pulmonary Disease Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Pulmonary Disease Board
Review Manual is a peer-reviewed study guide
for fellows and practicing physicians preparing
for board examinations in pulmonary disease.
Each manual reviews a topic essential to current practice in the subspecialty of pulmonary
disease.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
editorial director
Debra Dreger
Senior EDITOR
Robert Litchkofski
associate EDITOR
Rita E. Gould
Mesothelioma and Other
Asbestos-Related Pleural
Diseases
Series Editor and Contributor:
Gregory C. Kane, MD, FACP, FCCP
Professor of Medicine, Internal Medicine Residency Program Director,
Vice-Chairman, Department of Internal Medicine, Jefferson Medical
College, Philadelphia, PA
Contributor:
Rodrigo Cavallazzi, MD
Fellow, Division of Pulmonary and Critical Care Medicine, Thomas
Jefferson University Hospital, Philadelphia, PA
assistant EDITOR
Farrawh Charles
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
PRODUCTION Director
Suzanne S. Banish
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PRODUCTION assistant
Malignant Pleural Mesothelioma . . . . . . . . . . . . . . . . . . . . . 1
Nadja V. Frist
ADVERTISING/PROJECT Director
Patricia Payne Castle
sales & marketing manager
Deborah D. Chavis
Pleural Plaques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Diffuse Pleural Thickening. . . . . . . . . . . . . . . . . . . . . . . . . . 6
Rounded Atelectasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Benign Pleural Effusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
NOTE FROM THE PUBLISHER:
This publication has been developed without involvement of or review by the Amer­­
ican Board of Internal Medicine.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Cover Illustration by Kathryn K. Johnson
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contained within this publication should not be used as a substitute for clinical judgment.
Hospital Physician Board Review Manual
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Pulmonary Disease Board Review Manual
Mesothelioma and Other
Asbestos-Related Pleural Diseases
Rodrigo Cavallazzi, MD, and Gregory C. Kane, MD, FACP, FCCP
INTRODUCTION
Asbestos is a definitive carcinogen when inhaled
or ingested that has an established causal relationship
with cancer of the lung, mesothelioma of the pleura
and peritoneum, cancer of the larynx, and certain
gastrointestinal cancers. Furthermore, asbestos exposure causes asbestosis, a progressive fibrotic disease of
the lung, and several types of benign pleural diseases.1
This article reviews the most common asbestos-related
pleural diseases, with a primary focus on malignant
pleural mesothelioma (MPM) given its high mortality
rate. Aspects of the following benign asbestos-related
pleural diseases are discussed as well: pleural plaques,
diffuse pleural thickening, rounded atelectasis, and
benign pleural effusion.
MALIGNANT PLEURAL MESOTHELIOMA
Case presentation
An 85-year-old white man with chronic obstructive
pulmonary disease diagnosed several years ago pre­sents
to the outpatient clinic with shortness of breath and
chest pain. His symptoms started 2 months prior to his
visit and are characterized by progressive shortness of
breath and dull, nonpleuritic anterior chest pain not
related to exertion. He also has noticed anorexia and
a 20-lb weight loss over the same period. His social history is significant for a 50-pack-year smoking history. He
worked as a school teacher and has lived most of his life
in a neighborhood near a company that repairs roofs.
Physical examination reveals decreased breath sounds
and dullness to percussion at the right hemithorax.
Chest radiograph reveals volume loss of the right hemithorax with moderate right pleural effusion and nodular pleural thickening. He undergoes therapeutic and
diagnostic thoracocentesis, and analysis of the pleural
fluid reveals a lymphocytic exudate with atypical mesothelial cells. Chest computed tomography (CT) after
thoracocentesis reveals findings suggestive of MPM
(Figure 1). The pa­tient undergoes thoracoscopic pleural biopsy, which establishes the diagnosis of MPM.
Definition and Epidemiology
Malignant mesothelioma is a tumor that arises from
the surface serosal cells of the pleural, peritoneal, and
pericardial cavities and from the tunica vaginalis.2 The
overall age-adjusted 1999–2002 US incidence rate of
mesothelioma was 1.11 cases (95% confidence interval
[CI], 1.09–1.13) per 100,000 persons, according to an
analysis that used cancer registry data covering 88% of
the US population.3 The male-to-female ratio was 5.1:1,
and whites had a higher incidence than African Americans, Native Americans and Alaska Natives, and Asian/
Pacific Islanders. The incidence was higher in nonHispanics than in Hispanics. The sex predilection is largely related to gender differences in occupational exposures. The incidence rate rises with increasing age, peaking at the 75-to-84-year age-bracket, with 8.66 cases (95%
CI, 8.39–8.94) per 100,000 persons. Pleural mesothelioma accounted for 83% of all cases, and peritoneal mesothelioma accounted for 7%. Among females, however,
peritoneal tumors made up 15% of the total, and 74%
were pleural.3
While estimates indicate that the incidence of mesothelioma is declining in the United States,4,5 estimates
for Western European countries and Australia predict
that the incidence of mesothelioma will peak between
2010 and 2015.6–8 Developing countries are also expected to experience a peak rate of mesothelioma in
the future due to increasing asbestos production and
consumption.9 For the period 1999 to 2001, the overall
mortality rate (number of deaths per million persons
per year) due to mesothelioma adjusted to the 2000 US
standard population was 11.52, with males (22.34) showing a 6-fold higher rate than females (3.94).10
Several case-control and cohort studies have demonstrated a clear association between asbestos exposure and malignant mesothelioma.11,12 The term asbestos
encompasses different fibrous silicate materials, each
with unique physical, chemical, and biologic properties.
