In this presentation I've tried to cover myopathies, its classification and related images with H&E and special stain wherever its possible. Hope it helps you guys to understand the entity better.
5. Can be identified by the esterase
reaction due to the presence of
acetylcholinesterase.
Neuromuscular
Junctions
Normal Structures: Muscle Spindle
and Associated Nerve Fibers
(Gomori trichrome)
6. Type I fibers are light
Type II fibers are dark (pattern reverses at ATPase pH 4.3)
Normal (ATPase pH
9.4)
7. Skeletal Muscle atrophy
• common features of many
disorders
• causes:- loss of innervation ,
disuse, cachexia, old age, and
primary myopathies
• patterns:-
– clusters or groups of atrophic
fibers are seen in neurogenic
disease
– perifascicular atrophy is seen
in dermatomyositis
– type ii fiber atrophy with
sparing of type i fibers is seen
with prolonged corticosteroid
therapy or disuse.
9. Muscle Biopsy
• Often necessary for final diagnosis of myopathy
• Choose site based on clinical, electrodiagnostic, or
imaging features
• avoid “end-stage” fatty muscle
• Frozen sections most useful
• routine stains
• histochemistry
• immunohistochemistry
12. Polymyositis
• Adult-onset inflammatory myopathy that shares myalgia and weakness
with dermatomyositis but lacks its distinctive cutaneous features.
• Pathogenesis:
– Believed to have an immunologic basis.
– CD8-positve cytotoxic T cells are a prominent part of the
inflammatory infiltrate in affected muscle (mediators of tissue
damage)
– Vascular injury does not play major role (unlike dermatomyositis)
• Morphology:
– Endomysial mononuclear inflammatory cell infiltrates
– Degenerating necrotic, regenerating and atrophic myofibers are
typically found in a random or patchy distribution
– Absent perifascicular pattern of atrophy (characteristic of
13. Polymyositis
(Longitudinal Paraffin-Embedded Section)
• in all myopathies, degenerating fibers stain pale initially
and then become digested by macrophages.
• mononuclear inflammatory cell infiltrates and many
basophilic regenerating fibers (arrow)
17. Dermatomyositis
• Immunologic disease in which damage to small blood vessels contributes to muscle
injury.
• Vasculopathic changes – Telangiectasias
• Pathogenesis :
– Inflammatory signature enriched for genes that are unregulated by type I
interferons is seen in muscle and in leukocytes (prominence – disease activity)
– Autoantibodies:
• Anti-Mi2 antibodies – Directed against a helicase implicated in nucleosome
remodeling. Strong association with prominent Gottron papules and heliotrope
rash.
• Anti-Jo1 antibodies – Directed against the enzyme histidyl t-RNA synthetase,
associated with interstitial lung disease, nonerosive arthritis and a skin rash
(Mechanic’s hand)
• Anti-P155/P140 antibodies – Directed against several transcriptional
18. • Morphology:
– Perimysial mononuclear inflammatory infiltrates in connective
tissue and around blood vessels.
– Myofiber atrophy is accentuated at the edges of the fascicles –
Perifascicular atrophy
– Segmental fiber necrosis and regeneration.
– Deposition of CD4+ T-helper cells and C5b-9 (MAC) in capillary
vessels.
– EM: tubuloreticular endothelial cell inclusion
19. Dermatomyositis
• perifascicular atrophy & degeneration
• perimysial nflammatory cells surround a blood vessel.
• inflammatory cells tend to be b-cells.
• vasculitis with bowel infarction and subcutaneous
calcifications sometimes occur in the childhood form.
23. INCLUSION BODY MYOSITIS
• Disease of late adulthood that typically affects patients older than 50
years and is the most common inflammatory myopathy in patients older
than age 65 years.
• Slowly progressive muscle weakness – m/c feature
– Most severe in quadriceps and distal upper extremity muscles.
– Dysphasia from esophageal and pharyngeal muscle involvement
• Lab investigation:
– S. creatine kinase level increased
– Myositis associated autoantibodies are absent.
24. • Morphology:
– Patchy often endomysial mononuclear inflammatory cell infiltrate rich in
CD8+ T- cells
– Increased sarcolemmal expression of MHC class I antigens
– Focal invasion of normal appearing myofibers by inflammatory cells
– Admixed degenerating and regenrating myofibers
– Abnormal cytoplasmic inclusions described as “rimmed vacuoles”
– Tubolofilamentous inclusions in myofibers – EM
– Cytoplasmic inclusions containing proteins typically associated with
neurodegenerative disease, like beta-amyloid, TDP-43, and ubiquintin
– Endomysial fibrosis and fatty replacement, reflective of a chronic disease
course.
