Low Power

Cellularity

At scanning power (x20-40) the feature suspicious of AMR is a "busy" look to the myocardium - a diffuse "B" pattern of increased cellularity giving a "busy B" appearance that, unlike cellular rejection, is present throughout the biopsy.

Interstitium

The "busy" appearance may be accompanied by interstitial edema, with separation of myocytes. In severe cases there may be extravasated red blood cells/hemorrhage as well, although this is very unreliable in biopsy tissue given the traumatic bioptome sampling. Severe AMR also typically shows widespread myocyte injury, such that there is overlap between severe AMR and grade 3R rejection.

Vasculature (capillaries vs. venules/arterioles)

The impression that the increased "cellularity" is in the vicinity of the microvasculature can sometimes be appreciated at a slightly higher power (x100). Cells within arterioles and larger venules should generally be ignored.

High Power

Endothelial Cells

Higher magnification (x200-400) allows inspection of capillaries and venules in the myocardial interstitium. Interstitial capillary injury is characterized by large and prominent ("swollen") endothelial cells. Enlarged nuclei and/or and expanded cytoplasms appear to narrow or occlude the lumens. Similar endothelial cell changes can also be seen in the setting of ischemic injury or settings besides AMR, so this finding should be interpreted in context (i.e. other ischemic injury features, biopsy site, presence of intravascular macrophages, etc.). Endothelial cells with pyknosis and/or karyorrhexis can reflect severe AMR.

Intravascular mononuclear cells

At high power, intravascular macrophages often distend and fill the capillary and venular lumens. These can be difficult to distinguish from endothelial cells in some cases, but if they are completely detached from the vessel wall and show typical morphologic features of macrophages, one can be reasonably certain of their identity. CD68 immunohistochemistry is confirmatory.

The prevalence of macrophages is variable (quantitative criteria discussed under CD68 below). The "swollen" endothelial cells are usually seen more diffusely. Most cases of AMR display diffuse or multifocal patterns of "activated mononuclear cells". If CD68 staining is not routinely done, cases with even focally prominent intravascular mononuclear cells should prompt staining for CD68. In some subtle cases the number of CD68 positive macrophages will be surprising.

Edema

Edema may be appreciated at lower power, but on closer inspection should show pale blue proteinaceous material in the interstitial space. The finding of edema may vary from sparse accumulations to prominent widespread collections, especially in cases of severe AMR.

Edema should not be confused with artifacts due to biopsy or histology preparation-induced spaces (which lack the pale blue staining). Edema should be also distinguished from interstitial fibrosis. The wavy fibrils of collagen or a connective tissue stain, such as Masson trichrome, can be used to confirm interstitial fibrosis.

Edema is also not specific for AMR. It can be seen in the setting of ischemic and perioperative "harvesting" injury.

Inflammation

Inflammatory cells other than macrophages may also be prominent in AMR. These are often present in the interstitium as well as intravascularly. This raises the issue of "mixed" rejection (discussed below), but in the setting of pure AMR, the inflammatory cells could include neutrophils and eosinophils (which are rarely seen in cellular rejection) as well as lymphocytes (especially T and NK cells). Interstitial inflammation is more prominent in severe AMR, in combination with edema, hemorrhage, endothelial cell pyknosis/karyorrhexis and extensive myocyte damage.

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