www.turner-white.comPulmonary Disease Volume 13, Part 5 Mesothelioma and Other Asbestos-Related Pleural Diseases
Figure 1. Transverse section chest computed tomography scan (5-mm collimation)
without contrast showing volume loss of
the right hemithorax and marked nodular circumferential right pleural thickening,
which extends into the fissure and mediastinum abutting the pericardium. Small
nodular opacities are present throughout
the right lung parenchyma and are less
prominent in the left lung parenchyma.
All forms of asbestos are hazardous, but the risk of
mesothelioma changes with exposure to different
fiber types.13 Asbestos fibers can come from naturally occurring sources or from the wearing down or
disturbance of manufactured products, including
insulation, automotive brakes and clutches, ceiling
and floor tiles, dry wall, roof shingles, and cement.14
Asbestos fibers belong to the mineral families serpentine and amphibole. The serpentine family contains
chrysotile, an asbestos fiber heavily used in industry. The amphibole family contains crocidolite and
amosite, which have been used in many industries, as
well as anthophyllite and tremolite, which can occur
as trace minerals in chrysotile and talc deposits.2 A
quantitative analysis found that the specific risk for
malignant mesothelioma associated with occupational
exposure for the 3 main commercial asbestos types is
highest for crocidolite followed by amosite and then
chrysotile.15 However, it is important to emphasize
that all asbestos fiber types can cause mesothelioma in
exposed individuals.12 Moreover, in industrial applications, it would be rare to encounter asbestos of only
1 fiber type. In addition to fiber type, other factors
determining mesothelioma risk include the time from
exposure to asbestos—the median latent period is
32 years after initial exposure—and cumulative exposure to asbestos.2,16
In the United States, the adjusted proportionate
mor­tality ratio (PMR) of malignant mesothelioma is
elevated for the following industries: ship and boat building and repairing (PMR 5.95 [95% CI, 2.39–12.27]),
industrial and miscellaneous chemicals (PMR 4.81 [95%
CI, 2.9–7.51]), petroleum refining (PMR 3.8 [95% CI,
1.23–8.87]), electric light and power (PMR 3.08 [95%
CI, 1.48–5.66]), and construction (PMR 1.55 [95% CI,
1.23–1.94]). By occupation, the following have an elevated adjusted PMR: plumbers, pipefitters, and steamfitters
(PMR 4.76 [95% CI, 2.81–7.51]); mechanical engineers
(PMR 3.04 [95% CI, 1.11–6.62]; electricians (PMR 2.42
[95% CI, 1.25–4.22]); and elementary school teachers
Hospital Physician Board Review Manual
(PMR 2.13 [95% CI, 1.13–3.64]. The PMR corresponded to the total number of deaths with the condition of
interest divided by the expected number of deaths with
that condition.10
A number of studies have also demonstrated an
elevated risk of mesothelioma from nonoccupational
asbestos exposure. The 2 main types of environmental
asbestos exposure are household and neighborhood.
Common sources of household asbestos exposures
include the installation, removal, and degradation of
asbestos-containing products and asbestos dust brought
home from the workplace on the clothes. Common
neighborhood exposures include residence close to asbestos mining and manufacture, release of fibers from
buildings, and erosion of asbestos from rocks.17
Pathogenesis
Inhaled asbestos fibers may pass the alveolar barrier
and reach the lung interstitium due to their relatively
indestructible nature. In the lung interstitium, fibers
can be pulled into the lymph flow and eventually reach
the blood stream with subsequent distribution to the
whole body, but for the most part they remain undigested in the lung. The translocation process develops
over decades and is influenced by fiber length and
other factors such as the presence of inflammation,
which induces vessel permeability.18 Asbestos fibers are
phagocytized by mesothelial cells and induce injury
to them by promoting intracellular oxidation, DNA
strand breakage, apoptosis, and cell-cycle delay.19 These
events are linked to carcinogenesis.
