Ebook High-Resolution CT of the lung (7/E): Part 2

12

Sarcoidosis
I M P O R T A N T

T O P I C S

PATHOLOGIC FINDINGS  313
RADIOGRAPHIC FINDINGS  313
HIGH-RESOLUTION COMPUTED TOMOGRAPHY
FINDINGS 313

ASSOCIATED CONDITIONS AND SARCOID-LIKE
REACTIONS 337
DIFFERENTIAL DIAGNOSIS  338

UTILITY OF HIGH-RESOLUTION COMPUTED
TOMOGRAPHY 333

Abbreviations Used in This Chapter
CWP
DLCO
EBUS
18
FDG-PET
FEV1
FVC
67
GA
HAART
HLA

IFN
IL
IPF
MRI
PFT
PH
PLC
SLR
TBNA
TLC
WTC

coal worker’s pneumoconiosis
carbon monoxide diffusing capacity
endobronchial ultrasound
18-fluoro-deoxy-glucose positron emission tomography
forced expiratory volume in 1 second
forced vital capacity
gallium-67-citrate
highly active antiretroviral therapy
human leukocyte antigen
interferon
interleukin
idiopathic pulmonary fibrosis
magnetic resonance imaging
pulmonary function test
pulmonary hypertension
pulmonary lymphangitic carcinomatosis
sarcoid-like reaction
transbronchial needle aspiration

total lung capacity
World Trade Center

First described in 1877 by Jonathan Hutchinson, sarcoidosis is a multisystem granulomatous disease of unknown
cause, characterized by the presence of noncaseating
granulomas (1–4). These may resolve spontaneously or
progress to fibrosis (5). Sarcoidosis may involve almost
any organ, but most morbidity and mortality is the result of pulmonary disease (6). Pulmonary manifestations
are present in 90% of patients. Although 30% to 60% of
patients with pulmonary sarcoidosis are asymptomatic,
312

with their disease identified incidentally on routine chest
radiographs, 20% to 25% of patients will ultimately develop permanent functional impairment (3,4,7,8).
Extrathoracic manifestations of sarcoidosis are present in 25% to 50% of cases and are almost always
associated with intrathoracic disease. Extrathoracic
­abnormalities commonly include involvement of the liver,
spleen, peripheral lymph nodes, and skin, with common
cutaneous manifestations, including erythema nodosum and lupus pernio (8). Erythema nodosum occurs in
approximately 10% of cases and is typically self-limited,
resolving in less than a month. The triad of intrathoracic
lymphadenopathy, erythema nodosum, and arthritis,
­
typically involving the ankles, is referred to as Löfgren
syndrome and is considered pathognomonic of acute sarcoidosis, obviating ­biopsy (9). Lupus pernio refers to sarcoidosis involving the nose, lips, and ears, and is far more
aggressive, frequently associated with erosion of underlying cartilage and bone (3). Cutaneous disease more often
occurs in women than in men.
Sarcoidosis is a worldwide disease, with the highest
rates reported among northern European and AfricanAmerican individuals (3,7,10). Approximately 70% of
patients are between 25 and 45 years of age, with a second

peak reported in Europe and Japan, especially in women
older than 50 years (11). To date, sarcoidosis has been reported to occur in association with a number of airborne
antigens, including organic dusts, emissions from woodburning stoves, and tree pollen, as well as inorganic dusts,
including silica (3). Also, clusters of cases of sarcoidosis
have been reported among health care workers, metal
workers, automobile manufacturers, firefighters, and others (8,12,13). Although long suspected of having an association with antigens related to infectious organisms,


C hapter 12 Sarcoidosis

in particular those associated with Mycobacterium tuberculosis and Propionibacterium acnes, a definitive causation has never been established (14).
The incidence of sarcoidosis varies widely among different populations, with African Americans being especially susceptible, at greater risk for extensive disease, and
having higher rates of cutaneous, ophthalmologic, hepatic,
and lymphatic involvement (3,7,10). Worldwide,it has
been estimated that sarcoidosis has a prevalence of
4.7 to 64 in 100,000 and an incidence of 1  to 35.5 in
100,000, per year (11), variations likely reflecting interactions between genetic, occupational, and environmental
factors (3,7,10). Similarly, although Löfgren syndrome
occurs in approximately 30% of Caucasians with sarcoidosis, it is diagnosed in only 10% of Asians, and rarely
in African Americans (7). Genetic susceptibility also plays
a clear role in the development of disease, with evidence
most clearly implicating class II human leukocyte antigen
(HLA) markers, where some HLA patterns are associated
with a good prognosis and others portend more severe
disease (3,15).

PATHOLOGIC FINDINGS
Pathologically, the most characteristic feature of sarcoidosis is the presence of noncaseating granulomas in a lymphatic or perilymphatic distribution (see Chapter 4) (Figs.
4-6 and 12-1) (16). These granulomas represent a chronic
immunologic response resulting from a cell-mediated response to specific antigenic stimulation, with activated

macrophages and T lymphocytes releasing a variety of
cytokines, with interferon gamma (IFN-γ), interleukin
(IL)-12, and IL-18 playing a critical role (3,7,8). The granulomas are well formed, with histiocytes centrally, surrounded by a collarette of lymphocytes and mononuclear
cells (17,18). The lung parenchyma between granulomas
is usually normal in patients who have sarcoidosis, and
although there may be a mononuclear infiltrate in the alveolar walls immediately adjacent to a granuloma, there is
usually no discernible evidence of a diffuse alveolitis (19).
Sarcoid granulomas, which are the hallmarks of this
disease, are distributed primarily along the lymphatics
in the peribronchovascular interstitial space (extending
from the parahilar regions into the centers of pulmonary
lobules), and, to a lesser extent, in the subpleural interstitial space and interlobular septa (Figs. 4-6 and 12-1). This
characteristic perilymphatic distribution of sarcoid granulomas is difficult to recognize on plain radiographs, but
is clearly seen on high-resolution computed tomography
(HRCT) and in macroscopic illustrations of the pathology
of this disease (Fig. 12-1) (20–23). The perilymphatic distribution of granulomas is one of the features of sarcoidosis that is most helpful in making a pathologic diagnosis,
and is also responsible for the high rate of success of diagnosis by bronchial and transbronchial biopsy (5,24).
Although sarcoid granulomas are microscopic, they often
coalesce to form macroscopic nodules several millimeters
in diameter.

313

RADIOGRAPHIC FINDINGS
Approximately 60% to 70% of patients who have sarcoidosis have abnormal chest radiographic findings
(5,6,25–29). These have been traditionally classified into
four stages initially proposed by Scadding: (a) stage 1,
defined as isolated intrathoracic adenopathy; (b) stage 2,
defined as intrathoracic adenopathy associated with pulmonary parenchymal disease; (c) stage 3, defined as predominant or isolated parenchymal disease; and (d) stage
4, defined as lung fibrosis (30). Although these stages do

not correlate with disease duration or pulmonary functional abnormalities (3), initial radiographic findings
have been shown to have a prognostic value. Spontaneous resolution occurs in up to 90% of patients with stage
1 disease, whereas higher stages are associated with a
worsening prognosis. Resolution occurs in up to 70% of
patients with stage 2 disease and only 20% of those with
stage 3 disease (7,30–32). Overall, classic stage 1 findings
of paratracheal and bilateral hilar adenopathy are identified in approximately 85% of patients presenting with
abnormal chest radiographs (33). Pulmonary parenchymal disease is seen in 20%.
An alternate method for scoring sarcoidosis, based
on a modification of the International Labor Organization radiographic scoring system for pneumoconiosis,
has also been proposed (34). With this approach, abnormalities are characterized as belonging to four subtypes,
defined by the following letters—R for reticulonodular
opacities, M for lung masses, C for confluent opacities,
and F for fibrosis. Each lettered abnormality is scored
separately in each of four segments in each lung (a ­total
of eight segments), according to extent and severity.
The advantage of this system is improved interobserver
variability when compared with the standard Scadding
grading system for both initial evaluation and follow-up
examinations (35,36).
Nonspecific or atypical radiographic findings have
been described in 25% to 40% of cases, most often in
patients older than 50 years (26). In 5% to 10% of cases,
the chest radiograph is normal. Rarely, focal nodules or
masses are associated with air bronchograms (so-called
“alveolar sarcoidosis”). Cystic disease typically occurs
only in association with advanced fibrosis and is usually
due to cystic bronchiectasis or large bullae. True cavitary
nodules are exceedingly rare, usually as a manifestation
of necrotizing sarcoidosis (37). Pleural involvement, manifested as either small, spontaneously resolving effusions

or focal pleural thickening, has been reported to occur in
less than 5% of cases and does not appear to have any
functional significance (7,38–40).