25. Inclusion Body Myositis (IBM)
• Features of chronic myopathy with endomysial inflammation and
rimmed vacuoles are characteristic.
Vacuole
Invaded fiber
41. Centronuclear myopathy
Internalized nuclei predominant.
Consistent with centronuclear myopathy.
Can be seen in other disorders such as myotonic dystrophy with
congenital onset.
42. Muscle Biopsy from an Infant:
Centronuclear Myopathy
• Central position of the nucleus
resembling an embryonic
46. Duchenne and Becker musclar
dystrophy
• Most common muscular dystrophies x-linked and stem from mutations that disrupt the
function of a large structural protein called dystrophin.
• Early onset form – Duchenne muscular dystrophy
– Severe progressive phenotype
• Late onset form - Becker muscular dystrophy
– Isolated cardiomyopathy, asymptomatic elevation of creatine kinase, exercise
intolerance
• Pathogenesis:
– Loss of function mutations in the dystrophin gene on X- chormosome
– Dystrophin provide mechanical stability to the myofiber and its cell complex
• Morphology:
– Chnages in Duchenne and Becker muscular dystrophy are similar, but differ in
degree.
– Chronic muscle damage that outpaces the capacity for repair.
– Segmental myofiber degeneration and regeneration with an admixture of atrophic
myofirbers.
– Fatty replacement as disease progress
– IHC studies show absence of the normal sarcolemmal staining pattern in
Duchenne muscular dystrophin and reduced stationing in Becker muscular
47. • Clinical Feature
– Duchenne muscular dystrphy
• Normal at birth
• Early motor milestones
• Walking is delayed
• Clumsiness & inability to keep up with peers
• Pseudohyperthrophy of muscle
• Mean age of wheel chair dependence around 9.5 years
• Cardiomyopathy & arrhythmias
• Frank mental retardation
• Mean age of death 25 to 30 years
– Becker muscular dystrophy
• Later onset and slowly progressive
48. Frozen Section from a Patient with
Duchenne Muscular Dystrophy
• Opaque or hyaline fibers (arrows)
• Increase in endomysial connective tissue
Group of basophilic regenerating fibers
52. Female Carrier of Duchenne Muscular
Dystrophy
(A Mosaic Staining Pattern)
53. Myotonic Dystrophy
• Autosomal dominant multisystem disorder associated with skeletal
muscle weakness, cataracts, endocrinopathy, and cardiomyopathy.
• Myotonia key feature
• Pathogenesis
– Expansions of CTG triplet repeats in 3’-noncoding region of
myotonic dystrophy protein kinase (DMPK)
– Toxic gain of function
– CUG-repeats in the DMPK mRNA transcript appear to bind and
sequester a protein called muscleblind-like1 – Important role in
RNA splicing.
– This inhibits muscleblind-like-1function leading to missplicing of
other RNA transcripts including transcript for a chloride channel
called CLC1and is responsible for characteristic myotonia.
57. Emery-Dreifuss Muscular
Dystrophy
• Caused by mutation in genes that encode nuclear lamina proteins.
• Triad
– Slowly progressive humeroperoneal weakness
– Cardiomyopathy
– Early contractures of the Achilles tendon, spine & elbow
• X-linked form [EMD1]– mutation in genes encoding emerin
• Autosomal form [EMD2] – mutation in genes encoding lamin
• These protein helps in maintaining the shape and mechanical stability of the
nucleus during muscle contraction.
58. Emery-Dreifuss Muscular Dystrophy
(Gomori Trichrome-Stained Frozen Section)
Necrotic fiber
Variation in fiber size with many hypertrophic fibers
Increase in endomysial connective tissue
Nonspecific so-called dystrophic changes seen in many of the muscular
dystrophies.
Can also be seen in any chronic myopathic disorder.
This disorder is due to loss of the protein emerin.
59. Fascioscapulohumeral
Dystrophy
• Characteristic pattern of muscle involvement that includes prominent
weakness of facial muscles and muscles of the shoulder girdle.
• Autosomal Dominant
• Pathogenesis:
– Overexpression of a gene called DUX4, located in a region of
subtelomeric repeats on the long arm of chromosome 4.
– Deletion in flanking repeats causes changes in chromatin that derepress
the remaining copies of DUX4 thus leading to overexpression.
60. Fascioscapulohumeral Dystrophy (FSHD)
• The majority of dystrophies do not have a specific histopathologic appearance.
• Clinical features are also very important.
• For example, winging of the scapula is characteristic of FSHD.
61. FSH Dystrophy
• Variable non-specific changes
• Range from scattered atrophy to “dystrophic” features.
