Proteinosis alveolar

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AFIP ARCHIVES 883

From the Archives of the AFIP
Pulmonary Alveolar Proteinosis1
CME FEATURE Aletta Ann Frazier, MD • Teri J. Franks, MD • Erinn O. Cooke, MPH
See accompanying Tan-Lucien H. Mohammed, MD, FCCP • Robert D. Pugatch, MD
test at http://
www.rsna.org
Jeffrey R. Galvin, MD
/education
/rg_cme.html
Pulmonary alveolar proteinosis (PAP) may develop in a primary (idio-
LEARNING pathic) form, chiefly during middle age, or less commonly in the set-
OBJECTIVES
ting of inhalational exposure, hematologic malignancy, or immuno-
FOR TEST 6
After reading this
deficiency. Current research supports the theory that PAP is the result
article and taking of pathophysiologic mechanisms that impair pulmonary surfactant
the test, the reader
will be able to:
homeostasis and lung immune function. Clinical symptomatology is
■ Discuss the clini- variable, ranging from mild progressive dyspnea to respiratory fail-
cal manifestations, ure. There is a strong association with tobacco use. The predominant
diagnostic patho-
logic features, and computed tomographic feature of PAP is a “crazy-paving” pattern
theoretic pathogen- (smoothly thickened septal lines on a background of widespread
esis of pulmonary
alveolar proteinosis. ground-glass opacity), often with lobular or geographic sparing. The
■ Describe the spec- radiologic differential diagnosis of crazy-paving includes pulmonary
trum of radiologic edema, pneumonia, alveolar hemorrhage, diffuse alveolar damage, and
manifestations of
pulmonary alveolar lymphangitic carcinomatosis. Definitive diagnosis is made with lung
proteinosis and for- biopsy or bronchoalveolar lavage specimens that reveal intraalveolar
mulate a differential
diagnosis of crazy- deposits of proteinaceous material, dissolved cholesterol, and eosino-
paving at CT. philic globules. Symptomatic treatment includes whole-lung lavage,
■ List the original
AFIP observations
and multiple procedures may be required. New therapies directed to-
made at radiologic- ward the identified defect in immune defense have met with moderate
pathologic correla-
tion in pulmonary
clinical success.
alveolar proteinosis. radiographics.rsnajnls.org

TEACHING
POINTS
See last page

Abbreviations: AFIP = Armed Forces Institute of Pathology, BAL = bronchoalveolar lavage, GM-CSF = granulocyte-macrophage colony-stimulat-
ing factor, H-E = hematoxylin-eosin, ILS = interlobular septa, PAP = pulmonary alveolar proteinosis, WLL = whole-lung lavage

RadioGraphics 2008; 28:883–899 • Published online 10.1148/rg.283075219 • Content Code:
1
From the Departments of Radiologic Pathology (A.A.F., J.R.G.) and Pulmonary and Mediastinal Pathology (T.J.F.), Armed Forces Institute of
Pathology, 14th St and Alaska Ave NW, Washington, DC 20306; Department of Diagnostic Radiology, University of Maryland School of Medicine
(A.A.F., R.D.P., J.R.G.), and University of Maryland School of Medicine (E.O.C.), Baltimore, Md; and Section of Thoracic Imaging, Division of
Radiology, Cleveland Clinic, Cleveland, Ohio (T.-L.H.M.). Received December 3, 2007; revision requested December 19 and received February 5,
2008; accepted February 21. All authors have no financial relationships to disclose. Address correspondence to A.A.F. (e-mail: frazier@afip.osd.mil).

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as representing the views
of the Departments of the Navy, Army, or Defense.