HIGH-RESOLUTION COMPUTED
TOMOGRAPHY FINDINGS
HRCT findings in sarcoidosis have been described in
detail (41–46). HRCT is far superior to plain chest radiographs in detecting and characterizing parenchymal


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s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

A

B

D

C
FIGU RE 12-1   Perilymphatic nodules in sarcoidosis. A and B: Gross pathologic specimen cut in the transverse plane, at two levels
through the right upper lobe in a 55-year-old woman who has sarcoidosis. B: Noncaseating sarcoid granulomas are located within the
peribronchovascular interstitium (long arrows), subpleural regions (short arrows), and, to a lesser extent, in relation to interlobular
septa containing veins (curved arrows). (From Müller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of
25 patients. AJR Am J Roentgenol 1989;152:1179; Müller NL, Miller RR. Computed tomography of chronic diffuse infiltrative lung
disease: part 2. Am Rev Respir Dis 1990;142:1440, with permission.) Gross (C) and microscopic (D) pathologic specimens in a different
patient than illustrated in A and B also show a characteristic perilymphatic distribution of noncaseating granulomas. In the gross specimen,
clusters of granulomas are visible in a subpleural location (black arrow) and in relation to centrilobular bronchioles and arteries
(blue arrows). D: The microscopic image shows clustered noncaseating granulomas in relation to bronchioles and arteries.

disease. Typical findings include perilymphatic nodules;
large coalescent nodules or masses, rarely cavitary; focal ground-glass opacity; mosaic perfusion and air trapping on expiratory images; and findings indicative of

parenchymal scarring, including bronchial distortion and
traction bronchiectasis, coarse linear and reticular opacities with or without architectural distortion, and honeycombing or cystic abnormalities (47).


315

C hapter 12 Sarcoidosis

A

B
FIGU RE 12-2   Peribronchovascular nodules. A–C: Extensive nodular
involvement of the peribronchovascular interstitium (arrows) within both
parahilar and peripheral lung is visible. Small nodules are visible at the edges of
larger masses, and extensive involvement of the pleural surfaces and fissures is
also visible.

C

Perilymphatic Nodules
The most characteristic HRCT abnormality in patients
with sarcoidosis consists of small nodules, occurring in a
perilymphatic distribution, and visible in relation to (a)
the peribronchovascular axial interstitium, that serves
to support and invest the central, parahilar vessels and
bronchi (Figs. 12-2 to 12-5), (b) the fissures (Figs. 12-2 to

12-6), (c) the costal subpleural regions (Figs. 12-2 and
12-6), (d) interlobular septa (Fig. 12-6), and (5) the centrilobular (peribronchovascular) regions (Figs. 12-3 and
12-6) (22,41–46,48) (Table 12-1). The degree to which
these structures are involved may vary considerably
among individual patients (Figs. 12-7 to 12-9). Typically,
nodules predominate in relation to the peribronchovascular interstitium, in relation to pleural surfaces such as
the fissures, and in the centrilobular regions.
Nodules visible on HRCT may appear as small as 1 or
2 mm in diameter. They characteristically have less welldefined margins than nodules seen in some other diseases,
such as silicosis, but usually appear relatively well defined. In most cases, these nodules represent coalescent
groups of microscopic granulomas (33,48,49), although

nodules visible on HRCT can also represent nodular areas
of fibrosis in patients with progressive disease (48). The
nodules may be numerous and distributed throughout
both lungs. However, in up to 50% of patients, nodularity may be scant or focal and localized to small areas in
one or both lungs (Figs. 12-6 and 12-9). The presence of
bilateral nodules with upper lobe predominance is common, but not invariable (Figs. 12-10 and 12-11).
Sarcoid granulomas frequently cause nodular thickening of the axial perihilar, peribronchovascular interstitium
as seen on HRCT, and extensive peribronchovascular
nodules are characteristic and highly suggestive of this
disease (Fig. 12-2). Subpleural nodules are also typical
of sarcoidosis, adjacent to the fissures or costal pleural
surfaces; clusters of subpleural nodules may result in a
“pseudoplaque” (22,50). Irregular or nodular interlobular septal thickening may be identified in the majority of
patients, but in most, it is not an extensive or obvious
finding (Figs. 12-6 and 12-9) (25,51). On the other hand,

A
FIGU RE 12-3   Sarcoidosis with minimal involvement of the

peribronchovascular interstitium. A: In the upper lobes, granulomas occurring in
relation to the centrilobular peribronchovascular interstitium result in the appearance
of clusters of nodules (arrows). B: At a lower level, peribronchovascular nodules are
visible in relation to larger arteries (arrows). Nodules in relation to the major fissures
are also seen.
(Continued)


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s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

B
FIGU RE 12-3   (Continued)

A

B
FIGU RE 12-6   Perilymphatic distribution of nodules with septal thickening.

One-millimeter-thick HRCT at the level of the carina (A) and middle lobe bronchus
(B) show the classic appearance of perilymphatic nodules in sarcoidosis, with
involvement of the costal pleural surfaces and fissures, peribronchovascular bundles,
centrilobular regions, and interlobular septa (arrows). Although the nodules are
diffuse, there is relative sparing of the anterior aspect of the upper lobes.

FIGU RE 12-4   HRCT with 1-mm targeted reconstruction through the right
mid-lung shows the characteristic appearance of perilymphatic nodules involving the
axial peribronchovascular interstitium. Nodules are visible along both central airways

(large arrows) and both large and small blood vessels (small arrows). Nodules
involving the major fissure are also visible.

A

in some patients, nodular interlobular septal thickening
may be a predominant feature of this disease, and, on
occasion, it may mimic the appearance of lymphangitic
carcinomatosis, especially when asymmetric or basilar in
distribution (Fig. 12-11).
Granulomas occurring in relation to the peripheral,
centrilobular peribronchovascular interstitium can be

B

FIGU RE 12-5   Sarcoidosis with minimal parenchymal involvement. A: Several clusters of granulomas are visible in the peribronchovascular and subpleural regions
(arrows). B: At a lower level, a few nodules are visible in relation to the major fissure (arrows). Hilar lymph node enlargement is visible.


C hapter 12 Sarcoidosis

317

TABLE 12-1  HRCT Findings in Early or Active
Sarcoidosis
Small, well-defined nodules occurring in perilymphatic distribution
(i.e., in relation to the peribronchovascular interstitium, pleural
surfaces and fissures, interlobular septa, and centrilobular
structures)a,b
Note: Centrilobular clusters of nodules may mimic tree-in-bud

A diffuse or random distribution of small nodules
Isolated discrete nodules
Parahilar predominance of nodules in the upper lobesa,b
Large nodules (>1 cm), masses, or areas of consolidation, often with
air bronchograms; may be associated with satellite nodules or the
galaxy signa,b
Ground-glass opacity, focal or patchy

A

A patchy distribution of abnormalities
Lymph node enlargement, usually symmetric, calcification often hazy
or eggshella
Airway wall thickening, nodularity, or narrowing
Mosaic perfusion or air trappinga
a
b

Most common findings.
Findings most helpful in differential diagnosis.

B
FIGU RE 12-9   A and B: Coronal and sagittal images reconstructed

A

C

B

D

FIGU RE 12-7   A–D: Sequential sections through the mid- and lower
lung fields, respectively, show perilymphatic nodules with a distinctly perihilar/axial
interstitial distribution.

A

from contiguous 1-mm sections obtained using a 16-detector MDCT scanner show
perilymphatic nodules primarily involving the mid-lung zones. Note that there is
evidence of nodular thickened interlobular septa (A, arrows), involvement of the
fissures, and small clusters of nodules in relation to centrilobular structures.

