“A 34 y/o Man With Fever and a
Lung Infiltration
California Tumor Tissue Registry’s
Case of the Month
CTTR COTM Vol. 14:11
www.cttr.org
August, 2012
A 34-year-old Caucasian male accountant for a powder factory and brass foundry experienced
low-grade fever, debility (fatigue?), and weakness. He was found to have a slight infiltration in
the right lower and mid lung fields. Cultures were negative, however he continued to have
progressive dyspnea for the next two years. During that time he also developed a chronic cough
productive of a copious amount of white sputum which was occasionally greenish or streaked
with blood. He was admitted with severe dyspnea on exertion.
A physical examination revealed no significant findings, however the chest x-ray showed diffuse
bilateral mottling in all lung areas, mostly in the lower lobes. Hemoglobin levels were slightly
high at 18.2, and sputum cultures grew alpha streptococcus and staphylococcus epidermis. A left
thoracotomy was performed. No pleural adhesions were noted, however the surgeons observed
that the lung did not expand normally. Biopsies were taken from the left lingular segment and the
left upper lobe.
Two tissue samples were examined. One was soft, fluffy, red-pink, and well aerated. The other
contained firm, gray nodules up to 0.8 cm in greatest diameter.
Histologic sections showed focal, nodular areas (Fig. 1) comprised of alveoli which were filled
with an intensely eosinophilic material made up of tiny granules and amorphous debris (Figs. 25). These areas were immediately adjacent to essentially normal lung tissue, without a
surrounding inflammatory response. No other significant abnormalities were identified.
Diagnosis: “Pulmonary Alveolar Proteinosis”
Christine M. Birsan M.D., and Donald R. Chase, M.D.
Department of Pathology and Human Anatomy, Loma Linda University and Medical
Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California
Pulmonary alveolar proteinosis (PAP) is a rare condition in which a lipid-rich, granular
proteinaceous eosinophilic material fills the alveoli. “Primary” cases are found in isolation, while
“secondary” PAP may occur in the setting of infection (tuberculosis, Pneumocystis jirovecii),
malignancy (especially leukemia and lymphoma), immune deficiency (chemotherapy, congenital
alymphoplasia, hypogammaglobulinemia, juvenile dermatomyositis), environmental dust
exposure (wood, aluminum, silica, kaolin), and lysinuric protein intolerance. A history of
smoking is present in many, but not all cases. Most patients present between the ages of 20-50,
however 18% of cases occur in infants and children. A congenital form is described by Leslie
and Wick as a lethal disease caused by defects in surfactant production and metabolism, some of
which are in association with mutations of the surfactant protein B gene and genes related to
secretion of surfactant proteins. “Secondary” PAP has also been observed in infants, most
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commonly seen with viral infections (respiratory syncytial virus, cytomegalovirus, and
parainfluenza virus). “Primary” PAP is unusual in infants and children, but may be seen in
adolescents. Males are affected more often than females at a ratio of approximately 2:1-4:1, and
the disease may be more common in Caucasians.
The pathogenesis of PAP is unknown. Studies have suggested that macrophage dysfunction may
play a role, in which there is a reduced ability to process surfactant (a significant component of
the accumulated intra-alveolar material). Mutant mice lacking the gene for granulocytemacrophage-colony-stimulating factor (GM-CSF) develop a similar disease process which is
reversed when GM-CSF is replaced. In addition, antibodies against GM-CSF have been
discovered in human cases of PAP (especially “primary” PAP), further supporting this
hypothesis. Alternatively, defective production of surfactant may be a consideration, as the
pathologically accumulated surfactant lacks its usual surface-active properties, while surfactant
extracted from uninvolved areas of the patient’s lung shows normal activity. It has been shown
experimentally that the material from PAP produces macrophage dysfunction in normal human
blood monocytes and reduces activity of lymphocytes, raising the possibility that the macrophage
dysfunction may be a secondary result rather than a primary cause. The wide variety of clinical
situations in which this process is observed suggests that PAP represents a common tissue
reaction to a broad range of insults.
Clinically, the onset of PAP is often insidious. About one-third of patients are asymptomatic at
presentation despite having extensive radiologic abnormalities. Patients who are symptomatic
may have a nonproductive cough, a cough productive of chunky, gelatinous material, and/or
streaky hemoptysis. Dyspnea on exertion, fatigue, weight loss, chest pain, and low-grade fever
may also be present. Occasionally clubbing and cyanosis are observed. Crackles are sometimes
heard on auscultation however they are often absent.
Radiographic findings usually include bilateral and symmetric areas of vaguely nodular airspace
consolidation or hazy ground-glass opacity. Peri-hilar regions and lower lobes are most severely
affected. Interlobular septal thickening and ground-glass opacities seen on CT scans produce a
characteristic “crazy paving” appearance. This pattern, although suggestive of the diagnosis, is
also seen in other conditions.