884 May-June 2008 RG ■ Volume 28 • Number 3

Introduction genetic mutations appear to lead to a deficiency
Pulmonary alveolar proteinosis (PAP) is a rare of surfactant proteins or impaired function of
disease characterized by abnormal intraalveolar granulocyte-macrophage colony-stimulating fac-
accumulation of surfactant-like material (1). tor (GM-CSF), an essential regulator of immune
This year marks the 50th anniversary of its initial defense and surfactant homeostasis (3,5–7).
description by the eminent pathologists Rosen, Patients with idiopathic PAP (but not those with
Castleman, and Liebow (2). In 1958, Dr Rosen secondary or congenital PAP) also have high lev-
was Chief of Pulmonary and Mediastinal Pathol- els of autoantibodies against GM-CSF in blood
ogy at the Armed Forces Institute of Pathology and tissues, including the pulmonary alveoli
(AFIP), and the majority of patients in his article (3,5,6). Research suggests that these antibodies
originated from the AFIP. In the intervening neutralize the role of GM-CSF in the terminal
years, less than 500 cases have been reported in differentiation of alveolar macrophages, thereby
the literature (3). In this article, we discuss and critically impairing the process of surfactant
illustrate PAP in terms of clinical manifestations clearance in the lung (6,8). Furthermore, these
and evaluation, radiologic findings and differ- antibodies appear to neutralize the antimicrobial
ential diagnosis, treatment and prognosis, and activity of GM-CSF by inducing lung neutrophil
radiologic-pathologic correlation. In so doing, we dysfunction (6,9).
make use of the largest collection of PAP cases
to date, contained in the archives of the Depart- Clinical Manifes-
ments of Radiologic Pathology and Pulmonary tations and Evaluation
and Mediastinal Pathology at the AFIP. Patients with idiopathic or secondary PAP experi-
Despite the rarity of PAP, the conceptual ence nonspecific, moderate respiratory symptoms
understanding and the factors linked to the including progressive dyspnea (mean duration, 7
pathogenesis of this disease entity have advanced months; however, onset may last for years) and
remarkably in recent decades. Three distinct dry or minimally productive cough (3,4). Less
Teaching subgroups of PAP are currently recognized: idio- common signs and symptoms include fatigue,
Point pathic, secondary, and congenital. Idiopathic PAP weight loss, low-grade fever, chest pain, and he-
(also termed “acquired” or “adult-type” PAP) ac- moptysis (3,4). Physical examination may reveal
counts for the great majority of cases (90%). This crackles, clubbing, or cyanosis (3). The mean pa-
form occurs worldwide, with an incidence of 0.36 tient age at diagnosis is 40 years (SD ± 13 years).
new cases per 1 million persons each year and a There is a strong association with tobacco use:
prevalence of 3.7 cases per 1 million persons (4). About three-quarters of PAP patients are smok-
Secondary PAP (5%–10% of cases) is recognized ers, and in this subgroup, men are three times
in patients with industrial inhalational exposure more frequently affected than women. In non-
to materials such as silica particles, cement dust, smokers, there is no gender predilection (3,4,9).
aluminum dust, titanium dioxide, nitrogen diox- The most common elevated serologic marker
ide, and fiberglass; underlying hematologic malig- for PAP is an elevated lactate dehydrogenase level
nancy; or immunodeficiency disorders (including (82% of cases), but this finding is nonspecific.
cytotoxic or immunosuppressive therapy and Blood gases show moderate hypoxemia with
human immunodeficiency virus infection) (1,3). increased arterial oxygen tension (PaO2) and
Congenital PAP is quite rare (2% of cases) and increased alveolar-arterial oxygen tension differ-
manifests in the neonatal period with severe hy- ence (AaPO2) (3,5). Pulmonary spirometry in
poxia (3,4). “Congenital PAP” is not universally PAP reveals gas exchange impairment (decreased
regarded as a true form of PAP, but may instead carbon monoxide–diffusing capacity) and mild
represent the disease entity termed “chronic to moderate restrictive ventilatory defect (3,4).
pneumonitis of infancy” (1); in any case, the As noted earlier, patients with idiopathic PAP
prognosis is poor in this subtype (1). also have antibodies to GM-CSF in the blood
PAP appears to be the final common expres- and tissues, as well as in bronchoalveolar lavage
sion of distinct but related pathophysiologic (BAL) fluid (5,10,11). Although these antibod-
mechanisms that affect pulmonary surfactant ies are considered highly sensitive and specific
and lung immune function. Inherited or acquired markers for idiopathic PAP, the titers do not
correlate with other markers of disease severity
such as serum lactate dehydrogenase, PaO2, or
AaPO2 (5,9–11).

RG ■ Volume 28 • Number 3 Frazier et al 885

Figure 1. (a) PAP in a 61-year-old man with
chronic myelogenous leukemia and recent onset of
fatigue and cough. Posteroanterior chest radiograph
shows symmetric, perihilar ground-glass and reticu-
lonodular opacities. Note the relative sparing of the
costophrenic angles. (b) PAP in a 17-year-old boy with
mild cough and dyspnea that had persisted for several
years. Chest radiograph shows dense bilateral con-
solidation with relative sparing of the apices and right
costophrenic angle. (c) PAP in a 36-year-old man with
a history of inhalational exposure to beryllium. Chest
radiograph shows symmetric perihilar consolidation
with sparing of the costophrenic angles and apices.

tibodies (9). It is considered surprising that PAP
patients develop microbial infection relatively un-
commonly, given the conditions of macrophage
and neutrophil dysfunction (8,12).

Radiologic Findings
and Differential Diagnosis
Chest radiography is a helpful first step in diag-
Superimposed infectious pneumonia affects nostic imaging but remains nonspecific for PAP.
approximately 13% of all PAP patients (9). The The typical radiograph reveals bilateral central
increased risk of developing pneumonia in PAP and symmetric lung opacities, with relative spar-
may be due to macrophage dysfunction or the ing of the apices and costophrenic angles (Fig 1)
microbial growth medium provided by intraal- (2,3). Less commonly, radiographs show multifo-
veolar proteinaceous material (12). Complicating cal asymmetric opacities or extensive diffuse con-
infectious pneumonias in PAP are often oppor- solidation without any clear zonal predominance
tunistic, and agents include Nocardia, Candida, (Fig 2) (3,9,16). Opacities range from a ground-
Cryptococcus neoformans, Aspergillus, cytomegalovi- glass appearance with indistinct margins, to re-
rus, tuberculous and nontuberculous mycobacte- ticular or reticulonodular, to consolidation with
ria, Histoplasma capsulatum, Pneumocystis jirovecii, air bronchograms (Fig 2b) (2,17–19). Although
and Streptococcus pneumoniae (9,12–15). These
infections may be disseminated, suggesting a sys-
temic disorder such as the proposed “neutraliza-
tion” of GM-CSF activity by circulating autoan-