B

FIGURE 12-8   A and B: One-millimeter targeted reconstructions through the

FIGURE 12-10   Unusual distribution in sarcoidosis. HRCT with a 1-mm slice

left mid-lung show localized perilymphatic nodules, easily identifiable along the left major
fissure and causing nodular thickening of a subsegmental bronchial wall in the superior
segment of the left lower lobe (arrow). In cases of limited parenchymal disease, CT may
be of value by identifying optimal sites for performing transbronchial biopsies.

through the lower lobes shows evidence of markedly asymmetric or unilateral disease with
nodular interlobular septal thickening in the right lower lobe. This mimics the appearance
of lymphangitic carcinomatosis. Images through the upper lobes showed a more
characteristic appearance of symmetric adenopathy and diffuse perilymphatic nodules.

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s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

A

B

FIGU RE 12-11   Sarcoidosis with interlobular septal thickening and a basal

C

seen as centrilobular nodules or branching opacities on
HRCT (48,50,52), and clusters of nodules occurring in
relation to the branching centrilobular artery may mimic
the appearance of tree-in-bud (Fig. 12-12). The finding
of tree-in-bud is usually taken to indicate airways disease
(53,54), and in patients with sarcoidosis that show this
finding, other abnormalities indicative of a perilymphatic
(rather than centrilobular) distribution of nodules are
usually more obvious (54).
Less commonly, in patients with extensive disease, the
nodules may mimic a random pattern, typical of miliary

A

distribution. A: The upper lobes appear normal. B: In the lower lobes, nodular
thickening of the fissures is evident, and there is nodular thickening of interlobular
septa (arrows). C: These findings are also visible at the lung base.

tuberculosis (Fig. 12-13), or they may be scant and appear
as distinct, isolated, well-defined opacities without an obvious perilymphatic distribution (Fig. 12-14). In these
cases, differential diagnosis is more problematic.

Coalescent Nodules
Confluence or coalescence of granulomas may result
in large nodules or masses with ill-defined contours or
regions of dense consolidation (Figs. 12-2, 12-15, and
12-16) (42,46). Large nodules measuring from 1 to 4 cm

B

FIGU RE 12-12   Centrilobular nodules in sarcoidosis. HRCT at two levels (A and B) shows clusters of nodules in the centrilobular regions (arrows). Some clusters
of nodules occurring in relation to centrilobular arteries (A, arrows) mimic the appearance of tree-in-bud.


C hapter 12 Sarcoidosis

319

A
B

FIGU RE 12-13   Sarcoidosis with diffuse lung involvement. A: In

C
in diameter were seen in 15% to 25% of patients in
several studies (22,41,49,55). Grenier et al. (56) reported the presence of confluent nodules larger than
1  cm in 53% of patients who had sarcoidosis. In our
experience, these predominate in the upper lobes and

A

the upper lobes, granulomas predominate in relation to interlobular septa
(arrows). B: At a lower level, scattered nodules are visible diffusely.
C: Near the lung bases, nodules are less profuse.

the peribronchovascular regions. Air bronchograms may
be seen within these nodules and appearance, formerly
termed “alveolar sarcoid” (Fig. 12-15). Large nodules
can cavitate, but this is uncommon; Grenier et al. (56)
reported this finding in only 3% of cases. Coalescence

B

FIGU RE 12-14   Scattered nodules in sarcoidosis. A: CT through the lower lobes in a patient with biopsy-proven sarcoid and diffuse mediastinal and hilar

adenopathy shows several well-defined nodules in the lung periphery (arrows). B: HRCT with a 1-mm section through the mid-thorax shows a focal irregular spiculated
nodule in the periphery of the right upper lobe. Although the finding of isolated well-defined nodules is unusual, it is not inconsistent with the diagnosis of sarcoidosis in the
appropriate clinical setting.


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s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

A

B

FIGU RE 12-15   Sarcoidosis with a conglomerate mass of granulomas.

C
of many small nodules may also result in the so-called
sarcoid galaxy sign, an appearance characterized by
a central mass surrounded by numerous small satellite
nodules (Figs. 12-3, 12-15, and 12-16) (57). The presence of a mass surrounded by satellite nodules (i.e., the
galaxy sign) may be seen in a number of granulomatous
diseases, including ­tuberculosis (58).
Less often, a large nodule may present as a solid lesion surrounded by a rim of ground-glass opacity (i.e., the
CT halo sign) (59,60). In sarcoidosis, this appearance has
been shown to result from clusters of granulomas, with aggregates of macrophages in adjacent alveolar spaces (61).

A

A: A large mass is visible in the left upper lobe, with smaller nodules seen at its
periphery and in other lung regions. B: At a lower level, peribronchovascular
involvement typical of sarcoidosis is more easily identified (small arrows), as is
involvement of the major fissure (large arrow). C: At a level below the carina,
fewer abnormalities are visible. As in this patient, sarcoidosis often has upper lobe
predominance.

Initially thought to be characteristic of cryptogenic organizing pneumonia, the reversed halo sign (atoll sign) may
also be seen in sarcoidosis and other diseases, including
fungal infections, TB, noninfectious etiologies, including
cryptogenic organizing pneumonia, pulmonary embolism,
and lepidic predominant adenocarcinoma. In a recent
study comparing 41 patients with infectious etiologies to
38 with noninfectious causes of a reversed halo sign, the
presence of either nodular walls or nodules inside the halo

proved highly suggestive of a granulomatous etiology, in
particular sarcoidosis or granulomatous infections. Of
five patients with proven sarcoidosis, four proved to have

B

FIGU RE 12-16   Coalescent nodules and scarring in sarcoidosis. A and B: Target reconstructed images through the mid- and lower lung fields, respectively show
evidence of coalescent perilymphatic nodules with a distinctly peribronchial distribution. Note in addition that within areas of dense coalescence, there is evidence of air
bronchograms indicative of traction bronchiectasis and fibrosis.


C hapter 12 Sarcoidosis

A

321

B

FIGU RE 12-17   A–C: Sarcoidosis with patchy lung involvement by

C
multiple lesions, and all had evidence of other lesions, including perilymphatic nodules (62).

Ground-Glass Opacity
Patients with sarcoidosis may show focal or patchy areas of ground-glass opacity on HRCT, with reported
frequencies ranging from 18% to 83% (47,55,63–65)
(Figs. 12-17 to 12-20); this may be superimposed on a
background of small interstitial nodules (Figs. 12-17 and
12-19) or fibrosis. Pathologic specimens, obtained in a

small number of patients with sarcoidosis, indicate that
areas of ground-glass opacity are usually due to the presence of extensive interstitial sarcoid granulomas rather
than alveolitis (22,49,66). In distinction to other causes
of ground-glass opacity, in patients with sarcoidosis, this
finding is usually upper lobe in distribution, overlaid on a
background of small perilymphatic nodules, and findings
of symmetric mediastinal and hilar adenopathy (67).

small nodules and ground-glass opacity. Large foci of confluent granulomas may
mimic consolidation. In less abnormal regions (B, arrows), small clusters of
granulomas and fissural nodules can be identified.

abnormalities, including erythema, edema, granularity,
plaques, nodules, and “cobblestoning.” Bronchial stenosis,
especially involving lobar and segmental bronchi, is less
common. Although reported to occur in up to 14% of patients with sarcoidosis, bronchial stenosis, with greater than
50% narrowing of the airway lumen, is rarely identified

Airway Abnormalities
Pathologically, airway involvement is common, and can occur at any level from the epiglottis to the peripheral bronchioles (33,68–72). Airway involvement may be manifested
by a wide variety of findings, most frequently mucosal

FIGU RE 12-18   Sarcoidosis appearing as ground-glass opacity. An ill-defined
region of ground-glass opacity is visible in the right upper lobe within which tiny
“micronodular” densities can be identified. In this case ground-glass opacity results
from clustering of innumerable tiny nodules. Biopsy proved sarcoid


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s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

FIGU RE 12-19   Sarcoidosis with ground-glass opacity and nodules. Onemillimeter section through the upper lobes shows a focal region of ground-glass
opacity associated with small nodules.

