Muscle PathologySurgical Pathology Unknown Conference

November, 2008

Philip Boyer, M.D., Ph.D.

Abnormal

Neoplastic Non-Neoplastic

Normal

Vascular

- Ischemic

Toxic -

MetabolicDegenerative

Traumatic

Developmental

Symptoms / Signs / Imaging / Biopsy / CSF Analysis

Other

Primary“Metastatic” /

Hematogenous

Spread /Direct extension

Infectious -

Inflammatory

(neoplastic divide)

Reactive /

Hyperplastic

Etiologic Approach to Differential Diagnosis

Case 1

� A 75-year-old man presented with a rapid onset and progression of generalized skeletal muscle aches and weakness over a 4-5 day period prior to hospital admission. � Difficulty raising his arms above the level of the shoulders� Difficulty getting out of chairs and off the commode

� Laboratory evaluation identified a CPK level of greater than 13,390 U/L (not titrated, normal range, adult male 40-210 U/L)

� Past history was significant for:� Atherosclerotic coronary and peripheral vascular disease

treated with three-vessel coronary vessel bypass grafting� Hypercholesterolemia treated with the statin medication

Zocor for over a year. � He recently had been diagnosed with diabetes and was begun on

Glucotrol (glipizide), a sulfonylurea class oral hypoglycemic agent, 2 weeks prior to hospitalization.

History

Acid Phosphatase Histochemistry: Lysosomal Protein

Case 2

� 56 year-old woman

� 15 year history of “seronegative rheumatoid arthritis”

� Finger stiffness and swelling (PIPs and MCPs)

� Treatment:

� Plaquenil

� Methotrexate

� Recent 6 – 12 months:

� Progressive proximal weakness of arms and legs

� Dysphagia to pills and water

History

H&E Stain

Acid Phosphatase Histochemistry

Acid Phosphatase Histochemistry

Case 3

- 6-year old male- History of difficulty walking, particularly in negotiating stairs- Neurologic Examination:

- Weakness, proximal greater than distal- “Gower sign” on arising from floor- Calf muscle hypertrophy

- Laboratory Evaluation:- Creatine Kinase = high: >10,000

History

H&E

H&E

Trichrome

DystrophinSpectrin

Case 4

History

- l year old girl (A.O.)

- History of congenital weakness

- Neurologic Examination:

- Weakness, proximal greater than distal

- Laboratory Evaluation:

- CK elevated (>1,000)

- MRI:

- White matter abnormality

- No evidence of malformation

Dystrophin Laminin Alpha-2 (Merosin)

Case 5

H&E – Low Power

H&E

Electron Micrograph

Electron Microscopy

Case 6

Histologic Findings

H&E

Histologic Findings

H&E

Histologic Findings

Trichrome

Electron Microscopy

Case 7

History

� 21-year-old G2P2 woman with a past medical history significant only for obesity� A year prior to the current admission, during the third trimester of her second pregnancy,

developed symptoms which continued after delivery of healthy 40-week gestation infant

� Weight loss - 80-90 pounds� Night sweats which continued after term delivery of a healthy infant; total weight loss

was

� Four months prior to admission� Arthralgias of the hips and knees

� Non-pruritic hyperpigmented macular rash involving her arms and torso but sparing her face

� Working diagnosis: "lupus-like syndrome“

� Course of prednisone which resulted in resolution of the rash and cessation of weight loss

� Tapering of the prednisone, weight loss continued� Two weeks prior to admission

� Burning sensation involving the soles of both feet with extension to the ankles in a stocking distribution

� Admitted for evaluation.

� Thin habitus

� Liver palpable to 4 cm below the right costal margin

� Extreme sensitivity to light touch of the feet to the level of the ankles bilaterally

� Strength and reflexes were normal� Labs: CPK 34 U/L (normal adult female 38-176 U/L), C-reactive protein 6.0 mg/dL

(normal < or= 0.8 mg/dL), sedimentation rate 67 (normal female 0-29 mm in 1 hour), and angiotensin converting enzyme 59 U/L (normal 7.0-46.0 U/L )

� Chest X-ray: normal

Histology - Muscle

Histology - Nerve

Histology - Liver

Histology - Liver

Case 8

� 28-year-old woman

� Past Medical History: History of antibody negative myasthenia gravis

� Medications: None

� Presentation: Ptosis and swallowing difficulty

� Neurologic Examination:

� Ptosis

� Laboratory Evaluation:

� CPK 100

� Myasthenia panel: negative

History

H&E

Trichrome

Succinate Dehydrogenase Histochemistry

Electron Microscopy

Case 9

- 14-year old boy

- History of difficulty keeping up with peers during physical activity- Not running, jumping, playing like others due to “pain” after exercise