Figure 2. (a) PAP in a 45-year-old female smoker with a 3-month history of dyspnea and productive
cough (whitish sputum). Chest radiograph shows asymmetric reticulonodular opacities and multifocal
consolidation. (b) PAP in a 31-year-old man with a 6-month history of mild dyspnea and digital club-
bing. Chest radiograph demonstrates bilateral asymmetric opacities ranging from consolidated to reticu-
lonodular to ground-glass opacities.

Figure 3. PAP in a 46-year-old man with mild progressive dyspnea. (a) Chest radiograph shows bilateral reticu-
lonodular and patchy consolidated opacities limited to the midlung zones. (b) Follow-up chest radiograph obtained
5 months later shows increased opacification in the right lung with partial interval resolution of left-sided opacities,
findings that reflect the evanescent nature of PAP in some cases.

the radiographic appearance of PAP suggests tomography (CT) are rarely detectable on radio-
pulmonary interstitial edema, pleural effusion graphs (2,16,21). There is often notable disparity
and cardiomegaly are absent (12,13,16,17,20). between the moderate clinical symptomatology
The Kerley B (septal) lines depicted at computed of PAP and the more impressive radiographic
abnormalities (“clinicoradiologic discrepancy”)
(3,17,19).


Figure 4. (a) Known PAP in a 43-year-old woman with a 6-month history of cough and acute onset
of complicating pneumonia. Chest radiograph shows rounded consolidation with central cavitation (ar-
rowheads) in the retrocardiac portion of the left lower lobe. (b) Known PAP in a 46-year-old woman
who presented with acute fever and chills. Chest radiograph reveals the recent development of dense left
perihilar consolidation and pleural effusion, findings that are suggestive of superimposed pneumonia in
the appropriate clinical setting. Nocardial pneumonia was confirmed at autopsy.

Figure 5. PAP in a 50-year-old man with
severe dyspnea. CT scan (lung window) ac-
quired through the upper lobes demonstrates
widespread ground-glass opacity with focal
areas of sparing and strikingly prominent sep-
tal lines (crazy-paving pattern).

as a primary lung infection, usually active tuber-
culosis or “burnt-out” pneumocystis pneumonia
(2,14,23).
CT provides greater anatomic detail and infor-
mation concerning disease extent. The CT appear-
ance of “crazy-paving,” defined as a network of Teaching
smoothly thickened reticular (septal) lines super- Point
imposed on areas of ground-glass opacity, was
first described in a group of six patients with PAP
Prior to the routine use of therapeutic lung (Fig 5) (16,24,25). Areas of crazy-paving in PAP
lavage, abnormalities at chest radiography might are typically widespread and bilateral, often with
persist or evanesce over months or years (Fig 3); sharply marginated areas of geographic or lobu-
only in exceptional cases did opacities resolve sig- lar sparing (Fig 6) (13,16,22). There are widely
nificantly. In that era, findings of pleural effusion, variable patterns of regional or zonal predomi-
lymphadenopathy, or focal cavitary consolidation nance, including symmetric or asymmetric apical,
were considered highly suggestive of complicating basilar, central, peripheral, lobar, or diffuse lung
pulmonary infection, a principle that is still op- involvement (13,19,22). Extent and degree of
erative today (Fig 4) (2,13,14,17,20,22). Before CT ground-glass opacity or consolidation appear
the broad clinical and radiographic recognition of
PAP, this disease was occasionally misdiagnosed


Figure 6. Crazy-paving in PAP. (a) Coronal reformatted image (lung window) obtained in a 35-year-old man
shows geographic areas of ground-glass opacity and septal thickening in an asymmetric distribution. (b) Coronal re-
formatted image (lung window) obtained in a 45-year-old man demonstrates an extensive crazy-paving pattern with
sparing of the costophrenic angles, basilar subpleural zones, and lung apices.

Figure 7. PAP in a 50-year-old man. (a) CT scan (lung window) obtained prior to therapeutic BAL shows patchy
areas of ground-glass opacity, thickened septal lines, and consolidation. (b) Post-BAL CT scan (lung window) ob-
tained at the same level reveals residual septal lines but near-complete resolution of the ground-glass opacity.

to correlate directly with severity of compromised lational, and idiopathic conditions as well as in
pulmonary functional parameters—namely, re- straightforward hydrostatic pulmonary edema.
strictive ventilation, decreased diffusing capacity, Therefore, the radiologic differential diagnosis of
and hypoxemia (19). Posttherapeutic BAL CT may crazy-paving is broad and includes left heart fail-
reveal persistent septal lines despite interval resolu- ure, pneumonia (especially pneumocystis pneu-
tion of ground-glass opacity (Fig 7) (17,19,22). monia), alveolar hemorrhage, bronchoalveolar
Teaching Although the CT finding of crazy-paving is carcinoma, lymphangitic carcinomatosis, diffuse
Point highly characteristic of PAP, it is also seen in alveolar damage (adult respiratory distress syn-
several infectious, hemorrhagic, neoplastic, inha- drome), radiation- or drug-induced pneumonitis,
hypersensitivity pneumonitis, and pulmonary
veno-occlusive disease (Fig 8) (26–32).