(68). More commonly encountered is airway distortion,
resulting from granulomatous lesions in and adjacent to
the airways, resulting in secondary traction bronchiectasis.
Although airway distortion has been reported to occur in
up to 47% of cases, it only rarely causes symptoms (47).
Less common still is evidence of extrinsic compression due
to enlarged mediastinal and hilar lymph nodes.

Clinical findings resulting from airway involvement are
frequent. These include hemoptysis, especially in patients
with advanced lung involvement, those with cavitary or cystic lung disease complicated by Aspergillus superinfection,
and those with extensive bronchiectasis. Also commonly
encountered are findings of airway hyper-reactivity, occurring in up to 20% of patients, although it is reported to be
independent of airway involvement, and airflow limitation
with forced expiratory volume in 1 second (FEV1)/forced
vital capacity (FVC) ratios of less than 80% occurring in as
many as 60% of patients, in any stage of the disease (72).
Bronchial abnormalities on HRCT have been reported
in as many as 65% of patients with sarcoidosis, primarily
consisting of irregular or nodular bronchial wall thickening and bronchial luminal abnormalities (Figs. 12-8,
12-21, and 12-22) (70).
HRCT manifestations of bronchial or bronchiolar obstruction are uncommon but may be seen (Figs. 12-21
and 12-22) (68,73). Obstruction of lobar, lobular, or segmental bronchi resulting in collapse may occur because of
endobronchial granulomas, or, less commonly, enlarged
peribronchial lymph nodes.

Although HRCT is highly sensitive for detecting abnormal airways, in the absence of distinct endobronchial

A

B

C

D

FIGU RE 12-20   A–D: Sarcoidosis with ground-glass opacity. Hazy peribronchovascular ground-glass opacity represents sarcoidosis. Definite nodules
are not visible.


C hapter 12 Sarcoidosis

C

B

A

323

FIGU RE 12-21   Airway disease. A: HRCT with 1-mm targeted reconstruction through the carina shows a typical appearance of diffuse perilymphatic nodules.
Note the marked nodular irregularity and narrowing (A, arrow) of the right upper lobe bronchus beginning at its origin and extending to involve the anterior segmental
bronchus. Airway abnormalities may result from a variety of mechanisms, including extrinsic compression and granulomatous involvement of the bronchial wall. B:
Follow-up CT several months later, following steroid therapy, at the same level as (A) shows marked regression in the extent of nodularity throughout the lungs. In this
case, persistent narrowing of the right upper lobe bronchus indicates likely irreversible scarring. C: Bronchial involvement in a different patient with sarcoidosis. Multiple
endobronchial nodules (arrows) represent granulomas. (Courtesy of Martha Warnock, MD.)

lesions, it may be difficult to distinguish a true bronchial
wall abnormality from thickening of the peribronchovascular interstitium. In a study by Lenique et al. (70),
when HRCT showed a luminal abnormality, bronchoscopy showed mucosal thickening in 86% of patients, and
a positive transbronchial biopsy was obtained in 93%.
However, in patients believed to show bronchial wall
thickening on HRCT, only 59% had mucosal thickening on bronchoscopy. This differs little from the 43%
incidence of mucosal thickening seen at bronchoscopy
in sarcoidosis patients who had normal-appearing airways on HRCT (Fig. 12-23). It is also worth noting that

A

many of the airway abnormalities identified by CT in
patients with sarcoidosis, in themselves, are nonspecific.
Given these limitations, it has been suggested that CT
has little role in the serial follow-up of airway disease in
sarcoidosis (72).

Mosaic Perfusion and Air Trapping
Focal areas of decreased attenuation and vascularity (i.e.,
mosaic perfusion) may be seen on inspiratory HRCT in
some patients who have sarcoidosis (74–76) (Figs. ­12-24
to 12-26). Air trapping on expiratory HRCT is more

B

FIGU RE 12-22   Airway disease. A: CT shows a typical pattern of perilymphatic nodules involving the mid-lungs. Note that there is
marked narrowing of the left upper lobe anterior segmental bronchus at its origin (arrow) consistent with focal bronchostenosis. B: Corresponding
bronchoscopic image in the same patient confirming this finding (arrow). Despite appearances, this may still be reversible if identified early in the
course of disease.

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s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

A

B

FIGU RE 12-23   Airway disease. A: CT at the level of the right upper lobe bronchus shows evidence of bilateral hilar and subcarinal adenopathy.
Visualized airways appear grossly normal. B: Corresponding bronchoscopic image from within the right upper lobe bronchus shows subtle but definite
mucosal changes with evidence of nodularity along the airway surface, subsequently confirmed to be due to granulomatous involvement of the airway.
Although the finding of an airway abnormality on CT is nearly always indicative of significant airway pathology, the airway may appear normal in the
presence of disease.

A

B

FIGU RE 12-24   Sarcoidosis with ground-glass opacity, mosaic perfusion, and air trapping. A: The primary abnormality in this patient is ground-glass opacity,
although low-attenuation regions of mosaic perfusion and a few small nodules are also visible. B: An expiratory image shows areas of air trapping in the lung periphery.

A

B

FIGU RE 12-25   Sarcoidosis with mosaic perfusion and air trapping. A: Inspiratory image shows irregular peribronchovascular and pleural mass typical of
sarcoidosis. Areas showing reduction in vascular size are visible in the lung periphery, related to mosaic perfusion. B: Dynamic expiratory HRCT shows patchy air
trapping (arrows).

common, due to endoluminal or submucosal sarcoid
granulomas, or more often fibrotic obstruction of small
airways (77). Air trapping was observed in 40 of 45
(89%) patients in one study (78), and 25 of 30 (83%)
in another (79). More recently, in a report of 22 patients

with pulmonary sarcoidosis, expiratory air trapping suggestive of small airways disease could be identified in 20
(95%) cases (80). Air trapping may be the only abnormality present on HRCT; air trapping was the only abnormality seen in 10% of cases reviewed by Magkanas et al. (79)


C hapter 12 Sarcoidosis

A

325

B

FIGU RE 12-26   Sarcoidosis with air trapping. A and B: Air trapping is visible in this patient with a long-standing diagnosis of sarcoidosis. Few nodules are visible.

(Fig. 12-26). Air trapping may persist after resolution of
nodules or other findings of active disease.

TABLE 12-2  HRCT Findings in Fibrotic Sarcoidosis
Smooth or nodular peribronchovascular interstitial thickeninga,b

Parenchymal Fibrosis

Small nodules decreased in number but may persist; often appear

more irregular than with early diseasea,b

Abnormalities in patients with “severe” (stage 4) sarcoidosis correlate with the presence of lung fibrosis, and occur
in up to 50% of cases (42,45,55,65). Three broad patterns of lung fibrosis have been described (47): (a) fibrosis
primarily manifested as bronchial distortion, (b) linear
scarring, and (3) end-stage honeycombing. Each of these
patterns tends to be associated with different functional
abnormalities. Airway distortion is typically associated
with obstructive lung function, while honeycombing typically presents as restrictive lung disease. In distinction,
predominantly reticular forms of scarring are typically
manifested by only mild functional abnormalities (47).
In stage 4 sarcoidosis, patients with lung fibrosis commonly show (a) increased irregularity of the margins of
nodules or masses, (b) distortion of fissures, (c) bronchial
irregularity with traction bronchiectasis, (d) parahilar
conglomerate masses of fibrous tissue encasing vessels
and airways, and (e) coarse linear or reticular opacities
(Table 12-2) (47,73).
In patients with sarcoidosis, HRCT may be of value
in distinguishing between active inflammation and irreversible fibrosis, with areas of nodularity, consolidation, and ground-glass opacity tending to decrease over
time or following treatment (Figs. 12-21, 12-27, and
12-28). Although fibrosis need not occur with healing of
granulomatous lesions, findings of fibrosis may become
more evident over time. As fibrosis develops, irregular
reticular opacities, including irregular septal thickening, often become a predominant feature (Fig.  12-29).
Reticular opacities are frequently seen along the parahilar bronchovascular bundles (Figs. 12-30 and 12-31)
(22,41,81).
The most common early HRCT findings of fibrosis
include distortion of fissures and posterior displacement of the main and upper lobe bronchi (Figs. 12-32

