—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 10 - Pulmonary Alveolar Proteinosis (PAP)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
This 54 year old man presented with a year long history of persistent shortness of breath on exertion. He was hospitalized elsewhere 5 months prior to admission for a right lower lobe "pneumonitis" without an identified etiology. His dyspnea worsened and he developed a daily cough productive of scant yellow to clear sputum. He smoked a pack of cigarettes a day for 35 to 40 years. Occupational history included significant exposure to asbestos and calcium silicate powder in a steel mill. Admission CT scans showed extensive areas of ground glass attenuation.

Microscopic Description:


Case 10 - Figure 1 - Photomicrograph illustrating extensive filling of alveolar spaces by a granular eosinophilic exudate.
Case 10 - Figure 2 - High magnification photomicrograph showing the granular, paucicellular, eosinophilic exudate typical of PAP. The exudate includes occasional histiocytes and "ghosts" of necrotic mononuclear cells.

Your sections from the wedge lung biopsy demonstrate a predominantly airspace-filling process. At higher magnification the affected airspaces contain a peculiar granular eosinophilic exudate. The exudate includes a background of amorphic granular eosinophilic debris containing scattered necrotic mononuclear cells and occasional "cholesterol clefts". Alveolar septa are only mildly thickened with no appreciable fibrosis. Special stains for acid-fast bacilli, fungi, and pneumocystis were negative.

Discussion
Pulmonary alveolar proteinosis (PAP), also called pulmonary alveolar lipoproteinosis or phospholipoproteinosis, is a distinctive lesion characterized by the presence of amorphous granular eosinophilic debris within alveolar spaces. This tissue response can be seen in various clinical contexts. In most patients PAP represents a form of primary idiopathic lung disease, while in others it likely results from some other primary event such as occupational exposure to inorganic dusts (e.g. silica, aluminum or titanium), lung transplantation, or lysinuric protein intolerance. PAP also occurs in immunocompromised patients, especially those with underlying hematopoietic malignancies. "Secondary" PAP has been reported as a cause of reversible respiratory failure in patients with underlying leukemia and may be especially common with myeloid leukemias. Associated opportunistic infections are common in immunocompromised patients and should be vigorously excluded with appropriate special stains and cultures. For the most part our discussion will focus on primary PAP.

PAP typically presents in young adults in the third or fourth decade of life, although all age groups can be affected. Men are affected more commonly than women by a ratio of about 3-to-1. Over seventy percent of affected patients have a history of cigarette smoking. A significant minority of patients may be immunocompromised. The most common presenting complaints are dyspnea and dry cough. Low grade fever may also occur, but the combination of an acute onset and fever should raise the possibility of superimposed infection. Digital clubbing occurs in as many as a third of patients. Laboratory studies may include elevated serum levels of lactic dehydrogenase. Radiographic studies demonstrate a nonspecific patten of patchy consolidation that is usually bilateral and extensive. Associated thickening of interlobular septa is best seen on high resolution CT scans, resulting in a "crazy paving" pattern that is characteristic but not pathognomonic of PAP. Diagnosis is usually made on the basis of wedge lung biopsy. Transbronchial biopsies and bronchoalveolar lavage specimens can also be diagnostic in some patients. Whole lung lavage is the current mainstay of therapy, although alternatives based on an evolving understanding of pathogenesis are being vigorously investigated (see below). Prognosis for PAP is variable, with about 75 percent of patients surviving at five years. A small number of patients (less than 10 percent) spontaneously recover, while the bulk of patients have stable but persistent disease.

Diagnosis requires recognition of the distinctive granular eosinophilic exudate that defines PAP. The morphologic changes are similar regardless of the underlying cause and consist of alveolar filling by granular eosinophilic debris containing cholesterol casts and cellular "ghosts." The granular exudate stains positively using PAS and is also immunoreactive for surfactant apoprotein. The interstitium is usually relatively unaffected, although associated alveolar septal fibrosis has been described in rare examples. Ultrastructural studies reveal free lamellar bodies as well as tubular myelin and myelin structures which are thought to represent surfactant breakdown products. These ultrastructural features can be helpful in supporting the diagnosis in bronchoalveolar lavage specimens. Special stains should always be done to exclude the possibility of superimposed infection.

The pathogenesis of PAP is unknown, but evidence from animal and human studies suggests that several different abnormalities may result in the same histopathologic phenotype. Neonatal alveolar proteinosis is histologically similar to its adult counterpart but differs in that it appears to result from surfactant protein B deficiency. Affected newborns usually die within the first year of life. At least some of the reported neonates may have a form of chronic interstitial pneumonia referred to as chronic pneumonitis of infancy rather than alveolar proteinosis. Perturbed surfactant homeostasis appears to be a key component of the pathogenesis in primary acquired disease, in many patients linked to autoantibodies directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). The presence of anti-GM-CSF autoantibodies has been proposed as a sensitive and specific marker for PAP, and therapeutic trials of exogenous GM-CSF administration are underway with promising results.