Figure 8. CT scans show a spectrum of lung diseases that are part of the differential diagnosis of PAP and mani-
fest with varying degrees of ground-glass opacity, septal lines, and consolidation: cryptococcal pneumonia (a), dif-
fuse alveolar damage (b), Erdheim-Chester disease (c), pulmonary veno-occlusive disease (d), cardiogenic pulmo-
nary edema (e), pneumocystis pneumonia (f), pulmonary hemorrhage (g), and lymphangitic carcinomatosis (h).


Treatment and Prognosis to pulmonary fibrosis (3,34). PAP has been
In unusual cases, clinical remission or quiescence reported to recur following double transplanta-
of PAP may occur, but intervention is required tion, which argues in favor of a systemic disorder
in the majority of patients, and treatment de- probably related to the circulating antibody to
pends on the particular form of disease (4,9). GM-CSF (9,34). It is interesting to note that a
Congenital PAP requires supportive measures or PAP-like condition may also develop in lung al-
lung transplantation. Secondary PAP demands lograft recipients without prior PAP, possibly
removal of the inciting agent from the patient’s secondary to immunosuppressive therapy (3,35).
environment. Patients with idiopathic PAP are Overall survival rates for PAP now approach
treated with sequential therapeutic whole-lung 100%, but if death does result directly from PAP,
lavage (WLL), a procedure for removing lipopro- it is due to either respiratory failure (80% of
teinaceous material from pulmonary alveoli with cases) or pulmonary infection (20%) (3,4).
use of saline solution and chest percussion (3).
Approximately 63% of patients with idiopathic AFIP Archives Case Review
PAP require WLL within 5 years of diagnosis (4). Ninety-eight cases of PAP were identified in the ar-
Therapeutic lung lavage originated in 1960, chives of the Departments of Radiologic Pathology
when Dr Ramirez-Rivera performed “segmental and Pulmonary and Mediastinal Pathology at the
flooding” of the lung in PAP patients, inciting AFIP (Table). Some cases may have been pub-
copious “white viscid” sputum production that lished previously, given the secondary consulta-
led to significant respiratory functional improve- tion nature of practice at the AFIP. Clinical infor-
ment; Ramirez-Rivera initiated WLL for PAP in mation was not always available, but many cases
1964 (9). The mortality rate in PAP approached included records of clinical presentation, surgery
30% prior to the broad application of WLL, but reports, pathology reports, or hospital discharge
over the past 3 decades, the 5-year survival rate summaries. Chest radiographs were available in
of patients receiving WLL has been 95% (3). 89 patients and CT scans in 28 patients. Imaging
The Cleveland Clinic reports equal success with studies were reviewed retrospectively by three tho-
unilateral WLL or bilateral WLL performed in a racic radiologists (A.A.F., J.R.G., R.D.P.). Selected
single session. Potential postprocedural complica- gross specimen photographs and hematoxylin-eo-
tions include pneumonia, sepsis, adult respira- sin (H-E)–stained tissue sections were reviewed by
tory distress syndrome, and pneumothorax (3). a pulmonary pathologist (T.J.F.) with two thoracic
The mean symptom-free interval after WLL is 15 radiologists (A.A.F., J.R.G.).
months, and repeat treatments are often neces- Patients ranged in age from 8 months to 64
sary (3). After undergoing two sequential WLLs, years (mean age, 38 years). The ratio of male to
more than 60% of patients regain normal “exer- female patients was greater than 2:1. Data on
tional capacity” (3). Recent investigation suggests clinical presentation were available in 72 of 98
that BAL fluid levels of anti–GM-CSF antibod- patients. The most common presenting symp-
ies may prove helpful in predicting the need for toms were dyspnea (59% of cases) and cough
repeated WLL, but the utility of assessing serum (54%). The mean period of clinical onset was
or BAL levels of anti–GM-CSF antibodies for 4 months (range, 3 days–10 years). Less com-
monitoring disease activity or treatment response mon signs and symptoms included fever (13%
remains uncertain (5). of cases), chest pain (11%), fatigue (10%), he-
Efforts since 1994 to address the underlying moptysis (6%), cyanosis and clubbing (4%), and
pathophysiology of idiopathic PAP have met with respiratory distress requiring intubation (1%).
moderate success (6,33). To combat GM-CSF Twenty-one patients had a documented history
autoantibodies, exogenous GM-CSF has been of tobacco use, but we believe this is a significant
administered as an aerosol or subcutaneously to underestimation given the fact that in many of
several PAP patients, with an overall response rate the earlier AFIP cases, the patients were male sol-
of approximately 50% (3,4,9). Unfortunately, diers. Fourteen patients had some form of docu-
because of differences in underlying pathogenesis mented inhalational exposure to materials includ-
and genetic defects, patients with congenital PAP ing beryllium, cement dust, wood dust, drywall,
do not respond to GM-CSF therapy (3). masonry and bricks, embalming fluid, agricul-
Double lung transplantation may be performed tural materials, and metal dust. There were 11
in congenital PAP, when a patient fails to im- cases of complicating pulmonary infection, two
prove with WLL, or when PAP (rarely) progresses of which were specifically identified as nocardial
pneumonia and two as cryptococcal pneumonia.
Hematologic malignancy (myeloid leukemia) was
documented in two patients.