Parahilar predominance of abnormalities in the upper lobesa,b

Conglomerate masses associated with traction bronchiectasis,
usually parahilar; satellite nodules absent or decreased in number
compared to patients with active diseasea,b
Irregularity of fissuresa,b
Posterior displacement of upper lobe bronchia,b
Interlobular septal thickening
Honeycombing or cystic disease, often with an upper lobe
predominanceb
Lymph node enlargement, usually symmetric, calcificationa
Airway wall thickening, nodularity, or narrowing
Mosaic perfusion or air trappinga
a
b

Most common findings.
Findings most helpful in differential diagnosis.

to 12-34); this finding indicates loss of volume in the
posterior segments of the upper lobes (42,46). Progressive fibrosis leads to central conglomeration of parahilar
bronchi and vessels associated with masses of fibrous tissue, typically most marked in the upper lobes (15). With
more extensive fibrosis, there is evidence of progressive
bronchial distortion, resulting in sharp angulation of
central airways associated with traction bronchiectasis.
This combination of conglomerate fibrotic masses and
central bronchial distortion is especially characteristic of
advanced sarcoidosis. The only other diseases that commonly result in conglomerate masses of fibrosis with or
without traction bronchiectasis are silicosis, tuberculosis,
and talcosis.
Honeycombing and/or lung cysts can be present in patients who have sarcoidosis, but are less common than
in those of other fibrotic lung diseases such as idiopathic

pulmonary fibrosis (IPF). Lung cysts vary in diameter


326

s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

A

B

FIGU RE 12-27   Sarcoidosis before and after treatment. A: Targeted reconstruction through the right mid-lung shows
peribronchovascular and subpleural abnormalities. B: Follow-up image at the same level as A following steroid therapy shows
complete resolution.

from 3 mm to 2 cm, with walls smaller than 1 mm in
thickness, and are usually subpleural or parahilar in location; these may represent areas of emphysema or cystic bronchiectasis (Figs. 12-33 and 12-35 to 12-37) (73).
Honeycombing is usually limited to patients who have
severe fibrosis and central fibrous masses with traction
bronchiectasis (48). The honeycombing seen in patients

A

who have sarcoidosis involves mainly the middle and
upper lung zones, with relative sparing of the lung bases
(82). It should be emphasized that it is rare in sarcoidosis
for honeycombing to predominate in the subpleural and
basilar lung regions, as is typically seen in patients with
usual interstitial pneumonia/IPF and fibrotic nonspecific
interstitial pneumonia (47,83).

B

FIGU RE 12-28   A and B: Sarcoidosis before and after treatment. A: Targeted reconstruction through the right midlung shows a characteristic appearance of peribronchovascular nodules in sarcoidosis. B: Follow-up image at the same level
as A following steroid therapy showing complete resolution of perilymphatic nodules.


C hapter 12 Sarcoidosis

A

327

B

FIGU RE 12-29   A and B: Pulmonary sarcoidosis and findings of pulmonary fibrosis in a 32-year-old man. HRCT at the level of the tracheal carina shows extensive
irregular or nodular septal thickening (B, arrows), irregular interfaces, and traction bronchiectasis. Posterior displacement of the upper lobe bronchi is an early sign of lung
distortion. Extensive bilateral ground-glass opacities correlated with increased 67Ga uptake, reflecting the presence of active inflammation.

Lymph Node Abnormalities
HRCT demonstrates characteristic symmetric hilar and
paratracheal lymphadenopathy in many patients, but
lymph node enlargement need not be present in patients
with extensive pulmonary abnormalities. On CT, lymph
node enlargement is often seen in other locations as well,
including the anterior mediastinum (Fig. 12-38A), internal mammary chain, posterior mediastinum, retrocrural
regions, and axilla (26); it has been suggested that the
presence of enlarged internal mammary and paracardiac
lymph nodes, while often seen in sarcoid, should raise the

possibility of lymphoma (84). Lymph node calcification is
not uncommon, and when present, is often hazy, feathery,
or eggshell-like in appearance (Fig. 12-38A), in distinction to the densely calcified lymph nodes typically seen in
tuberculosis (Fig. 12-38B).
HRCT may be useful in detecting hilar lymphadenopathy in lungs distorted by fibrosis (Fig. 12-38C). Enlarged nodes due to sarcoidosis rarely cause significant
compression of critical mediastinal structures such as the
central pulmonary arteries, the superior vena cava or the
esophagus.

Thoracic Complications of Sarcoidosis
A number of specific complications are known to occur
in patients with sarcoidosis, for which imaging may play
an important diagnostic role (48). These include infection
with mycetoma formation in pre-existing cavities, bronchostenosis and/or bronchomalacia resulting in central

A
FIGU RE 12-30   Sarcoidosis with fibrosis. Coronal HRCT section shows a
typical appearance of marked architectural distortion with traction bronchiectasis
(arrows) primarily involving the parahilar upper lobes. Note that the lung apices
are lucent despite upper lobe volume loss and bilateral hilar retraction. In this case,
perilymphatic nodules are also seen. Focal diaphragmatic retraction (arrowheads) is
another sign of upper lobe volume loss.

B

FIGU RE 12-31   A and B: Sarcoidosis with fibrosis. Noncontiguous 1-mm
HRCT through the right lower lung field shows the classic appearance of peribronchial
fibrotic masses with marked architectural distortion, traction bronchiectasis, and focal
emphysema. Note that although the distribution of these findings primarily affecting
the lower lung zones is atypical, there is evidence of perilymphatic nodules consistent

with the diagnosis of sarcoidosis.


328

s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

C
FIGU RE 12-33   (Continued)
FIGU RE 12-32   Pulmonary sarcoidosis and findings of pulmonary fibrosis in
a 32-year-old man. HRCT at the level of the tracheal carina shows extensive irregular
or nodular septal thickening (arrows), irregular interfaces, and traction bronchiectasis.
Posterior displacement of the upper lobe bronchi is an early sign of lung distortion.
Extensive bilateral ground-glass opacities correlated with increased67 Ga uptake.

airway obstruction, pulmonary vascular involvement
with pulmonary hypertension (PH), pleural disease, and,
more rarely, necrotizing angiitis.

More often, patients with sarcoid develop pseudocavities
representing bullae or cystic bronchiectasis typically seen
in patients with extensive fibrosis (33,86) (Figs. 12-34
and 12-35).
True cavities are more often multiple and may be either thin or thick walled in appearance. In the absence
of a known etiology, differential most importantly includes potential infectious etiologies, especially tuberculosis (Fig.  12-39), or saprophytic fungal infections with

Cystic and Cavitary Disease
True cavitary sarcoidosis is rare and has been reported to
be the result of either ischemic necrosis of angiitis (85).

A

A

B

B
FIGU RE 12-33   Extensive pulmonary fibrosis due to sarcoidosis. A: In the
upper lobes, fibrous masses associated with traction bronchiectasis and posterior
displacement of bronchi are visible (white arrows). B: At a lower level, a fibrous
mass (white arrow) is visible on the left. Subpleural bullae (black arrows) reflect
adjacent fibrosis. C: Near the lung base, small areas of subpleural honeycombing
(arrows) are visible.

FIGU RE 12-34   Sarcoidosis with fibrosis. A and B: Sequential sections
through the carina and subcarinal space, respectively, show typical findings of lung
fibrosis with marked architectural distortion, traction bronchiectasis, and thickening of
bronchovascular bundles. Note that there is also evidence of cystic bronchiectasis, as
well as apparent cavitation (B). Differentiation between severe cystic bronchiectasis
and cavitation may be difficult, especially in the setting of extensive lung scarring.
There is also evidence of pleural thickening on the right side, a finding usually seen
only in association with extensive underlying lung disease. C: Coronal reconstruction
through the carina shows the global extent of these findings to good advantage.
Apical pleural thickening is visible.


