A Revision of the 1990 Working Formulation
for the Classification of Pulmonary Allograft Rejection:
Lung Rejection Study Group (LRSG)
Histologic Grading of Lung Allograft
Rejection
TABLE I. Working Formulation for Classification and Grading of
Pumonary Allograft Rejectin
| A. Acute Rejection |
|
B.* Airway inflammation - lymphocytic bronchitis/bronchiolitis
|
| Grade 0 - None |
With/Without |
|
| Grade 1 - Minimal |
| Grade 2 - Mild |
| Grade 3 - Moderate |
| Grade 4 - Severe |
|
| C. Chronic airway rejection - bronchiolitis
obliterans |
| a. Active |
| b. Inactive |
|
| D. Chronic vascular rejection - accelerated
graft vascular sclerosis |
| * Pathologist may choose to grade B lesions (see text).
|
The LRSG recognized that alloreactive injury to the donor
lung can affect the vasculature and the airways in both acute and chronic
rejection. Acute rejection is characterized by perivascular and subendothelial
mononuclear infiltrates, and by lymphocytic bronchitis and bronchiolitis. Chronic
rejection, by definition, manifests as bronchiolitis obliterans - dense
eosinophilic fibrous scarring of the bronchioles - and accelerated vascular
sclerosis affecting pulmonary arteries and veins.2,3,12 While it is probable that
a continuum of vascular and airway histopathologic changes exists in the lung
allograft, these changes have been divided into histologic grades based on the
intensity of the cellular infiltrate and the presence of dense eosinophilic hyaline
fibrosis. It should be emphasized that the presence of such irreversible hyaline
eosinophilic scarring of the airways and vessels represents the key histologic
discriminator between acute and chronic rejection.
A. ACUTE REJECTION
The diagnosis of acute rejection is based exclusively on
the presence of perivascular and interstitial mononuclear cell infiltrates. In
grading acute rejection, attention should be directed at the intensity of the
perivascular mononuclear cell cuffs which surround the blood vessels and at whether
the mononuclear cells extend beyond the vascular adventitia and percolate into the
adjacent alveolar septa. This latter feature denotes a higher grade of rejection.
While rejection processes usually affect more than one vessel, solitary
perivascular infiltrates should be evaluated using criteria that are identical to
those which are applied to multiple infiltrates, as outlined below. Infiltrates
surrounding small vessels in the submucosa of airways are interpreted as part of
the spectrum of airway inflammation and are not diagnostic of acute rejection.
GRADE 0 (no acute rejection)
In grade A0 normal pulmonary parenchyma is seen without
evidence of mononuclear infiltration, hemorrhage, or necrosis.
GRADE A1 (minimal acute rejection)
In grade A1 there are scattered infrequent perivascular
mononuclear infiltrates in alveolated lung parenchyma that are not obvious at low
magnification (40x magnification); blood vessels, particularly venules, are cuffed
by small round, plasmacytoid, and transformed lymphocytes forming a ring of 2 to 3
cells in thickness in the perivascular adventitia (Figure 1).
GRADE A2 (mild acute rejection)
In grade A2 frequent perivascular mononuclear infiltrates
surrounding venules and arterioles are readily recognizable at low
magnification(Figure 2); they usually consist of activated lymphocytes, small round
lymphocytes, plasmacytoid lymphocytes, macrophages, and eosinophils. There is
frequently subendothelial infiltration by the mononuclear cells with hyperplastic
or regenerative changes in the endothelium ("endothelialitis"); although there is
expansion of the perivascular interstitium by inflammatory cells, there is no
obvious infiltration by mononuclear cells into the adjacent alveolar septae or air
spaces. Concurrent lymphocytic bronchiolitis is not uncommon.
Mild acute rejection is distinguished from minimal acute
rejection by the presence of unequivocal mononuclear infiltrates which are
identified at scanning magnification. Additional helpful features which suggest
mild rejection are the presence of subendothelial mononuclear infiltrates,
eosinophils, and coexistent airway inflammation. It is also important to note
that a solitary perivascular mononuclear infiltrate of significant intensity to be
noted at low magnification still warrants a diagnosis of grade A2 (or greater)
rejection.
GRADE A3 (moderate acute rejection)
Grade A3 shows readily recognizable cuffing of venules and
arterioles by dense perivascular mononuclear cell infiltrates, which are usually
associated with endothelialitis (Figures 3,4); eosinophils and occasional
neutrophils are common; by definition, there is extension of the inflammatory cell
infiltrate into perivascular and peribronchiolar alveolar septae and air spaces
(Figure 5). Collections of alveolar macrophages are common in the airspaces in the
zones of septal infiltration.
GRADE A4 (severe acute rejection)
In grade A4 there are diffuse perivascular, interstitial,
and air space infiltrates of mononuclear cells and prominent alveolar pneumocyte
damage usually associated with intra-alveolar necrotic cells, macrophages, hyaline
membranes, hemorrhage, and neutrophils (Figures 6,7); there may be associated
parenchymal necrosis, infarction, or necrotizing vasculitis.
Grade A4 acute rejection may be separated from
post-transplantation acute lung injury (diffuse alveolar damage) by the obvious
presence of numerous perivascular and interstitial mononuclear cells, which are not
present in peri - operative (reperfusion/ischemic) lung injury.
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