(“exercise intolerance”)- CPK 8,600

- EMG: myopathic motor units

- Biopsy at age 4 identified focal inflammation, diagnosed with “inflammatory myopathy

- Treated with corticosteroids with some symptomatic improvement- Attempts to reduce corticosteroids resulted in increased CPK levels (500

– 10,000) but without associated symptoms

- Needed wheel-chair by age 12-13- After strength testing: severe pain and stiffness for several hours but not

persistent - Re-evaluated now

- Weakness, proximal greater than distal

- Laboratory Evaluation:- Creatine Kinase = ~normal

- Re-biopsied

History

H&E

Trichrome

Electron Microscopy

Myophosphorylase – PatientMyophosphorylase – Control

2005

Biopsy

Case 10

� 37-year-old man

� History since childhood of proximal weakness, lower extremities greater than upper extremities.

� Family history is significant for "muscular dystrophy" in aunts and uncles

� Biopsy of one uncle was non-diagnostic with a "whorling pattern" on oxidative preparations

� The differential diagnosis included a limb-girdle muscular dystrophy and a congenital myopathy.

History

H&E

Trichrome

Electron Microscopy

Case 11

History

� Newborn, 37 weeks gestation, with marked hypotonia

� Etiology uncertain clinically

� Muscle biopsy performed

H&E

Trichrome

Case 12

History - A

- Newborn; delivered at 36 weeks gestation due to a breech position

- Respiratory distress was noted at birth- Hypotonia - Congential bilateral hip dislocations- There is no known family history

TrichromeATPase pH 4.3H&E

NADH

NADH

Electron Microscopy

-- 54-year-old man-- Life-long history of exertional fatigue and muscle tightness-- With multiple episodes of rhabdomyolysis / myoglobinuria-- He has a 5-year-old son

- - Easily fatigued- - Proximal weakness

History - B

Histology

Thick Section, T. BlueNADH NADH

Electron Microscopy

NADHTrichromeATPase 4.3H&E

Case 13

� 35-year-old man

� Past Medical History: Unremarkable

� Medications: None

� Presentation: Diffuse muscle pain / soreness, proximal and distal

� Neurologic Examination:

� Pain in multiple muscles; no weakness

� Laboratory Evaluation:

� CPK 600

� Social History: Hunter in the Upper Peninsula of Michigan

History

Case 14

History

- 56-year-old woman- Past medical history: lupus erythematosus X 5 years- Medications: Immunosuppressives including corticosteroids- Symptoms: Progressive weakness, profound

- Proximal-predominant

ATPase pH 9.4

Histochemical Fiber Typing

Type 1 Type 2

� Twitch sLow fast

� Turkey Meat Dark – drumstick White – Breast

analogy (weight bearing) (rapid / skilled movement)

� Metabolism Oxidative Glycolytic

� Fat More Less

� Glycogen Less More

� NADH (oxidative) Dark Light

� ATPase

� 4.3 Dark Light

� 9.4 Light Dark

“One Slow Fat Red Ox”

Case 15

� 56-year-old man

� Past Medical History: Unremarkable

� Medications: None

� Presentation: Slowly progressive weakness, left leg, then right leg and arms; difficulty swallowing

� Neurologic Examination:

� Weakness, distal and proximal

� Laboratory Evaluation:

� CPK 150 (normal < 220)

History

Esterase

Fiber type grouping – groups of type 1 and type 2 fibers (ATPase pH 9.4 – type 2 fibers dark)

Neurogenic Changes

Case 16

• 60 year old woman with a history of chronic obstructive pulmonary disease.

• Suffered an episode of respiratory failure that required intubation approximately 3 weeks prior to biopsy

• She has received

• Neuromuscular blocking agent

• High dose corticosteroid therapy

• She has now been extubated and is manifesting significant weakness, legs greater than arms.

History

Electron Microscopy

Electron Microscopy, 30000 X Magnification: Evaluation of intact (left) and affected (right) myofibers.

ANSWERS

� 1. Myofiber necrosis from statin medication� 2. Vacuolar myopathy

� 3. Duchenne muscular dystrophy� 4. Congenital muscular dystrophy, merosin

negative� 5. Dermatomyositis

� 6. Inclusion body myositis� 7. Sarcoid

� 8. Mitochondrial disease

� 9. McArdle's Disease� 10. Nemaline myopathy

� 11. Centronuclear myopathy� 12. Central core disease

� 13. Trichinella spiralis

� 14. Steroid-induced atrophy� 15. ALS

� 16. Critical Care myopathy