Revised Working Formulation for Lung Allograft Rejeciton

Revised Working Formulation for Classification and Grading of Lung Allograft Rejection - 1995
Acute Rejection*

Grade Histopathological Findings

A0 (None) No mononuclear inflammation, hemorrhage or necrosis

A1 (Minimal) Scattered infrequent perivascular mononuclear infiltrates not obvious at low magnification (40X). Blood vessels, particularly venules, are cuffed by small round, plasmacytoid, and transformed lymphocytes forming a ring of 2 to 3 cells thick in the perivascular adventitia.

A2 (Mild) Frequent perivascular mononuclear infiltrates surrounding venules and arterioles readily recognizable at low magnification and usually consist of activated lymphocytes, small round lymphocytes, plasmacytoid lymphocytes, macrophages, and eosinophils. Frequent subendothelial infiltration by the mononuclear cells with hyperplastic or regenerative changes in the endothelium (endotheliitis); 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. A solitary perivascular mononuclear infiltrate of significant intensity to be noted at low magnification still warrants a diagnosis of grade A2 (or greater) rejection

A3 (Moderate) Readily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, which are usually associated with endothelialitis; 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. Collections of alveolar macrophages are common in the airspaces in the zones of septal infiltration.

A4 (Severe) 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; there may be associated parenchymal necrosis, infarction, or necrotizing vasculitis. The obvious presence of numerous perivascular and interstitial mononuclear cells seen with grade A4 rejection permits distinction from peri-operative (reperfusion/ischemic) lung injury.

* Pathologists should mention airway inflammation and may choose to grade B lesions (see below).

Chronic Airway Rejection (Bronchiolitis Obliterans)

Classification Histopathological Findings

Active In addition to the fibrosis, there are intra and/or peribronchiolar submucosal and peribronchiolar mononuclear cell infiltrates usually associated with ongoing epithelial damage

Inactive Dense fibrous scarring without cellular infiltrates; this represents old cicatricial change in the small airways with a lack of significant submucosal and peribronchiolar inflammatory infiltrates

Chronic Vascular Rejection

Refers to the vaso-obliterative process affecting arteries and veins, that affects most solid organ transplants, and reflects accelerated atherosclerosis with fibrointimal thickening of the subendothelial area by loose myxomatous connective tissue. A mononuclear cell and foamy cell infiltrate is common

Airway Inflammation§

Grade Histopathological Findings

B0 (None) No airway inflammation

B1 (Minimal) Rare scattered mononuclear cells within the submucosa of the bronchi and/or bronchioles

B2 (Mild) Circumferential band of mononuclear cells and occasional eosinophils within the submucosa of bronchi and/or bronchioles unassociated with epithelial cell necrosis (apoptosis) or significant transepidermal migration by lymphocytes

B3 (Moderate) Dense band-like infiltrate of activated mononuclear cells in the lamina propria of bronchi and/or bronchioles including activated lymphocytes and eosinophils, accompanied by evidence of satellitosis of lymphocytes, epithelial cell necrosis (apoptosis) and marked lymphocyte transmigration through epithelium

B4 (Severe) Dense band-like infiltrate of activated mononuclear cells in the lamina propria of bronchi and/or bronchioles, associated with dissociation of epithelium from the basement membrane, epithelial ulceration, fibrinopurulent exudates containing neutrophils, and epithelial cell necrosis

BX Ungradeable because of sampling problems, infection, tangential cutting, etc

§ All cases of acute rejection should have a designation indicating whether coexistent airway inflammation is present and may choose to grade the intensity.

Reference Yousem SA, et al. A revision of the 1990 Working Formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Groug (LRSG) J Heart Lung Transplantation 1996;15:1-15.

Revised Working Formulation for Classification and Grading of Lung Allograft Rejection - 1995
Acute Rejection*
Grade	Histopathological Findings
A0 (None)	No mononuclear inflammation, hemorrhage or necrosis
A1 (Minimal)	Scattered infrequent perivascular mononuclear infiltrates not obvious at low magnification (40X). Blood vessels, particularly venules, are cuffed by small round, plasmacytoid, and transformed lymphocytes forming a ring of 2 to 3 cells thick in the perivascular adventitia.
A2 (Mild)	Frequent perivascular mononuclear infiltrates surrounding venules and arterioles readily recognizable at low magnification and usually consist of activated lymphocytes, small round lymphocytes, plasmacytoid lymphocytes, macrophages, and eosinophils. Frequent subendothelial infiltration by the mononuclear cells with hyperplastic or regenerative changes in the endothelium (endotheliitis); 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. A solitary perivascular mononuclear infiltrate of significant intensity to be noted at low magnification still warrants a diagnosis of grade A2 (or greater) rejection
A3 (Moderate)	Readily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, which are usually associated with endothelialitis; 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. Collections of alveolar macrophages are common in the airspaces in the zones of septal infiltration.
A4 (Severe)	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; there may be associated parenchymal necrosis, infarction, or necrotizing vasculitis. The obvious presence of numerous perivascular and interstitial mononuclear cells seen with grade A4 rejection permits distinction from peri-operative (reperfusion/ischemic) lung injury.
* Pathologists should mention airway inflammation and may choose to grade B lesions (see below).
Chronic Airway Rejection (Bronchiolitis Obliterans)
Classification	Histopathological Findings
Active	In addition to the fibrosis, there are intra and/or peribronchiolar submucosal and peribronchiolar mononuclear cell infiltrates usually associated with ongoing epithelial damage
Inactive	Dense fibrous scarring without cellular infiltrates; this represents old cicatricial change in the small airways with a lack of significant submucosal and peribronchiolar inflammatory infiltrates
Chronic Vascular Rejection
Refers to the vaso-obliterative process affecting arteries and veins, that affects most solid organ transplants, and reflects accelerated atherosclerosis with fibrointimal thickening of the subendothelial area by loose myxomatous connective tissue. A mononuclear cell and foamy cell infiltrate is common
Airway Inflammation§
Grade	Histopathological Findings
B0 (None)	No airway inflammation
B1 (Minimal)	Rare scattered mononuclear cells within the submucosa of the bronchi and/or bronchioles
B2 (Mild)	Circumferential band of mononuclear cells and occasional eosinophils within the submucosa of bronchi and/or bronchioles unassociated with epithelial cell necrosis (apoptosis) or significant transepidermal migration by lymphocytes
B3 (Moderate)	Dense band-like infiltrate of activated mononuclear cells in the lamina propria of bronchi and/or bronchioles including activated lymphocytes and eosinophils, accompanied by evidence of satellitosis of lymphocytes, epithelial cell necrosis (apoptosis) and marked lymphocyte transmigration through epithelium
B4 (Severe)	Dense band-like infiltrate of activated mononuclear cells in the lamina propria of bronchi and/or bronchioles, associated with dissociation of epithelium from the basement membrane, epithelial ulceration, fibrinopurulent exudates containing neutrophils, and epithelial cell necrosis
BX	Ungradeable because of sampling problems, infection, tangential cutting, etc
§ All cases of acute rejection should have a designation indicating whether coexistent airway inflammation is present and may choose to grade the intensity.
Reference Yousem SA, et al. A revision of the 1990 Working Formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Groug (LRSG) J Heart Lung Transplantation 1996;15:1-15.

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