often perihilar in distribution (64% of cases) and
AFIP Case Review of 98 Cases of PAP
much less commonly diffuse (22%) or peripheral
No. of (14%). The midlung zones were most severely
Features Cases* affected in 44% of cases, the lower lung zones in
Patients (n = 98)
27%, the entire lung in 25%, and the upper lung
Male 67 (68) zones in 5%. Chest radiographs showed regional
Female 31 (32) sparing in 84% of cases. With some overlap in
Symptoms (n = 72) findings, there were patterns of costophrenic
Dyspnea 43 (59) angle sparing in 73% of cases, apical sparing in
Cough 39 (54) 73%, and peripheral sparing in 47%.
Fever 9 (13) Although the preponderance (75%) of CT
Chest pain 8 (11) cases demonstrated the crazy-paving pattern,
Fatigue 9 (10)
25% alternatively showed ground-glass opacity
Hemoptysis 8 (6)
Cyanosis and clubbing 7 (4) without evidence of prominent septal lines; ad-
Respiratory distress requiring intubation 1 (1) ditional focal areas of consolidation were present
Radiographic findings (n = 89) in 46% of cases. CT opacity was always bilat-
Disease distribution eral and demonstrated the following spectrum
Perihilar 57 (64) of distribution patterns: diffuse (71% of cases),
Peripheral 12 (14) chiefly central (14%), multifocal-patchy (11%),
Diffuse 20 (22) and chiefly peripheral (4%). Disease was distrib-
Patterns of sparing uted most often throughout all lung zones (71%
Costophrenic angle 65 (73)
of cases), followed by an equal number of cases
Apical 65 (73)
Peripheral 42 (47) in which the disease predominantly affected the
CT findings (n = 28) upper (14%) or lower (14%) lung zones. Overall
Disease distribution extent of parenchymal opacification was divided
Diffuse 20 (71) into four categories: 75%–100% of the lungs
Central 4 (14) (57% of cases), 50%–75% (21%), 25%–50%
Peripheral 1 (4) (11%), and 0%–25% (11%). Three patterns of
Multifocal 3 (11) sparing were noted, with some overlap in find-
Patterns of sparing
ings: geographic-lobular (54% of cases); costo-
Costophrenic angle 14 (50)
Subpleural 9 (32)
phrenic angle, including the supradiaphragmatic
Geographic-lobular 15 (54) area (50%); and subpleural (32%). The airways
Disease extent† demonstrated irregularity in 39% of cases. Fis-
0%–25% 3 (11) sural irregularity or distortion was evident in
25%–50% 3 (11) 29% of cases. Two CT scans demonstrated lobar
50%–75% 6 (21) atelectasis. Pleural effusion and lymphadenopathy
75%–100% 15 (57) were absent at all CT studies.
Airway irregularity 17 (39)
Fissural distortion 20 (29)
Radiologic-Pathologic
*Numbers in parentheses indicate percentages. Correlation at the AFIP
†Percentage of lungs. Although the disease was first named and is
generally still known as “pulmonary alveolar
proteinosis,” the term lipoproteinosis is often used
Several patterns of radiographic opacity were and better describes the chemical composition of
appreciated at posteroanterior chest radiography. the material filling alveoli (2). Evidence of lipid
The most common pattern was reticulonodular content is present grossly as well as microscopi-
opacity (26% of cases), followed by combined cally. At gross examination, portions of lung pa-
reticulonodular opacity and consolidation (25%), renchyma involved by PAP are firm with yellow
consolidation only (25%), ground-glass opac- cut surfaces that protrude above the level of the
ity only (17%), and combined ground-glass and adjacent uninvolved lung. Tissue firmness results
reticulonodular opacity (8%). Disease extent was from filling of alveolar spaces, whereas the yellow
bilateral in 99% of cases and unilateral in 1%. color reflects the presence of lipid (Fig 9).
The majority of cases (56%) demonstrated bilat-
eral symmetric opacities, whereas 44% appeared
asymmetric. Radiographic opacities were most


Figure 9. Photograph of a gross specimen
shows areas involved by PAP with yellow cut
surfaces that protrude above the adjacent un-
involved lung.