C hapter 12 Sarcoidosis

329

mycetoma formation, typically due to Aspergillus species
(Fig. 12-37) (26,33,46,86). Although often asymptomatic, superimposed fungal infection may lead to recurrent
episodes of hemoptysis, sometimes severe and requiring
bronchial artery embolization or surgical resection for
control. Fatality rates as high as 50% have been reported
in these cases, usually as a result of severe underlying lung
disease rather than infection (87).
Cavitation of nodules or masses may also be seen in patients with necrotizing sarcoid granulomatosis (33). This
rare entity, in fact, represents a systemic disease first described by Liebow (88), and is characterized by sarcoid-like
granulomas and vasculitis associated with variable degrees
of necrosis. CT features reported in this entity include diffuse infiltrates, bilateral nodules, and solitary nodules, with
intrathoracic adenopathy present in a minority of cases (37).
C
FIGU RE 12-34   (Continued)

A

C

Bronchostenosis
Bronchostenosis may result from extrinsic compression
by adjacent enlarged or fibrotic hilar lymph nodes, distortion of lung parenchyma due to extensive fibrosis resulting in severe airway angulation, or direct granulomatous
inflammation or subsequent fibrosis of the bronchial

B

FIGU RE 12-35   Sarcoidosis with cystic disease, bronchiectasis, or
honeycombing. A and B: HRCT through the upper lobes show evidence of
extensive honeycombing or cystic disease associated with bronchiectasis. C: Coronal
reconstruction shows the apical distribution of disease. Note that although there is

mild basilar honeycombing on the right side, this pattern of predominant upper lobe/
apical disease is inconsistent with most other causes of lung fibrosis, in particular, IPF.


330

s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

FIGU RE 12-36   Prone HRCT in a patient who has end-stage sarcoidosis

B

manifested by upper lobe honeycombing.

FIGU RE 12-37   End-stage sarcoidosis with upper lobe fibrous masses,
adjacent emphysema, and a mycetoma (arrow).

C
FIGU RE 12-38   (Continued)

A
FIGU RE 12-38   Lymph node abnormalities in sarcoidosis. A: Unenhanced
CT at the level of the aorta shows the typical appearance of amorphous or hazy nodal
calcifications in sarcoidosis. In this case, note that there are enlarged pretracheal,
prevascular mediastinal, and left internal mammary lymph nodes (arrow). B: An
image through the upper abdomen in the same patient as in A showing a cluster
of enlarged retroperitoneal nodes. CT may be of value by identifying disease in
atypical locations prior to attempted biopsy. C: Coronal reconstructed HRCT shows
mediastinal lymph node calcification in a patient with extensive parenchymal disease
and fibrosis.

wall (Figs. 12-21 and 12-22) (68–70). It is typically associated with respiratory symptoms, including cough,
dyspnea, wheezing, and hemoptysis. In one study of 18
patients with documented bronchial stenoses, therapeutic response was most efficacious when initiated less than
3 months from the onset of symptoms (68). In a similar
study of 11 patients presenting with airway obstruction,
defined as FEV1/FVC less than 70%, due to documented
endobronchial granulomas, Lavergne et al. (69) showed
improvement in 8 (72%) and normalization of respiratory function in 4, with prompt initiation of therapy.

Pulmonary Hypertension
Although rare, another important complication seen in
patients with sarcoidosis is PH. Variably defined as mean
pulmonary arterial pressure of 25 to 40 mm Hg, PH has
been reported to occur in 5% to 12% of cases (7,89).
Proposed mechanisms include direct granulomatous


C hapter 12 Sarcoidosis

A

B

C

D

331

FIGU RE 12-39   A–D: Sequential sections through the upper lobes show perilymphatic nodules associated with thick-walled cavities in the right lung. In the
absence of extensive fibrosis or coalescent nodules, this appearance should raise the suspicion of a superimposed infectious process, in this case proven active TB.

infiltration of vessel walls with obliteration of the pulmonary vascular bed and marked vasoconstriction due to
advanced lung disease.
CT findings suggestive of PH are described in detail
in Chapter 22 and include a pulmonary artery diameter
greater than 29 mm, a segmental artery-to-bronchus ratio
greater than 1 in three of four lobes, and a main pulmonary artery to aorta diameter ratio greater than 1 (90,91).
Although absence of these signs does not preclude the diagnosis of PH, CT may still be of value by first suggesting
this diagnosis.
In a prospective study of 246 consecutive patients
with sarcoidosis evaluated by Doppler echocardiography,
12 (5.7%) proved to have PH defined as mean pulmonary
arterial pressure greater than 40 mm Hg (92). ­Radiographic
and HRCT findings in 9 of these patients were compared
with those in 122 patients without PH. ­Although all patients with PH had radiographic evidence of advanced
disease and a marked decrease in pulmonary functional parameters, there was no significant correlation with either
the presence of lymph node enlargement or the finding of
thickened bronchovascular bundles (in the absence of lung
fibrosis). This led the investigators to conclude that the
likely mechanism of PH in sarcoidosis is the presence of

lung fibrosis causing obliteration of the pulmonary arterial
bed rather than extrinsic compression of pulmonary arteries (Figs. 18-13 and 23-13) (92). Similar findings have been
reported by Sulica et al. (93); they found that PH in sarcoidosis is associated with a higher prevalence of stage 4 disease.
More recently, in a cross-sectional study of 313 consecutive patients with biopsy-proven sarcoidosis evaluated with
cardiac magnetic resonance imaging (MRI) and Doppler
echocardiography, 37 (11.8%) were found to have pulmonary artery hypertension with pulmonary arterial systolic
pressure greater than 40 mm Hg. Compared with patients

without PH, those with PH were significantly older and had
greater lung function impairment. PH proved to be secondary to either pulmonary fibrosis, left ventricular diastolic
dysfunction due to cardiac sarcoidosis, or other comorbidities in the majority of cases. In patients without pulmonary
fibrosis, a reduced carbon monoxide diffusing capacity
(DLCO) was associated with the presence of PH (89).

Pleural Disease
Pleural abnormalities can be demonstrated in 5% to
10% of cases with radiographic evidence of sarcoidosis
(Fig. 12-34). Small to moderate-size effusions are typical
and usually clear spontaneously in 2 to 3  months (33).


332

s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

In one study of 61 consecutive patients with documented
sarcoidosis, evaluated with CT, 25 (41%) had evidence of
pleural disease, including 20 with pleural thickening and
5 with effusions, compared with only 7 (11%) with pleural abnormalities identified on plain chest radiographs
(40). Although pleural thickening was commonly noted
in association with restrictive pulmonary function tests
(PFTs), this did not prove significant when adjusted for
the presence of parenchymal fibrosis.

Extrapulmonary and Extranodal
Manifestations of Sarcoidosis
Extrapulmonary and extranodal abnormalities are sometimes visible in patients with sarcoidosis on CT obtained
for assessment of the lungs or mediastinum. These include

abnormalities of the musculoskeletal system, liver and
spleen, and heart.
Musculoskeletal abnormalities may be more common
than previously believed. In one study of 56 MRI scans
obtained in 40 patients with documented sarcoidosis and
unexplained musculoskeletal complaints, 42% proved
to have bone lesions, in particular, large bone or axial
­skeletal lesions, whereas 17% had abnormal joints and
22% had soft-tissue lesions (Fig. 12-40) (94). Skeletal
­abnormalities are not commonly visible on HRCT.
CT findings in patients with splenic and hepatic involvement have been described, and although more easily

FIGU RE 12-40   Musculoskeletal disease. T2-weighted coned down view
oblique sagittal image of the left humerus shows numerous high signal foci in
the proximal humeral shaft. In this case, identical lesions were also preset in the
contralateral right shoulder, leading to an erroneous initial diagnosis of metastatic
tumor despite previously documented sarcoidosis. The true incidence of soft tissue
and bony abnormalities in patients, especially with advanced disease, is likely
underdiagnosed. (Case courtesy of Sandra Moore, MD, New York University-Langone
Medical Center, New York.)