• Inflammation can be present (arrow).
62. Limb-Girdle Muscular Dystrophy
• Heterogeneous group
– 6 AD
– 15 AT
• Characterized by muscle weakness that preferentially involves proximal
muscle groups.
• Pathogenesis
– Genes encoding structural components (sarcoglycans) of the
dystrophin glycoprotein complex
– Genes encoding enzymes that are responsible for glycosylation of a-
dystroglycan, a component of the dystrophin glycoprotein complex
– Genes encoding proteins that associate with the Z-disks of sarcomeres
– Genes encoding proteins involved in vesicle trafficking and cell
signaling
– Genes that seemingly stand alone, such as those encoding the
protease calpain 3 and laminA/C (which is also mutated in some
patients with Emery-Dreifuss muscular dystrophy)
63. INHERITANCE
GENETIC
ABNORMALITY
DISORDER
X-linked
Dystrophin
Emerin
Duchenne, Becker MD
Emery-Dreifuss MD
AD
Myotilin
Lamin A/C
Caveolin – 3
PABP2
αβ-crystallin/Desmin
Limb-Girdle MD (LGMD 1A)
LGMD 1B
LGMD 1C
Oculopharyngeal
Myofibrillar Myopathy
AR
Calpain – 3
Dysferlin
g Sarcoglycan
a Sarcoglycan
β Sarcoglycan
Δ Sarcoglycan
Telethonin
LGMD 2A
LGMD 2B
LGMD 2C
LGMD 2D
LGMD 2E
LGMD 2F
LGMD 2G
Mutations in “Limb-Girdle” and Other
Dystrophies
64. Mitochondrial Myopathies
• Complex systemic conditions that can involve many organ systems,
including skeletal muscle.
• Manifest as weakness, elevations in serum creatine kinase levels, or
rhabdomyolysis.
• Morphology:
– Most consistent pathologic change in skeletal muscle is abnormal
aggregates of mitochondria that are seen preferentially in the
subsarcolemmal area.
– Ragged red fibers appearance.
– Morphologically abnormal mitochondria – EM
• Clinical feature
– Chronic progressive external ophthalmoplegia
– Mitochondrial encephalomyopathy with lactic acidosis and strokelike
episodes
– Kearns-Sayre syndrome
– Myoclonic epilepsy with ragged red fibers
– Leber hereditary optic neuropathy
65. Metabolic: Inherited – Mitochondrial
Myopathy
Ragged red fiber present (Gomori trichrome)
Due to proliferation of abnormal mitochondria
66. SDH-rich fibers are seen with mitochondrial proliferation.
SDH is a respiratory chain enzyme encoded by nuclear DNA.
Mitochondrial Myopathy
(Succinic Dehydrogenase
Reaction)
70. Disease of Lipid or Glycogen
Metabolism
• Inborn errors of lipid or glycogen metabolism
• Severe muscle cramping and pain
• Extensive muscle necrosis (rhabdomyolysis)
• Example
– Carnitine palmitoyltransferace II deficiency (m/c)
– Myophosphorylase deficiency (McArdle ds)
– Acid maltase deficiency
71. • Increased lipid storage
• Seen in carnitine deficiency states (primary or secondary)
• Sometimes as a consequence of certain toxins
• Focal increases can be non-specific.
(Oil-Red-O
Stain)
73. Glycogen Storage Myopathies
• Some glycogen storage myopathies, such as myophosphorylase deficiency
(McArdle’s Disease), cause subsarcolemmal blebs.
• PAS-positive due to the presence of glycogen.
• Only with acid maltase deficiency is glycogen deposited in lysomsomes.
74. Acid Maltase Deficiency
(Acid Phosphatase)
• Due to the intralysosomal activity of this enzyme
• Prominent staining with acid phosphatase in vacuoles
Vacuolarmyopathy noted.
77. Ion Channel Myopathies
(Channelopathies)
• KCNJ2 :
– mutations affecting this potassium channel cause Andersen-Twail
syndrome
• AD, Periodic paralysis, Heart arrhythmias, skeletal abnormalities
• SCN4A :
– Mutations affecting this sodium channel cause several AD with
presentations ranging from myotonia to periodic paralysis.
• CACNA1S :
– Missense mutations in this protein, a subunit of a muscle calcium
channel, are the most common cause of hypokalemic paralysis.
• CLC1:
– Mutations affecting this chloride channel cuases myotonia congenita
– Expression decreased in myotonic dystrophy
• RYR1:
– Mutation in the RYR1 gene disrupt the funciton of the ryanodine
receptor , which regulated calcium release from the sarcoplasmic
reticulum
– Central core myopathy