Lung Biopsy Interpretation
Case 10 -
Pulmonary Alveolar Proteinosis (PAP)
Anna-Luise A. Katzenstein & Jeffrey L. Myers
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.
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.
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
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
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.
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