Pulmonary function testing most commonly demonstrates a restrictive process, and a decrease in
the diffusion capacity for carbon monoxide (DLCO) out of proportion to the reduced lung volume
is sometimes seen. Hypoxemia and compensated respiratory alkalosis are frequent and are made
worse by exercise. An elevated shunt fraction is usually present.
Lab values may reveal polycythemia, hypergammaglobulinemia, and increased lactate
dehydrogenase. Serum levels of lung surfactant proteins A and D (SP-A, SP-D) have been found
to be markedly high which can help narrow the diagnosis, however, other lung processes can
have similar findings. Elevated levels of several tumor markers have been identified in the BAL
fluid from some patients, including carcinoembryonic antigen (CEA), carbohydrate antigens
sialyl Lewis (CA19-9), and sialyl SSEA-1 (SLX). KL-6, a mucin-like glycoprotein may also be
useful for diagnosis when found in serum or BAL specimens. Cultures may reveal Nocardia or
other opportunistic mycobacterial, fungal, and viral agents thought to represent secondary
infection.
Cytologic preparations may suggest the diagnosis of PAP. In BAL specimens, abundant
lipoproteinaceous material causes an opaque appearance, and large, acellular eosinophilic bodies
may be seen in a background of eosinophilic granules. PAS-positive proteinaceous material as
well as macrophages engorged with PAS-positive material point to the diagnosis.
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Tissue examination is frequently necessary for definitive diagnosis. Grossly, lung tissue is heavy
and viscid, containing yellow fluid which leaks from cut surfaces. Firm, yellowish-white nodules
scattered throughout the parenchyma range from a few millimeters to 2 cm. Microscopically,
eosinophilic proteinaceous granular material fills the alveoli and occasionally involves
bronchioles and alveolar ducts, leaving the interstitial architecture of the lung generally intact. A
diffuse pattern is usually seen, however focal or patchy involvement also exist, as seen in this
case. Hyperplastic, cuboidal, type 2 pneumocytes are often line the alveolar septae. Sharply
demarcated round, empty spaces, cholesterol clefts, and small, dense, globular eosinophilic
clumps are distinctive findings within the accumulated material which may also contain cellular
debris, foamy macrophages, ghosts of degenerated cells, and detached type 2 pneumocytes. It is
usually PAS-positive and diastase-resistant, while staining for antibody to surfactant apoprotein
may be positive especially in “primary” disease. Alcian and mucicarmine stains are negative.
Frozen sections shows abundant lipid, highlighted with Oil Red O staining. Examination by
electron microscopy demonstrates concentrically laminated myelin figures and lamellar bodies
within the proteinaceous material which look identical to the cytoplasmic inclusions of type 2
pneumocytes, suggestive of surfactant. Polarization microscopy may reveal birefringent needlelike particles if there has been an exposure to dust. Interstitial fibrosis or inflammation are
typically not prominent and if present may indicate an associated infection, but may also indicate
long-standing or recurrent PAP.
The differential diagnosis for PAP includes pulmonary edema, alveolar mucinosis, and
Pneumocystis jirovecii pneumonia. Pulmonary edema and alveolar mucinosis lack the granularity
of PAP, as well as the intense eosinophilic staining, cholesterol clefts, and engorged macrophages
containing PAS-positive debris. The intra-alveolar exudate seen in Pneumocystis jirovecii may
be distinguished from PAP by the cysts or organisms which appear as “bubbles” within the
eosinophilic material which stain positive for Gomori methenamine silver (GMS).
Treatment for PAP should be initiated when the patient becomes sufficiently symptomatic, as
many patients have little or no impairment and spontaneous remission may occur. Severe
dyspnea and hypoxemia at rest or with exercise warrant therapeutic whole lung lavage via a
double-lumen endotracheal tube, the most widely accepted and effective treatment. Patients often
feel dramatically better after this treatment, although potential complications include
malpositioning of the endotracheal tube, saline spillover into unlavaged and ventilated lung, and
hydropneumothorax. Thirty to forty percent of patients require lavage only once, while some
patients require repeat lavages at intervals of 6 to 12 months. Corticosteroids or other
immunosuppressives should not be used, as there is concern that they may increase mortality by
aggravating or inducing secondary opportunistic infections. Further study is necessary to
determine the potential use of GM-CSF as a therapeutic option.
Suggested Reading:
Travis W, Colby T, Koss M, et al. Non-neoplastic disorders of the lower respiratory tract. In King D, ed.
Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology, Armed Forces Institute
of Pathology; 2002.
Katzenstein AL III. Katzenstien’s and Askin’s Surgical pathology of non-neoplastic Lung disease. 3rd
edition. Philadelphia, PA: WB Saunders Company; 1997.
Hammar S. Pleural diseases. In: Dail D, Hammar S, eds. Pulmonary Pathology. 2nd ed. New York, NY:
Springer-Verlag; 1994.
Leslie K, Wick M. Practical pulmonary pathology. A diagnostic approach. 1st edn. Philadelphia: ChurchillLivingstone; 2005.
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