Department of Pathology - Room NW 625; Montefiore University Hospital; University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213-2582
Address reprint requests to Dr. Yousem at the above address
In 1990, the Lung Rejection Study Group and the International Society for Heart and Lung Transplantation proposed a working formulation for the standardization and grading of lung allograft rejection . The goal of this effort was to encourage the utilization of a single grading scheme in scientific studies and publications which would allow consistent comparison of results, inter-institutional communication, and histopathologic uniformity. As a result of a multitude of factors, this classification has been widely accepted. Nonetheless, in the intervening five years, new perspectives have evolved on the proposal and for this reason an expanded cohort of international pathologists met at the University of Pittsburgh in February, 1995 to revise the original pathological formulation .
The study group was strongly influenced by animal models of lung transplantation, international publications by a large number of lung transplant institutions, their own published work and empiric observations. The basic perception of this core of pathologists was that rejection of the lung allograft entailed alloreactive injury to the airways and vasculature by mononuclear cells[3, 4, 5]. Severe, persistent or repetitive damage to these two sites results in scarring and fibrosis of these sites primarily[4, 5]. This perspective formed the crux of the classification, much as it did in 1990 (Table #1). This classification is a purely histopathologic one and does not attempt to utilize clinical data or to espouse pathogenetic mechanisms of allograft damage. While early cellular rejection was recognized to affect the pulmonary vessels and bronchi and bronchioles, the grading of histologic acute rejection is largely based on the intensity of perivascular mononuclear infiltrates and the extent of mononuclear infiltration of perivascular alveolar septa. As the degree of perivascular infiltration increases, submucosal and lamina propria expansion of the bronchi and bronchioles by similar mononuclear cells occurs, with moderate to severe histologic acute rejection characterized by respiratory epithelial cell necrosis and ulceration.
What separates "acute" from "chronic" lung allograft rejection is the presence of dense eosinophilic hyalinized scarring of the airways and vessels. Because of the non-specificity of large airway fibrosis, "chronic airway rejection" or bronchiolitis obliterans is reflected in the presence of subtotal or total luminal compromise by dense scar tissue in the small airways or bronchioles. Similarly, subendothelial deposits of collagen accompanied by a cellular infiltrate characterizes the chronic injury to arteries and veins which is regarded as "chronic vascular rejection".
Of course, these histologic observations need to be integrated with clinical data so as to derive a clinicopathologic diagnosis of chronic allograft rejection [7, 8]. Also worthy of note in this context is the role of sampling error. While dense airway scarring can lead to a diagnosis of bronchiolitis obliterans, a critical number of airways must demonstrate airway fibrosis of sufficient severity to cause clinical airflow obstruction and patient symptoms. By the same token, scarring of airways can develop from severe reperfusion injury/diffuse alveolar damage, necrotizing infections of the airways, aspiration, or a combination of these processes and rejection. Finally, it must be emphasized that perivascular mononuclear infiltrates are not specific to acute rejection as infections, particularly cytomegalovirus and pneumocystis, can have similar inflammatory components .
The Revised Working Formulation is described in (Table #2). Much as in the 1990 scheme, acute rejection is divided into five grades.
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) (Figure
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.
GRADE A2 (mild acute rejection) (Figures
2 & 3)
In grade A2 frequent perivascular mononuclear infiltrates surrounding venules and arterioles are readily recognizable at low magnification; 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) (Figures
4 & 5)
Grade A3 shows readily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, which are usually associated with endotheliitis; 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.
GRADE A4 (severe acute rejection) (Figures
6 & 7)
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; 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.
All cases of acute rejection should have a designation indicating whether coexistent airway inflammation is present [3, 11, 12]. In some instances, pathologists may choose to grade the intensity of airway inflammation as follows:
Chronic vascular rejection refers to the vaso-obliterative process affecting arteries and veins, that affects most solid organ transplants . It reflects accelerated atherosclerosis with fibrointimal thickening of the subendothelial area by loose myxomatous connective tissue. A mononuclear cell and foamy cell infiltrate is common. (Figures 19, 20 & 21)
In summary, the 1995 Revised Working Formulation of Lung Rejection attempts to simplify the 1990 classification and yet maintain its biologic, scientific and functional accuracy. Correlation with pathogenetic mechanisms and clinical data, as in the Bronchiolitis Obliterans Syndrome criteria , ultimately results in clinicopathologic integration essential for the care of an individual lung allograft recipient.
Yousem SA, Paradis IL, Dauber JA, Zeevi A, Rabinowich H, Duquesnoy R, Hardesty R, Griffith BP. Large Airway Inflammation in Heart-Lung Transplant Recipients. Transplantation 1990; 49:654-656.