Figure 10. Histopathologic findings of PAP. (a) Medium-power photomicrograph (original magnification, ×200;
H-E stain) of the lung shows intraalveolar deposits of lipoproteinaceous material circumscribed by normal alveolar
walls (arrowhead). (b) On a different medium-power photomicrograph (original magnification, ×200; H-E stain),
the alveolar walls (*) appear thickened due to infiltrates of chronic inflammatory cells and type 2 pneumocyte hy-
perplasia lining the walls. The thick walls enclose alveolar spaces filled with finely granular eosinophilic deposits in
which there are acicular (needle-shaped) clefts of dissolved cholesterol; eosinophilic globules; and bluish, degenerat-
ing cell remnants. (c) Medium-power photomicrograph (original magnification, ×200; periodic acid–Schiff stain)
demonstrates the weak positivity and granularity of the intraalveolar deposits with this stain. (d) Low-power photo-
micrograph (original magnification, ×40; H-E stain) shows how, in PAP, the interlobular septa (ILS) are remarkably
abnormal, expanded by edema and massively dilated lymphatic channels (*).


Figure 11. (a) CT scan (lung window) obtained in a 47-year-old woman with PAP shows a crazy-paving pattern
with notable lobular and geographic sparing. (b) Low-power photomicrograph (original magnification, ×100; H-E
stain) shows a mildly edematous ILS (arrowhead) forming a barrier between secondary lobules, thereby limiting the
extension of intraalveolar material. (c) Low-power photomicrograph (original magnification, ×10; H-E stain) shows
the lung parenchyma, which has a vaguely nodular appearance owing to the limitation imposed by the ILS. (d) CT
scan (lung window) obtained in a 30-year-old man with PAP demonstrates bilateral, multifocal punctate nodules
(arrowheads) within patchy areas of ground-glass opacity.

At microscopic examination, PAP is character- of alveolar walls and intraalveolar substance. Prom-
Teaching
ized by intraalveolar accumulations of lipoprotein- inent septal lines at CT correspond to remarkably
Point
aceous material circumscribed by normal or thick- abnormal ILS that are expanded by edema and
ened alveolar walls (Fig 10a). The accumulations massively dilated lymphatic channels (Fig 10d).
are finely granular eosinophilic deposits containing CT often reveals geographic or lobular sparing
acicular clefts of dissolved cholesterol, eosino- of the lung, with affected areas that are sharply
philic globules, foamy macrophages, and ghost- demarcated from and interposed with normal-
like cell remnants (Fig 10b). Periodic acid–Schiff appearing lung (Fig 11a). Involved lung is sharply
stain highlights the granularity of the deposits, demarcated from uninvolved lung by the physical
which are weakly positive with this stain (Fig 10c). barrier of the ILS, which limits the extension of
Although the interstitium of the lung is most often intraalveolar material between secondary lobules
normal, alveolar walls can be quite abnormal, (Fig 11b, 11c). Discrete nodules are also occa-
thickened by type 2 pneumocyte hyperplasia and sionally evident at CT (Fig 11d), and at micro-
variable combinations of chronic inflammatory scopic examination, PAP may indeed appear as
cells and fibrosis (Fig 10a, 10b). The most com- well-circumscribed nodular areas (Fig 11c).
mon CT feature of PAP is widespread ground-
glass opacity and smoothly thickened ILS, the
so-called crazy-paving pattern. The ground-glass
opacity appears to represent the combined density


Figure 12. (a, b) PAP in a 34-year-old man with chronic progressive dyspnea. (a) CT scan (lung window) ob-
tained in the early phase of PAP shows extensive ground-glass opacity, scattered septal lines, and patchy consolidation
in the upper lobes. (b) CT scan (lung window) obtained 1 year later reveals substantial clearing of the crazy-paving
pattern and dependent consolidation. The upper lobe airways now appear distorted and ectatic (arrows), findings that
are compatible with intervening fibrosis. (c) Coronal reformatted image (lung window) obtained in a 42-year-old
woman with PAP shows bilateral lower lobe ground-glass opacity with associated mild bronchiectatic changes. Note
the relative paucity of thickened septal lines. (d, e) Medium-power (original magnification, ×200; H-E stain) (d) and
low-power (original magnification, ×100; H-E stain) (e) photomicrographs obtained in two other patients with PAP
show fibrosis of the alveolar walls (* in d) and ILS (* in e), findings that correlate with the presence of traction bron-
chiectasis at CT and that are seen in some cases of PAP.


Figure 13. PAP in a 50-year-old man. (a, b) Coronal
(a) and sagittal (b) reformatted images (lung window)
show irregular thickening and distortion of the lobar fis-
sures, accompanied by a patchy distribution of crazy-pav-
ing. (c) Low-power photomicrograph (original magnifica-
tion, ×10; H-E stain) shows how fibrotic ILS (*) may even
appear to tug on the pleural surface, producing a dimpled
or puckered surface contour.

