Thoracic Pathology: A Volume in the High Yield Pathology Series 1st Edition

Lung Transplantation Acute Rejection

Definition

• Cell-mediated process characterized by infiltration of mononuclear cells

Clinical features

Presentation

• Acute cellular rejection can occur within days to months to years after transplantation

• Fever, flu-like symptoms, including chills, dizziness, nausea, general feeling of illness, night sweats

• Increased difficulty in breathing

• Increased chest pain or tenderness

• Worsening pulmonary test results

Prognosis and treatment

• Usually resolves completely after augmentation of immunosuppression

• Repeated episodes predispose to the development of chronic rejection (bronchiolitis obliterans)

Pathology

Histology

• Acute cellular rejection grading is based on the evaluation of two components: acute perivascular rejection and airway inflammation

• Either the 1996 or the 2007 International Society for Heart and Lung Transplantation working formulations can be used (see Web Table 1 on the Expert Consult website for comparison)

• Acute perivascular rejection:

• Inflammatory cells infiltrates around vessels (artery, veins, lymphatics)

• Inflammatory cells primarily consist of activated lymphocytes and a few eosinophils, neutrophils, and plasma cells

• Minimal acute rejection: infrequent perivascular mononuclear infiltrates, not obvious at low magnification; the vessels are ringed by two to three layers of inflammatory cells

• Mild acute rejection: contains more than three complete layers (rings) of inflammatory cells surrounding vessels

• Moderate acute rejection: in addition, there is extension into alveolar septae and spaces

• Severe acute rejection: diffuse perivascular, interstitial, and airspace infiltrates with prominent pneumocyte damage, hemorrhage, neutrophils, necrotic debris, and hyaline membranes (rarely seen)

• Airway inflammation:

• Similar to acute perivascular rejection; airway inflammation is graded from minimal to mild to moderate to rarely seen severe

• Minimal airway inflammation: small and few foci of infiltrates located between the mucosa and muscle layer

• Mild airway inflammation: bandlike submucosal infiltrates

• Moderate airway inflammation: same as mild, except for the extension of infiltrates into overlying mucosa

• Severe airway inflammation: characterized by the presence of ulceration, fibrinopurulent exudates, and epithelial cell necrosis

Immunopathology/special stains

• C4d (immunofluorescence or immunohistochemistry [IHC]) and cytomegalovirus (CMV) stains are recommended

Main differential diagnoses

• Infection: an IHC stain for CMV may be helpful

• Aspiration: macrophages with large vacuoles

• Bronchial associated lymphoid tissue (BALT): rounded collection of small lymphocytes with associated small capillaries (CD21 immunostain is positive in BALT)

Fig 1 Lung transplantation: acute rejection. This medium-power view shows cellular lung parenchyma with reactive pneumocytes, few macrophages, and no evidence of perivascular lymphoid infiltration/acute cellular rejection (grade A0).

Fig 2 Lung transplantation: acute rejection. This high-power view shows a perivascular lymphoid infiltrate composed of lymphocytes and eosinophils forming an incomplete perivascular ring, characteristic of minimal acute rejection (grade A1).

Fig 3 Lung transplantation: acute rejection. This medium-power view shows more than three layers of perivascular lymphoid infiltrates characteristic of mild acute cellular rejection (grade A2).

Fig 4 Lung transplantation: acute rejection. This medium-power view shows an extensive perivascular lymphoid infiltrate that extends into the alveolar septae, as seen in moderate acute cellular rejection (grade A3).

Fig 5 Lung transplantation: acute rejection. At high power, lymphocytes, plasma cells, neutrophils, and eosinophils are identified in the mixed infiltrate characteristic of acute rejection. Endothelialitis is present but does not affect the grading of rejection.

Fig 6 Lung transplantation: acute rejection. This high-power view shows airway with small and few foci of lymphoplasmacytic infiltrates located between the mucosa and muscle layer (grade B1/B1R).

Fig 7 Lung transplantation: acute rejection. This medium-power view shows airway with a bandlike inflammatory infiltrate in the submucosa (grade B2/B1R).

Fig 8 Lung transplantation: acute rejection. The mixed inflammatory infiltrate extends into the epithelium in moderate airway rejection (B3/B2R).

Fig 9 Lung transplantation: acute rejection. This photomicrograph shows a rounded collection of small lymphocytes with associated small capillaries characteristic of BALT. Note presence of anthracotic pigment.

Fig 10 Lung transplantation: acute rejection. Immunostain for CD21 is positive in BALT. (It would be negative in acute rejection.)

Fig 11 Lung transplantation: acute rejection. This is an example of microaspiration with few coarsely vacuolated macrophages.

Fig 12 Lung transplantation: acute rejection. This medium-power view shows hemosiderin that is often present in transplantation recipients and may be associated with lymphocytes; it should not be called rejection.

WEB TABLE 1 Comparison of 1996 and 2007 Grading Formulations