FIGU RE 12-41   Sarcoid spleen. Multiple low-attenuation lesions are visible
on this contrast-enhanced CT. This appearance is typical of sarcoidosis.

seen on contrast-enhanced CT, may be visible on HRCT
studies as well. Low-attenuation hepatic or splenic nodules may be seen, isolated or innumerable, and ranging
in size from 1 mm to 3 cm. These are found more often
in the spleen than in the liver (Fig. 12-41) (95) and have
been reported to occur in up to 70% of autopsy studies.
Hepatic and splenic involvement occurs with a distinctly

higher frequency in African American patients, with cirrhosis and liver failure only rarely occurring (3).
Cardiac sarcoidosis is diagnosed clinically in less than
5% of cases, although it has been reported to be present
at autopsy in up to 25% of patients with systemic involvement (96,97). It carries a particularly poor prognosis. It
is most often manifested by a cardiac tachyarrhythmia,
often requiring the placement of an implantable defibrillator device to obviate sudden death resulting from ventricular fibrillation. Rarely, if ever, diagnosed using CT
(98), the diagnosis of cardiac sarcoidosis can be suggested
in patients with pulmonary sarcoidosis and cardiac abnormalities, when other etiologies of heart disease are absent.
CT findings may include cardiomegaly, pericardial effusion, and left ventricular aneurysm (98). Thallium (201TL)
single-photon emission CT, 18-fluoro-deoxy-glucose
positron emission tomography (18FDG-PET) scanning, or
gadolinium-enhanced MRI typically show lesions involving the interventricular septum and the free left ventricular lateral wall (Figs. 12-42 and 12-43) (31,99). The use
of one of these imaging studies appears to be appropriate
if cardiac symptoms are present.
In one study of 101 patients with sarcoidosis, 16 of
19 presenting with cardiac symptoms proved to have cardiac sarcoidosis, with 4 patients requiring a pacemaker;
in distinction, only 3 of 82 asymptomatic patients in this
study proved to have abnormal cardiac imaging findings
(99). On the basis of these findings, routine screening of
patients with known or suspected sarcoidosis, to diagnose
occult cardiac involvement, does not appear justifiable.
As recently reported by Teirstein et al. in a retrospective


C hapter 12 Sarcoidosis

A

FDG-PET

B

T2-weighted CMR

C

Late Gadolinium Enhancement CMR

D

Fused PET/CMR

333

FIGU RE 12-42   Cardiac involvement assessed by 18FDG-PET and MR. A: 18FDG-PET image showing foci of increased myocardial activity in a patient with

proved sarcoidosis. B: T2-weighted contrast enhanced. C: Late post-gadolinium-enhanced images show foci of decreased signal intensity (arrows) corresponding to
the same areas shown in A. D: Fused 18FDG-PET/MR imaging demonstrating precise co-registration between 18FDG-PET and MR. (Case courtesy of Kent Friedman,
MD, New York University-Langone Medical Center, New York.)

evaluation of 188 18FDG-PET scans performed in 137 patients with documented sarcoid, no cardiac involvement
was identified (100).

UTILITY OF HIGH-RESOLUTION
COMPUTED TOMOGRAPHY
High-Resolution Computed TomographyPulmonary Function Correlations
Most investigators believe that HRCT has a very limited
role in assessing or predicting pulmonary function in patients who have sarcoidosis (101). Although CT provides

a superior assessment of disease pattern, extent, and

distribution in patients with sarcoidosis, it is controversial whether it correlates better than chest radiographs
with clinical and functional impairment (101). In a review of 27 patients with sarcoidosis, Müller et al. (44)
demonstrated that CT and radiographic assessment of
disease extent had similar correlations with the severity
of dyspnea (r = 0.61 and 0.58, respectively; p < 0.001),
total lung capacity (TLC) (r = −0.54 and −0.62, respectively; p < 0.01), and gas transfer as assessed by DLCO
(r  = −0.62 and −0.52, respectively; p <0.01). In a prospective HRCT study of 44 patients, Brauner et al. (42)
found that the CT visual score had a lower correlation


334

s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

A

B

C

FIGU RE 12-43   A–C: Cardiac sarcoidosis. Evaluation of response to therapy. A: Initial pre-treatment 18FDG-PET image showing extensive involvement of the heart,
mediastinal and hilar nodes, liver and retroperitoneum (A). B and C: Sequential 18FDG-PET images over several months following immunosuppressive therapy showing
complete resolution of active granulomatous disease. In this case 18FDG-PET is of value by initially documenting the presence of myocardial involvement and subsequent
monitoring response to therapy. (Case courtesy of Kent Friedman, MD, New York University-Langone Medical Center, New York.)

than did the radiographic score with TLC (r = −0.30 and
−0.49, ­respectively), FEV1 (r = −0.41 and −0.40, respectively), and DLCO (r = −0.41 and −0.46, respectively).
Bergin et al. (41), in contrast, found that the CT scores
of disease correlated better with functional impairment
(all r > 0.49) than the radiographic scores (all r < 0.15).

Similarly, Drent et al. (102) found that HRCT abnormalities, but not the chest radiographic stage, were strongly
associated with functional parameters in patients with
sarcoidosis. Scores for the extent of various HRCT findings, particularly those associated with fibrosis (i.e.,
thickening or irregularity of the peribronchovascular
interstitium, linear opacities, and nodules) and the total
HRCT score, correlated with the FEV1, FVC, DLCO, arterial oxygen tension at maximal exercise (all p < 0.05),
and alveolar-arterial oxygen difference at maximal exercise (p < 0.001). The presence of consolidation, groundglass opacity, and lymph node enlargement did not show
a significant correlation with function (102).
Remy-Jardin et al. (45) also reported low, but statistically significant correlations between the HRCT extent
of various findings of sarcoidosis (with the exception of
nodules) and PFT results. The best correlations were between the overall extent of abnormalities seen on HRCT
and FVC (r = −0.40), FEV1 (r = −0.37), TLC (r = −0.48),
and DLCO (r = −0.49; all p < 0.0001). Specific HRCT
findings having the best correlations with PFTs were consolidation, ground-glass opacity, and lung distortion, although these correlations were generally low.
Carrington (20) suggested that poor correlation between the radiographic severity of disease and the functional impairment in patients who have sarcoidosis may
be due to the fact that the nodular lesions, although
easily seen and quantitated, cause minimal dysfunction.
This situation is similar to that seen in patients who
have silicosis, in whom the severity of interstitial fibrosis
rather than the number or size of nodules is responsible
for impaired function (20). In the study by Müller et al.
(44), patients who had predominantly irregular reticular

opacities had more severe dyspnea and lower lung volumes than patients who had predominantly nodular
opacities (p < 0.05). Also, as indicated previously, RemyJardin et al. (45) found that the extent of nodular opacities seen on HRCT in patients who had sarcoidosis lacked
a significant correlation with PFTs.
Recognizing that some patients who have sarcoidosis
show PFT findings of airflow obstruction and some show
findings of air trapping on expiratory HRCT, Hansell
et al. (78) attempted to identify HRCT findings correlating

with functional airway obstruction. Against expectations,
the extent of reticular abnormalities shown on HRCT,
rather than the extent of air trapping, correlated best
with airflow obstruction, as shown by inverse relationships with the FEV1 (p < 0.001), FEV1/FVC (p < 0.01),
and maximum expiratory flow rates (p < 0.001), and
a positive relationship with the residual volume-TLC
­ratio (p < 0.001). However, Magkanas et al. (79) found
a significant correlation between the air trapping extent
on expiratory HRCT with residual volume (r =  0.40;
p  =  0.04) and the ratio of residual volume to TLC
(r = 0.52; p = 0.006) (79).
Furthermore, in four patients with sarcoidosis, Fazzi
et al. (74) found that the presence of decreased attenuation on expiratory HRCT was associated with a reduction in DLCO, DLCO adjusted for alveolar volume, and
the maximum expiratory flow at 25% above the residual
volume. However, major indexes of airway obstruction
(FEV1 and FEV1/FVC) were normal in these patients (74).
Terasaki et al. (103) found that cigarette smoking confounds the correlation between the CT and PFT findings
in patients with sarcoidosis. In their study, inspiratory and
expiratory HRCT and PFTs were performed in 46 ­patients
(23 smokers and 23 nonsmokers) with histologically
proven sarcoidosis. Small nodules (all 46 patients, 100%)
and air trapping on expiration (45/46 patients, 98%) were
the most common HRCT findings. No ­significant difference was seen in the extent of air trapping, consolidation,
ground-glass attenuation, reticular opacities, or small


C hapter 12 Sarcoidosis

nodules between smokers and nonsmokers. The extent
of air trapping negatively correlated with FVC in smokers (p < 0.05), but not in nonsmokers. Furthermore, the

extent of small nodules negatively correlated with FVC
and positively correlated with the ratio of FEV1 to FVC in
nonsmokers (p < 0.05), but not in smokers. On stepwise
multiple regression analysis, the extent of air trapping on
CT was independently associated with decreased FVC
(p <0.05), and cigarette smoking was the main determinant of decrease in maximum mid-expiratory flow and
FEV1 at 50% of vital capacity (p < 0.01).

