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Graft vs Host Disease (GVHD)

General Myopathy Neuropathy

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Graft vs Host Disease: Neuromuscular, General

• Myopathy is more frequent than Neuropathy
• Tissue involvement
  • No overall single pattern
    • Individual patients often have disorders that involve more than one tissue
  • May include
    • Muscle
      • Perimysium: Most common involvement
        • Structure: Damaged
        • Inflammation: Histiocytic cells
        • C_5b-9 deposits
      • Endomysium
        • C_5b-9 deposits
        • Cells: Histiocytic, scattered
      • Endomysial capillaries
        • Large
        • Numbers: Reduced
        • Glycosylation: Ulex stain reduced
        • C_5b-9 deposits
      • Muscle fibers
        • MHC I upregulation: Very common
        • Glycosylation: Reduced α-Dystroglycan & Chondroitin-SO₄
        • Nuclei: Large; Abnormal distribution
        • Aggregates: Lysosomal
    • Nerve
      • Epineurium
      • Perineurium
      • Vessels
      • Axons
        • Wallerian degeneration
        • Axon loss: Differential fascicular
        • Often secondary to involvemnt of another tissue type
      • Myelin
• Inflammatory cells: Usually histiocytic

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GVH: Neuropathy

Toluidine blue stain Differential Fascicular Involvement: More axon loss in some regions than others

VvG stain

Neurofilament stain

ATPase pH 4.3 stain

Wallerian Degeneration: Intrafascicular variation Toluidine blue stain	Toluidine blue stain
Acid phosphatase stain

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Gomori trichrome stain

Immune damage: Connective tissue   Perineurium (Arrow) & Epineurium: Damaged structure (Above)   Epineurium: Alkaline phosphatase staining (Below)   Perineurium: CD4 cells (Right) Alkaline phosphatase stain

CD4 stain

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Gomori trichrome stain

GVH Muscle Denervation
  Pyknotic Nuclear Clumps

NADH stain

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cGVH: Myopathy

Capillaries Muscle fibers   Glycosylation   Morphology     Perifascicular   Myonuclei   MHC1 Perimysial connective tissue   Histiocytes

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cGVH: Perimysial pathology

H&E stain	Gomori trichrome stain
Perimysium: Fragmented and damaged; Contains scattered large cells. Muscle fibers neighboring abnormal perimysium: Mildly small.

H&E stain

Gomori trichrome stain

VvG stain

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H&E stain

Fragmented perimysium: Contains large histiocytic cells

Gomori trichrome stain

Fragmented perimysium: Contains large histiocytic cells

Acid phosphatase stain

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Muscle fibers at the edge of fascicles, near perimysium, tend to be smaller

NADH stain

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Acid phosphatase stain

Perimysium: Acid phosphatase positive cells Acid phosphatase stain

Acid phosphatase stain

Acid phosphatase stain

Histiocytic cells in perimysium Esterase stain

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Histiocytic cells in endomysium
  Often accompany upregulated MHC I by muscle fibers

Acid phosphatase stain

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cGvHD: C_5b-9 deposits, Locations
  Connective tissue: Perimysium; May extend into endomysium
  Capillaries: Endomysial

C5b-9 stain

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cGvHD: C_5b-9 deposits, Locations
  Perimysium
  Surface of some muscle fibers, more often near perimysium

C5b-9 stain

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cGvHD: Muscle Fiber Morphology
  Muscle Fibers
    Sizes: Varied
    Immature small fibers: Few
    Necrosis: None or Rare
  Endomysial Connective Tissue: Normal between fibers
 

H&E stain

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cGvHD: Muscle Fibers
  MHC Class I: Upregulated on all muscle fibers

MHC Class I stain

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cGvHD Muscle Fibers: α-Dystroglycan
  Reduced around surface of muscle fibers
  Similar pathology to: Hereditary Muscle Glycosylation disorders
    See FKRP

α-Dystroglycan stain: Glycosylation (Green); Protein (Red)
Normal   Costaining of α-Dystroglycan Protein & Glycoslyation	cGvHD   α-Dystroglycan Glycoslyation is Reduced & Punctate

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Chondroitin-SO4 stain
Normal   Strong staining on the surface of muscle fibers	cGvHD   Reduced staining on surface of muscle fibers

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cGvHD: Muscle Fibers, Unusual features
  Abnormal myonuclei

Congo red stain

Congo red stain

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Acid phosphatase stain

Cytoplasmic granules: Acid phosphatase positive

Acid phosphatase stain

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cGvHD: Capillary Pathology

UEA I stain GVH: Capillaries   Pale stained by UEA I   Number: Reduced; Many muscle fibers with no neighboring capillary   Size: Mildly large

UEA I stain Control muscle: Capillaries   Abundant: Capillaries neighboring most muscle fibers   Dark stained by UEA I

UEA I stain

UEA I stain

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Collagen 4 stain (Red)

Capillaries: Normal (Same muscle section above & below)
  All muscle fibers have adjacent capillaries (Top; Arrow)
  All Collagen 4 stained capillaries have associated endothelium (CD31; Yellow; Arrow)

Collagen 4 stain (Red); CD31 stain (Green & Yellow)

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Capillaries: cGvHD

Collagen 4 stain (Red); CD31 stain (Green & Yellow)

cGvHD Capillary Pathology
  Many Collagen 4+ capillary remnants with No CD31 endothelium (Red; Arrow)
  Remaining intact capillaries (Yellow, Green & Red): Large; Reduced in number

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cGvHD Capillary Pathology
  Capillaries are entirely lost: No Collagen 4+ capillary remnants
  Remaining intact capillaries (Yellow, Green & Red): Large; Reduced in number

Collagen 4 stain (Red); CD31 stain (Green & Yellow)

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cGvHD Capillary Pathology

UEA I (Ulex; Green & Yellow): CD31 Red)

Capillaries: Normal
  Costaining (Green & Yellow) of UEA I (Ulex) & CD31

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Capillaries: cGvHD
  UEA I (Ulex) is reduced in areas of CD31 stain (Red)

UEA I (Ulex; Green & Yellow): CD31 Red)

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Capillaries: C_5b-9 deposits

C5b-9 stain

Normal muscle: No C_5b-9 staining of capillaries

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cGvHD muscle: C_5b-9 deposits on misoriented endomysial capillaries

C5b-9 stain

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12/6/2019