(Fig 13). These histopathologic findings raise the
possibility that underlying interstitial fibrosis may
help explain the CT findings of airway traction,
pleural distortion, and increased lung opacity that
are occasionally evident in PAP.
Although the pathologic differential diagnosis
of PAP includes any disorder with eosinophilic
Unusual cases of PAP demonstrate CT findings intraalveolar deposits, pulmonary edema and
of mild traction bronchiectasis and focal fissural pneumocystis pneumonia are the most common
distortion (Fig 12a, 12b). In this setting, the crazy- considerations. In contrast to PAP, edema fluid
paving pattern is often absent or less distinct, and lacks granularity, acicular clefts, eosinophilic
there is an increase in the overall apparent density
of the lung (Fig 12c). Light microscopy reveals
evidence of fibrosis in the alveolar walls (Fig 12d)
and ILS (Fig 12e). Fibrotic ILS may even appear
to “tug on” or focally contract the pleural surface


Figure 14. Medium-power photomicrographs (original magnification, ×200; H-E stain) demonstrate the homoge-
neous quality of edema fluid (a) and the foamy or honeycomb appearance of pneumocystis pneumonia exudates (b).

Figure 15. (a) Photograph shows
a glass cylinder containing opales-
cent therapeutic BAL effluent. Scale
is in milliliters. (b) High-power pho-
tomicrograph (original magnifica-
tion, ×400; H-E stain) demonstrates
the granular quality of BAL effluent.
Granularity is characteristic of but
not specific for PAP. Chest CT scans
with features characteristic of PAP
provide support for the cytologic di-
agnosis; thus, correlation with imag-
ing studies in this setting is prudent.

globules, and foamy macrophages (Fig 14a). Pneu- Definitive diagnosis of PAP is typically made
mocystis gives rise to foamy or “honeycomb” exu- at transbronchial or surgical lung biopsy, but
dates, which are readily distinguished from PAP cytologic specimens from sputum or BAL fluid
by the presence of characteristic organisms noted can also be diagnostic (12). Cytologic prepara-
with a Gomori methenamine silver stain (Fig 14b). tions contain the characteristic finely granular
Exclusion of micro-organisms is essential when proteinaceous material with rare background
exudates are present, and other stains such as macrophages or inflammatory cells; however,
Ziehl-Neelsen stain for mycobacteria may be these findings are not specific (Fig 15). As with
required in addition to Gomori methenamine biopsy material, exclusion of morphologically
silver stain. similar entities is essential.

Discussion
At chest radiography, PAP typically manifests with
bilateral, symmetric central opacities. In our re-


Figure 16. PAP in a 46-year-old man with
a 3-month history of dyspnea. CT scan (lung
window) obtained at the level of the right
upper lobe bronchus shows a diffuse distribu-
tion of ground-glass-opacity nodules, with fo-
cal geographic and subfissural sparing.

Figure 17. (a) PAP in a 43-year-old woman. CT scan (lung window) shows a crazy-paving pattern with notable
subpleural sparing, particularly in the lateral lung zones. (b) PAP in a 50-year-old man. CT scan (lung window)
shows geographic and well-circumscribed nonuniform areas of subpleural sparing located predominantly in the pos-
terior lungs and costophrenic angles.

view, the opacities are most often reticulonodular, specific CT feature of PAP is diffuse or multifocal
either solely or combined with consolidation. Our crazy-paving; interestingly, however, 25% of AFIP
review further demonstrates the broad spectrum of cases demonstrate only ground-glass opacity (Fig
radiographic appearances of PAP (Fig 1), includ- 16). Furthermore, our review illustrates many pat-
ing a significant proportion (44%) of cases with terns of parenchymal sparing, including geographic,
asymmetry (Fig 2). Early AFIP cases with evanes- costophrenic angle, supradiaphragmatic, subpleural,
cent opacities evolving over months or years may and perifissural sparing (Figs 6, 16, 17). Our small
reflect the natural course of disease prior to the sample of postlavage CT scans helps confirm prior
era of therapeutic lung lavage (Fig 3). Dense focal descriptions of residual septal lines with diminished
consolidation, particularly with cavitation, suggests ground-glass opacity (Fig 7). Finally, it is important
a complicating pneumonia (Fig 4). to note that a large proportion of PAP patients are
At CT, there is often remarkably widespread smokers, and indeed, we found that PAP may be
lung involvement in PAP. During our review, we superimposed on emphysema; an underlying lung
noted a surprising discrepancy between the degree carcinoma may even be present (Fig 18).
of opacification at chest radiography and the more
extensive disease at CT (although our observations
are not quantified). The predominant but non-


