—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 4 - Pulmonary Alveolar Proteinosis

Anna-Luise Katzenstein
Suny Upstate Medical Center
Syracuse, NY


Click on each slide thumbnail image for an enlarged view
Clinical History
This 30 year old man presented with increasing shortness of breath and cough over one week. He had a history of pneumonia treated with antibiotics three months previously. On admission, his hematocrit was 60 and hemoglobin 20. His p02 on room air was 50. Chest radiographs showed bilateral ground glass infiltrates. He was initially treated with antibiotics but worsened and developed respiratory failure requiring mechanical ventilation. An open lung biopsy was performed.


Case 4 - Figure 1 - Low magnification view showing eosinophilic material filling airspaces.
Case 4 - Figure 2 - Higher magnification photomicrograph showing the granular appearance of the airspace exudate. Note that the alveolar septa are only minimally thickened, and there is no significant inflammation.
Case 4 - Figure 3 - High magnification photomicrograph showing the coarsely granular nature of the intraalveolar eosinophilic material. The adjacent alveolar septa are normal except for mild hyperplasia of type 2 pneumocytes.


(Case contributed by Dr. Robin Bideau, Louisville, KY).

Diagnosis:
Pulmonary Alveolar Proteinosis

Discussion:
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the intraalveolar accumulation of phospholipid rich proteinaceous material that is biochemically similar to surfactant. Two forms of PAP are recognized, a primary or idiopathic form, as in the current patient, and a secondary form. The secondary form occurs in patients with underlying immune alterations including those related to malignancy, immunosuppressive therapy, and HIV infection, and in patients with congenital immunodeficiency. Inhalation of certain dusts have been associated with PAP, including silica (acute silicoproteinosis), aluminum and titanium. Exposure to fibrous insulation material has been implicated in one case as well. PAP has also been described in children with lysinuric protein intolerance.

PAP occurs most often in adults, usually in their late 30's. Cases have been reported in newborn infants and young children, but the disease in newborns is probably different. Men are affected about twice as often as women. The most common symptoms are dyspnea and cough, although up to one third of patients are asymptomatic. Chest x-rays show bilateral, symmetric airspace opacities with perihilar accentuation. Ground glass densities are seen on CT scans and they are often associated with thickened interlobular septa that have characteristic polygonal shapes referred to as "crazy paving". Serum LDH levels are often increased, and elevated levels of surfactant proteins A and D and KL-6, a mucin like glycoprotein, have also been demonstrated. Serum IgG autoantibodies to granulocyte macrophage colony stimulating factor (GM-CSF) are uniformly present. The usual treatment in adults is whole lung lavage, although spontaneous recovery occurs in some patients without therapy. Recently, beneficial response to administration of GM-CSF has been demonstrated in some patients (see later on). The prognosis is excellent in adult patients without an underlying predisposing cause. The prognosis in young children is not good, however, with death occurring in the majority.

Histologically, PAP is characterized by the accumulation of amorphous, often coarsely granular, eosinophilic proteinaceous material within alveolar spaces. The material usually, but not always, stains positively with PAS after diastase digestion. Foamy macrophages are often scattered within the eosinophilic material, and needle shaped, clear "acicular" spaces likely resulting from cholesterol deposition are common. The adjacent alveolar septa are usually normal, although mild accompanying fibrosis sometimes is seen. The intraalveolar material stains with an antibody to surfactant apoprotein in primary PAP, but is said to be negative in the secondary form. By electron microscopy, there are laminated myelin figures and lamellar bodies similar to the cytoplasmic inclusions normally present in alveolar type 2 cells.

There are exciting recent developments in understanding the pathogenesis of PAP, and they may have relevance to therapy. For years the disease has been thought to be due to an abnormality of surfactant regulation causing either increased surfactant production or decreased clearance, or both. Recently, a PAP-like disease has been identified in mice genetically deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF). This cytokine is important in surfactant homeostasis by promoting macrophage differentiation and proliferation, and its lack leads to diminished clearance due to macrophage dysfunction. Although GM-CSF is not absent in humans with PAP, circulating serum autoantibodies to GM-CSF are uniformly present, and the theory is that these autoantibodies interfere with the action of GM-CSF. The current evidence, therefore, indicates that PAP is an autoimmune disease caused by the presence of anti-GM-CSF autoantibodies. Treatment with GM-CSF has ameliorated the disease in some patients. Some investigators suggest that identification of serum GM-CSF autoantibodies in the right clinical setting might obviate the need for tissue diagnosis.

Differential Diagnosis:
The differential diagnosis of PAP includes any disease characterized by intraalveolar accumulation of eosinophilic material. Pulmonary edema is the most common and differs in that edema fluid is homogeneous, lacking granularity and acicular spaces. Pneumocystis carinii pneumonia differs in that the intraalveolar xudates has a frothy or honey-comb appearance due to the presence of numerous cysts. In questionable cases a GMS stain will outline the cysts, although it is usually not necessary. Changes similar to PAP have been described distal to bronchial obstruction, but differ by the presence of significant associated fibrosis and inflammation.

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