal  pleomorphic  alveolar.

66. SYNOVIAL SARCOMA

67. Cell of origin is unknown
Age yrs.
10% of STS.
Most are in deep soft tissue, adjacent to joints (Knee commonest)
Rarely intra-articular (<10%)
Specific translocation: t(X;18) fusion gene involved in transcription
Biphasic or monophasic tumor of epithelial & stromal elements; +ve for CK
Aggressively treated
Lung, bone, regional LN metastases.
Only 10-30% live > 10 yrs.

68. Synovial Sarcoma