The sharply marginated zones of disease ad-
jacent to normal lung correspond with zones of
affected alveoli, filled with proteinaceous material
and limited by adjacent ILS. Our radiologic-
pathologic observations further reveal that promi-
nent septal lines in PAP correlate with remark-
Teaching
Point able ILS expansion due to edema and dilatation
of the pulmonary lymphatic system, a strong sign
of disturbed pulmonary fluid homeostasis. The
presence of such lymphatic engorgement raises
several questions. Is there an underlying abnor-
mality in PAP, either primary or secondary, that
leads to capillary injury and consequent leakage
of fluid into the interstitium? Does the intraalveo-
lar substance itself present a significant challenge
Figure 18. PAP in a 62-year-old male smoker. CT
to the lymphatic system as it strives to maintain
scan (lung window) shows bilateral widespread areas of
pulmonary homeostasis by removing fluid and ground-glass opacity, scattered septal lines, and paren-
macromolecules? Does the pathophysiology of chymal emphysema. Note the spiculated density in the
PAP affect the functional capacity of the lym- left upper lobe (arrowhead), a finding that represents a
phatic vessels by a mechanism of direct injury? lung cancer.
We found a surprising number of AFIP cases
with airway irregularity (almost 40%) and fissural
distortion (almost 30%). When CT depicts these nary homeostasis. As a complement to these ad-
abnormalities, often accompanied by increased vances, CT has shown objective correlation with
lung opacity, underlying interstitial fibrosis is evi- serologic, BAL, and functional markers of disease
dent at microscopic examination. It is interesting severity; thus, pulmonary imaging holds promise
to ponder the possible sequence of events in PAP for future disease assessment and surveillance.
disease progression: Do active inflammation and
edema in the early phase of PAP act as mediators, Acknowledgments: The authors express their deep
driving (at least in some patients) the disease pro- appreciation to the radiology residents—past, present,
and future—who provide case contributions to the
cess toward fibrosis? Department of Radiologic Pathology at the AFIP. We
At the 50th anniversary of the original descrip- extend sincere thanks to Tracy V. Faulkner, PharmD, for
tion of PAP, we stand on the threshold of active her skilled persistence in acquiring detailed patient infor-
research and discovery concerning this disease mation; and to E. James Britt, MD, at the University of
entity. The early years led us to appreciate three Maryland School of Medicine for his keen clinical in-
sights. We also thank Kim Jones, administrative assistant
distinct classes of PAP and to develop therapeutic in the Department of Pulmonary and Mediastinal Path-
measures such as WLL. More recently, exciting ology, as well as Janice Danqing Liu, Anika Torruella,
advances in animal model and human research and Robin E. Whitt in the Department of Radiologic
have provided new clues to the mechanisms of Pathology for their gracious research assistance.
pathogenesis in PAP. As Dr Ioachimescu at the
Cleveland Clinic asserts, “PAP may be the first References
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This article meets the criteria for 1.0 credit hour in category 1 of the AMA Physician’s Recognition Award. To obtain
credit, see accompanying test at http://www.rsna.org/education/rg_cme.html.

RG ■ Volume 28 • Number 3 • May-June 2008 Frazier et al

Pulmonary Alveolar Proteinosis
Aletta Ann Frazier, MD, et al
RadioGraphics 2008; 28:883–899 • Published online 10.1148/rg.283075219 • Content Code:

Page 884
Three distinct subgroups of PAP are currently recognized: idiopathic, secondary, and congenital....
Secondary PAP (5%–10% of cases) is recognized in patients with industrial inhalational exposure to
materials such as silica particles, cement dust, aluminum dust, titanium dioxide, nitrogen dioxide, and
fiberglass; underlying hematologic malignancy; or immunodeficiency disorders (including cytotoxic or
immunosuppressive therapy and human immunodeficiency virus infection) (1,3).

Page 887
The CT appearance of “crazy-paving,” defined as a network of smoothly thickened reticular (septal)
lines superimposed on areas of ground-glass opacity, was first described in a group of six patients with
PAP (Fig 5) (16,24,25). Areas of crazy-paving in PAP are typically widespread and bilateral, often with
sharply marginated areas of geographic or lobular sparing (Fig 6) (13,16,22).

Page 888
Although the CT finding of crazy-paving is highly characteristic of PAP, this pattern is also seen in several
infectious, hemorrhagic, neoplastic, inhalational, and idiopathic conditions as well as in straightforward
hydrostatic pulmonary edema. Therefore, the radiologic differential diagnosis of crazy-paving is broad and
includes left heart failure, pneumonia (especially pneumocystis pneumonia), alveolar hemorrhage, bron-
choalveolar carcinoma, lymphangitic carcinomatosis, diffuse alveolar damage (adult respiratory distress
syndrome), radiation- or drug-induced pneumonitis, hypersensitivity pneumonitis, and pulmonary veno-
occlusive disease (Fig 8) (26–32).

Page 893
At microscopic examination, PAP is characterized by intraalveolar accumulations of lipoproteinaceous ma-
terial circumscribed by normal or thickened alveolar walls (Fig 10a). The accumulations are finely granular
eosinophilic deposits containing acicular clefts of dissolved cholesterol, eosinophilic globules, foamy mac-
rophages, and ghostlike cell remnants (Fig 10b).

Page 898
Prominent septal lines in PAP correlate with remarkable ILS expansion due to edema and dilatation of
the pulmonary lymphatic system, a strong sign of disturbed pulmonary fluid homeostasis.

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