Although exposure to asbestos is the primary cause
of malignant mesothelioma, with more than 80% of malignant mesotheliomas developing in individuals with
more than background exposure to asbestos, less than
10% of individuals heavily exposed to asbestos develop
malignant mesothelioma.20,21 The differential susceptibility to development of mesothelioma among those
heavily exposed to asbestos underscores the importance
of cofactors in mesothelioma carcinogenesis.
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Mesothelioma and Other Asbestos-Related Pleural Diseases
The neurofibromin 2 gene (NF2) is located in chromosome band 22q12 and encodes merlin, a member
of the cytoskeleton-associated proteins. Merlin seems
to have an important function in the link between cell
membrane and cytoskeletal proteins, in cell-cell and
cell-matrix contact signaling, and as a tumor suppressor
gene.22 Expression of merlin inhibits p21-activated kinase
signaling, which promotes cell motility. Mutations in the
NF2 gene are present not only in neurofibromatosis type
2 but also in malignant tumors unrelated to neurofibromatosis type 2, including malignant mesothelioma. In
this light, a study found lack of expression of NF2 in 14
(56%) of 25 malignant mesothelioma cell lines.22 Furthermore, malignant mesothelioma cell lines frequently
have deletions of chromosome 9p21, which contains
the tumor suppressor genes p16(INK4a), p14(ARF), and
p15(INK4b).23 Platelet-derived growth factors are overexpressed in malignant mesothelial cells and act as a
regulatory factor in cell proliferation.24 Other factors
may contribute to the pathogenesis, but their role is
disputed: malignant mesothelioma has occurred after
irradiation for other types of cancer, and simian virus 40
was detected in patients with mesothelioma in some but
not all studies investigating their association.24,25
As is clear from this discussion, several mechanisms
can render mesothelial cells prone to malignant transformation. Robinson and Lake26 have enumerated 6 features commonly present in cancer cells and also found
in malignant mesothelioma: growth advantage, immortalization by the action of telomerase, absence of tumor
suppressor genes, induction of anti-apoptotic processes,
increased angiogenesis, and matrix interactions.
Clinical Manifestations
The onset of clinical manifestations of MPM is gradual, and patients usually present with dull, nonpleuritic
pain and shortness of breath.27,28 It is not unusual for
symptoms to be present for months to a year or more
before the diagnosis is established. Pain can be localized
to the shoulder, arm, chest wall, and upper abdomen.
Although typically described as heaviness or aching, pain
may have a neuropathic component due to entrapment
of intercostal thoracic, autonomic, or brachial plexus
nerves. Patients occasionally have unexplained chest
pain and a normal chest radiograph.29 On the other
hand, patients may not always have chest pain. In a series
of 272 patients, one third had pleural effusion accompanied by breathlessness but no chest pain.28 Other clinical
features include lassitude, weight loss, cough, and chest
wall mass.27,28 Dullness to percussion over the thorax or
decreased breath sounds due to pleural effusion are
the most common abnormal physical findings.30 Rarely,
Table 1. Computed Tomography Findings Suggestive of
Malignancy with Diffuse Pleural Thickening
Parietal pleural thickening > 1 cm
Circumferential involvement
Irregularity of pleural contour
Fissural involvement
Extrapleural fat plane invasion
Hilar or mediastinal adenopathy
Mediastinal involvement
clubbing may be present.26 Patients with peritoneal mesothelioma may present with abdominal pain, which is
localized and related to a dominant tumor mass, or with
ascites and prominent abdominal distention.31
Radiologic evaluation
The characteristic feature of MPM noted on plain
chest radiograph is unilateral pleural effusion with associated nodular pleural thickening. Pleural thickening
can be focal or extensive. Extensive thickening is present in 60% of cases and encases the entire lung surface,
producing a decrease in size of the affected hemithorax.
Bilateral pleural effusion is present in 10% of cases. In
some instances, pleural masses are present without an
effusion, or the effusion may be too small to be detected
by plain chest radiograph.32–34 Even in the presence of
massive pleural effusion, contralateral mediastinal shift
is not a common finding with malignant mesothelioma
since it tends to encase the lung, invade the fissures, and
freeze the hemithorax.34 Although suggestive of MPM,
circumferential pleural thickening is not specific, and it
can be found in other diseases such as adenocarcinoma
and asbestos-related benign pleural disease.34,35
Chest CT is considered the primary imaging modality for evaluation and staging of patients with MPM. It
gives significant anatomic information and precludes
surgery in those with metastasis or tumor extension
into the chest wall, mediastinum, or peritoneum. In
chest CT, the tumoral encasement of the lung gives an
orange rind-like appearance, and the fissure involvement is often apparent.36 Table 1 describes chest CT
findings suggestive of malignancy. While chest CT
provides far more information than plain radiographs,
it has distinct limitations in distinguishing simple contiguity of tumor with chest wall or mediastinum from
actual invasion.36,37 Magnetic resonance imaging (MRI)
can help in this regard.