High-Resolution Computed Tomography
Findings and Prognosis
Serial CT scans performed in patients who have pulmonary sarcoidosis, both with and without treatment, have
demonstrated that nodules, ground-glass opacity, consolidation, and interlobular septal thickening usually represent potentially treatable or reversible disease (42,45,65).
The extent of nodules and consolidation in sarcoidosis has
been shown to correlate with the intensity of lung gallium
uptake (48,64) and with serum angiotensin-­converting
enzyme levels (64). Although one study showed correlation between the extent of ground-glass opacity and gallium uptake (48), this was not confirmed in subsequent
studies (45,64).
Irregular lines and reticular opacities are usually irreversible, but may occasionally improve or resolve (65).
Architectural distortion and honeycombing represent irreversible disease (45,55,65).
More recently, Akira et al. (63) correlated HRCT patterns of disease with clinical outcome in 40 patients with
pulmonary sarcoidosis, and similar to prior reports, noted
that patients with predominant nodular disease had the
best prognosis. Patients presenting with conglomerate
masses typically showed the subsequent development of
bronchial distortion associated with airway obstruction
and FEV1/FVC ratios of less than 70%. Surprisingly, the
two patients in this study who presented with a pattern
of diffuse ground-glass opacity had the worst prognosis,
with the subsequent development of honeycombing. As
noted by the authors, in these two cases, ground-glass

opacity likely represented micro-honeycombing.

Radiography, High-Resolution Computed
Tomography, Magnetic Resonance
Imaging, and Radionuclide Imaging
Gallium-67-citrate (67GA) scintigraphy has shown
some correlation with radiographic and HRCT findings (45,64) and has previously been used to evaluate
patients with suspected sarcoidosis who have normal
or atypical radiographic findings, or to identify potential biopsy sites. Currently, 67GA has effectively been
replaced by both magnetic resonance (MR) and 18FDGPET scanning (Figs. 12-42 and 12-43) (97,100,104–107).

335

Teirstein et al. (100) retrospectively evaluated 188 whole
body 18FDG-PET scans in 137 patients with sarcoidosis,
some of whom also had chest radiographs performed, in
an attempt to identify biopsy sites and evaluate disease
activity and reversibility. In this study, mediastinal lymph
node abnormalities were found in 54 of 137 patients
(39%) of scans, and abnormal lung findings were seen in
24 of 137 (17.5%). PET scans positive for lung disease
were seen in 16 of 22 (72%) patients with radiographic
stages 2 and 3 sarcoidosis. However, abnormal lung activity was found in only 8 of 51 (16%) cases with stage 0, 1,
and 4 disease. This difference is likely a reflection of the
less active inflammation in early- and late-stage disease.
In a small number of cases, a decrease in the standardized
uptake value was noted in patients undergoing steroid
therapy. Despite these findings, these authors concluded
that at present there is no clinical indication for the routine use of 18FDG-PET scans either in the initial evaluation or in the follow-up of ­patients with sarcoidosis.
Although, to date, there are no routine indications

for the use of 18FDG-PET scanning in patients with sarcoidosis, PET scans have been reported to be of value in
patients (a) with persistent and, otherwise unexplained,
severe symptoms, especially in the absence of serologic
evidence of ongoing active inflammation; (b) in assessing patients with parenchymal fibrosis; and (c) to identify
otherwise unsuspected or optimal sites for biopsy (107).
In addition, PET scanning has been shown to be of value
for both the diagnosis and the management of patients
with cardiac sarcoidosis (38,97,107).

Current Indications for HRCT
in Sarcoidosis
As proposed by the American Thoracic Society/European
Respiratory Society/World Association of Sarcoidosis and
other Granulomatous Disorders Consensus Statement
on Sarcoidosis, HRCT is indicated in the presence of (a)
atypical clinical or radiographic findings, (b) clinical suspicion despite normal chest radiography, and (c) for the
detection of pulmonary complications (4). These conclusions are based on numerous reports, validating the value
of HRCT in comparison with routine chest radiographs
in the diagnosis of sarcoidosis.
HRCT can show parenchymal abnormalities in both
patients with sarcoidosis who have normal chest radiographs and patients with hilar or mediastinal lymphadenopathy as the only abnormal finding (22). HRCT has
also been shown to be superior to chest radiographs in
demonstrating early fibrosis and distortion of the lung
parenchyma in patients who have sarcoidosis (55). However, CT cannot be used to rule out parenchymal involvement; HRCT can be normal in patients who have
pulmonary involvement by sarcoidosis proved by transbronchial biopsy or lobectomy (22,48,108).
In one early study of 100 consecutive patients referred
for evaluation of possible sarcoidosis, 35 of whom were
evaluated using CT, no additional clinically relevant

336

s e c t i o n III High-Resolution CT Diagnosis of Diffuse Lung Disease

information was revealed (109). As a consequence, the
routine use of HRCT is not recommended to evaluate patients with suspected sarcoidosis (10,109,110). However,
CT studies are currently indicated in patients presenting
with atypical clinical or radiographic findings to identify
and/or characterize complications of sarcoidosis, including superimposed infections in patients with pre-existing
cavities or extensive lung fibrosis, or to exclude malignancy. CT is also of benefit for evaluating patients with
hemoptysis (3,7,110).
In this regard, it is interesting to recognize that the diagnosis of sarcoidosis is frequently delayed. As noted by
Judson et al. in a study of 189 patients with sarcoidosis,
the diagnosis was made on the first physician visit in only
15.3% of cases (111). Delay in diagnosis was more likely
to occur in patients with a higher radiographic stage and
the presence of pulmonary symptoms. In these settings,
a likely benefit of HRCT may be anticipated, because in
our experience, even in patients with extensive fibrotic
lung disease, there is almost always evidence of “classic”

A

B

findings to suggest the diagnosis, in particular, residual
perilymphatic nodules.
Currently, with the exception of patients presenting
with Löfgren syndrome, confirmation of the diagnosis
requires identifying patients with a compatible clinical

picture, coupled with histologic demonstration of noncaseating epithelioid cell granulomas and the exclusion
of other diseases capable of producing similar clinical
or histologic findings (3,7,110). Routine flexible fiberoptic bronchoscopy with transbronchial needle aspiration (TBNA) and transbronchial lung biopsy frequently
in combination with endobronchial biopsy are recommended procedures in most patients initially presenting
with suspected sarcoid, with diagnostic yields ranging
from 40% to 90%. Success depends on the number of
biopsies, radiographic stage of disease, and experience of
the bronchoscopist (2,112–114), and is enhanced by obtaining CT as a guide for determining optimal biopsy sites
(84) (Fig. 12-44). Despite this, although the addition of
TBNA of mediastinal or hilar nodes can further increase

C

D

E
FIGU RE 12-44   CT-guided biopsy in sarcoidosis. A–C: Coned 1-mm axial, sagittal, and coronal images through the left
upper lobe in a patient with bilateral hilar adenopathy and perilymphatic nodules with a patchy distribution (A–C, arrows). D: Virtual
bronchoscopic image corresponding to the subsegmental airway identified in A (arrow). In this case, virtual bronchoscopic images
were transferred to a standard laptop computer and were available at the time of bronchoscopy, which was performed under direct CT
guidance. E: CT obtained at the time of bronchoscopy confirms that the tip of a pediatric bronchoscope was properly situated in the
airway identified in A and D. Biopsies obtained at this site confirmed the diagnosis of sarcoidosis.