MSS Pathology SECTION 3

Diseases of skeletal muscle

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

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).

MUSCLE BIOPSY

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

I II ATPase

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

1- Muscular Dystrophy

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

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

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.

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

Normal Dystrophin

DMD

17

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

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

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

2- Muscle Atrophy

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

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

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

© 2007 Elsevier

3- Inflammatory Myopathies

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

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

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.

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)

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

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

4- Toxic Myopathies

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

5- Neuromuscular Junction Disorders

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%...

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

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

Soft Tissue Tumors

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

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.

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

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.

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

Fibrous Tumors & Reactive Proliferations

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

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.

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

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

Desmoid Tumor

Dupuytren’s contracture

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

Fibrosarcoma / Herringbone appearance

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

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.

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.

Tumors of Skeletal Muscle Almost all are malignant

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

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.

SYNOVIAL SARCOMA

Cell of origin is unknown Age 20-50 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.

Synovial Sarcoma