References

  1. Bedrossian C, Luna M, Conklin R, Miller W. Alveolar proteinosis as a consequence of immunosuppression. Hum Pathol 1980; 11:527-35.
  2. Carraway M, Ghio A, Carter J, Piantadosi C. Detection of granulocyte-macrophage colony-stimulating factor in patients with pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 161:1294-99.
  3. Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin J. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994; 149:788-94.
  4. de la Fuente A, Voorhout W, deMello D. Congenital alveolar proteinosis in the Netherlands: a report of five cases with immunohistochemical and genetic studies on surfactant apoproteins. Ped Pathol Lab Med 1997; 17: 221-31.
  5. Dranoff G, Crawford A, Sadelain M, et. al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 1994; 264:713-16.
  6. Godwin J, Muller N, Takasugi J. Pulmonary alveolar proteinosis: CT findings. Radiol 1988; 169:609-13.
  7. Goldstein L, Kavuru M, Curtis-McCarthy P, et. al. Pulmonary alveolar proteinosis. Chest 1998; 114:1357-62.
  8. Hoffman R, Rogers R. Serum and lavage lactate dehydrogenase isoenzymes in pulmonary alveolar proteinosis. Am Rev Respir Dis 1991; 143:42-46.
  9. Kariman K, Kylstra J, Spock A. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung 1984; 162:223-31.
  10. Katzenstein A-L, Gordon L, Oliphant M, Swender P. Chronic pneumonitis of infancy. A unique form of interstitial lung disease occurring in early childhood. Am J Surg Pathol 1995; 19: 439-47.
  11. Kavuru M, Sullivan E, Piccin R, et. al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 161:1143-48.
  12. Keller C, Frost A, Cagle P, Abraham J. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest 1995; 108:277-80.
  13. Kitamura T, Uchida K, Tanaka N, et. al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 162:658-62.
  14. Knight D, Knight J. Pulmonary alveolar proteinosis in the newborn. Arch Pathol Lab Med 1985; 109:529-31.
  15. Lee K, Levin D, Webb R, et. al. Pulmonary alveolar proteinosis. Chest 1997; 111:989-95.
  16. Miller R, Churg A, Hutcheon M, Lam S. Pulmonary alveolar proteinosis and aluminum dust exposure. Am Rev Respir Dis 1984; 130:312-15.
  17. Nogee L, deMello D, Dehner L, Colten H. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. New Eng J Med 1993; 328:406-10.
  18. Parto K, Kallajoki M, Aho H, Simell O. Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients. Hum Pathol 1994; 25:400-407.
  19. Parto K, Maki J, Pelliniemi L, Simell O. Abnormal pulmonary macrophages in lysinuric protein intolerance. Arch Pathol Lab Med 1994; 118:536-41.
  20. Prakash U, Barham S, Carpenter H, Marsh H. Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review. Mayo Clinic Proc 1987; 62:499-518.
  21. Rosen S, Castleman B, Liebow A, et. al. Pulmonary alveolar proteinosis. New Eng J Med 1958; 258(23):1123-42.
  22. Rubin E, Weisbrod G, Sanders D. Pulmonary alveolar proteinosis. Radiol 1980; 135:35-41.
  23. Rubinstein I, Brandon J, Mullen M, Hoffstein V. Morpholic diagnosis of idiopathic pulmonary alveolar lipoproteinosis-revisited. Arch Intern Med 1988; 148:813-16.
  24. Sakai Y, Abo W, Yoshimura H, et. al. Pulmonary alveolar proteinosis in infants. Eur J Pediatr 1999; 158:424-26.
  25. Seymour J, Begley C, Dirksen U, et. al. Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. Blood 1998; 92(8):2657-67.
  26. Seymour J, Presneill J. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002; 166: 215-35.
  27. Shah P, Hansell D, Lawson P, et. al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax 2000; 55:67-77.
  28. Steens R, Summers Q, Tarala R. Pulmonary alveolar proteinosis in association with Fanconi's anemia and psoriasis. Chest 1992; 102:637-38.
  29. Thomassen M, Yi T, Raychaudhuri B, et. al. Pulmonary alveolar proteinosis is a disease of decreased availability of GM-CSF rather than an intrinsic cellular defect. Clin Immunol 2000; 95(2): 85-92.
  30. Trapnell B, Whitsett J, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 2003; 349: 2527-39.
  31. Wang B, Stern E, Schmidt R, Pierson D. Diagnosing pulmonary alveolar proteinosis. Chest 1997; 111:460-66.
  32. Williams G, Christodoulou J, Stack J, et. al. Surfactant protein B deficiency: clinical, histological and molecular evaluation. J Pediatr Child Health 1999; 35:214-20.
  33. Wilson D, Rogers R. Prolonged spontaneous remission in a patient with untreated pulmonary alveolar proteinosis. Am J Med 1987; 82:1014-1016.
  34. Yousem S. Alveolar lipoproteinosis in lung allograft recipients. Hum Pathol 1997; 28(12):1383-86.