Lung Transplantation

2007 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Lung Rejection

Acute Rejection
Grade Histopathological Findings
A0 (None) No mononuclear inflammation, hemorrhage or necrosis
A1 (Minimal) Scattered infrequent perivascular mononuclear infiltrates in alveolated parenchyma. 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. Cuffing is loose or compact but generally circumferential. No eosinophils or endothelialitis present.
A2 (Mild) More frequent perivascular mononuclear infiltrates surrounding venules and arterioles readily recognizable at low magnification, Usually a mix 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 (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.
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. This may be single cell infiltration of alveolar walls or more prominent infiltration with septal expansion. Collections of alveolar macrophages and/or type 2 alveolar cell hyperplasia may be seen 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 and endothelialitis. May have intra-alveolar necrotic cells, macrophages, hyaline membranes, hemorrhage, and neutrophils; there may be associated parenchymal necrosis, infarction, or necrotizing vasculitis. Perivascular inflammation may actually appear to be diminished due to extension of inflammation into alveolar septa and spaces. However, the obvious presence of numerous perivascular and interstitial mononuclear cells seen with grade A4 rejection permits distinction from peri-operative (reperfusion/ischemic) lung injury.
Airway Inflammation: Lymphocytic Bronchiolitis
Grade Histopathological Findings
B0 (None) No small airway inflammation
B1R (Low-grade inflammation) Scattered to band-like collections of mononuclear cells with or without eosinophils within the submucosa of the bronchioles. No epithelial damage or intraepithelial lymphocytic infiltration.
B2R (High-grade inflammation) Mononuclear cells in small airways are larger and activated; more frequent eosinophils and plasmacytoid cells. Epithelial damage present (variable necrosis, metasplasia, marked intraepithelial infiltration). Note: disproportionately high number of neutrophils is suggestive of infection.
BX (Ungradeable inflammation) Sampling problems, infection, tangential cuts, or other artifacts preclude accurate assessment of small airway inflammation
Chronic Airway Rejection (Bronchiolitis Obliterans)
Classification Histopathological Findings
C0 (No evidence of obliterative bronchiolitis) No changes of obliterative bronchiolitis
C1 (obliterative bronchiolitis present) Submucosal eosinophilic hyaline fibrosis in membranous and respiratory bronchioles with variable luminal occlusion, variable inflammation, variable secondary effects such as injury to smooth muscle and elastica, downstream mucostasis and/or foamy histiocyte collections
Chronic Vascular Rejection
Also known as accelerated graft vascular sclerosis. Fibrointimal thickening of arteries and veins. Venous changes may be more common in older individuals. Generally evident only on open biopsy material.
Acute Antibody-Mediated (Humoral) Rejection
No histologic features for antibody-mediated rejection in the lung were agreed upon. Likely that capillary injury and small vessel intimitis suggest humoral rejection, but these can be nonspecific and a multidisciplinary approach is recommended to reach consensus before issuing specific criteria. If humoral rejection is suspected, stains for C4d, C3d, CD31, CD68 might be performed.
Non-Rejection Biopsy Findings and Other Differential Diagnostic Considerations
Condition Histopathologic Findings
CMV pneumonitis May have perivascular inflammation, more prominent alveolar septal inflammation relative to perivascular cuffing; perivascular edema; neutrophilic inflammation with or without microabscesses; pneumocyte atypia; intranuclear and intracytoplasmic inclusions
Pneumocystis pneumonia May have perivascular and interstitial inflammation mimicking acute rejection; granulomatous inflammation; diffuse alveolar damage, focal necrosis
Granulomatous pneumonitis May occur with mycobacterial, fungal or herpesvirus infection; can be seen with Pneumocystis (see above)
Aspiration pneumonitis May show exogenous material with foreign body giant cell reaction; Lipid droplets, macrophages with large vacuoles; distal organizing pneumonia may occur
Organizing pneumonia Intra-alveolar fibromyxoid tissue with variable interstitial inflammation (may occur in multiple settings, e.g., infection; reperfusion/ischemic injury; prior severe acute rejection; may also be idiopathic/cryptogenic).
Reperfusion/ischemic injury Usually early posttransplant; usu. associated with neutrophils and acute lung injury; may have perivascular and interstitial infitrates in some cases, may lead to organizing pneumonia (see above)
Large airway inflammation Most often seen in association with infection or aspiration; scarring of large airways is considered nonspecific (but should also prompt a search for similar changes in small airways).
Bronchus associated lymphoid tissue Generally B lymphocyte nodules normally without true germinal centers, in submucosa of distal bronchi and bronchioles usu. at bifurcation points. May have prominent vascularity, well circumscribed with macrophages containing particulate matter. No epithelial injury, eosinophilia or neutrophilia.
Smokers' type respiratory bronchiolitis Macrophages with brown or black pigment with or without iron accumulate around respiratory bronchioles. May have other features of chronicity such as goblet cell metaplasia, mucostasis, bronchiolar metaplasia, interstitial thickening with variable inflammation. May be donor-related.
Alveolar septal fibrosis Potential association with late onset upper lobe fibrosis; currently considered nonspecific and difficult to interpret.
Reference Stewart S et al., Revision of the 1996 Working Formulation for the Standardization of Nomenclature‚ in the Diagnosis of Lung Rejection. J Heart Lung Transplant 26:1229-42, 2007.

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