MRI is typically reserved to address equivocal findings
on chest CT in patients considered for surgery.38 MRI
has the potential to improve evaluation of mediastinal,
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Figure 2. Histology of a pleural biopsy
sample showing malignant mesothelioma, epithelial type. (A) Low-power view. (B) Highpower view.
A
B
chest wall, and diaphragmatic invasion.39 Integrated
positron emission tomography-CT (PET-CT) is useful in
identifying occult metastasis and may aid in determining
prognosis and treatment response of patients with malignant mesothelioma. Integrated PET-CT has suboptimal
accuracy for detecting mediastinal nodal metastasis and
subtle transdiaphragmatic extension; however, it is valuable for detecting extrathoracic metastases not suspected
after conventional clinical and radiologic evaluation.38
Diagnosis
After appropriate history, physical examination, and
imaging studies are undertaken, a diagnostic thoracocentesis is the next step in a patient with pleural effusion. Cytologic analysis is useful in determining that
the process is mesothelial but less helpful in separating
benign from malignant proliferations.39 Immunomarkers contribute to the cytologic diagnosis of MPM.26 If
the data converge to a diagnosis of mesothelioma, one
can accept the diagnosis based on the combination of
cytology and clinical data. However, caution should be
exercised as it is often difficult to reliably differentiate
malignant mesothelial cells from highly reactive cells.
Thus, when there is uncertainty or conflicting data,
pleural biopsy should be performed.29 Importantly, cytology alone cannot be used to exclude mesothelioma,
as a prospective study found a sensitivity of only 26%.40
When patients present with diffuse pleural thickening but no effusion, chest CT with contrast enhancement is the first step. The presence of CT findings
suggestive of MPM (Table 1) should prompt pleural
biopsy, which is usually performed via video-assisted
thoracoscopy.29
In recent years, new biomarkers have been investigated for both diagnosis and prognosis of malignant
mesothelioma. Osteopontin, a glycoprotein overexpressed in several types of cancer, is regulated by proteins in cell-signaling pathways that are associated with
asbestos-induced tumorigenesis. One study found that
serum osteopontin had a sensitivity of 77.6% and a
specificity of 85.5% for diagnosing malignant mesothelioma.41 Mesothelin, another glycoprotein thought
Hospital Physician Board Review Manual
to have a role in cell adhesion, is expressed in ovarian
cancer and other types of cancer. Elevated levels of
serum soluble mesothelin-related proteins were shown
to have a sensitivity of 84% and a specificity of 83% for
mesothelioma in a study that compared protein levels
in patients with histologically proven mesothelioma
with patients who had been exposed to asbestos but
did not develop mesothelioma.42 Importantly, the study
found that some of the asbestos-exposed patients with
elevated serum soluble mesothelin-related proteins
developed mesothelioma and lung carcinoma within 1
to 5 years. These studies highlight the potential to use
simple serum biomarkers as screening tests for early
diagnosis of mesothelioma in selected populations with
high exposure to asbestos. While helpful in suggesting
the malignant nature of a pleural process, at this point
biomarkers have not replaced histopathologic confirmation of the malignant tissue.
Pathology
There are 3 broad pathologic patterns of malignant
mesothelioma: epithelial, sarcomatous/fibrous, and biphasic or mixed. Approximately 50% of pleural and
75% of peritoneal mesotheliomas demonstrate the
epithelial pattern; 30% are biphasic; and 15% to 20%
are sarcomatous.2 The epithelial pattern tends to form
proliferations of the serosal membranes that appear
as nondescript solid sheets of neoplastic cells. Other
arrangements of the epithelial pattern are less difficult
to distinguish from other tumors; these include a pure
tubular configuration in which flattened-to-cuboidal
cells encircle hollow spaces, and a tubulopapillary configuration of branching tubules mixed with papillae and
trabeculae. The appearance of the sarcomatous/fibrous
pattern ranges from fibroblast-like spindle cells arranged
in a form reminiscent of fibrosarcoma to malignant
fibrous histiocytoma-like tumors with anaplastic and
sometimes multinucleated cells. The biphasic pattern
exhibits both epithelial and sarcomatous components.43
Figure 2 displays a histology sample from a patient with
an epithelial type of MPM.
Desmoplastic malignant mesothelioma, a subgroup
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Mesothelioma and Other Asbestos-Related Pleural Diseases
that can present as a paucicellular and collagenous
tumor, often mimics reactive fibrous scar tissue. Attanoos and Gibbs2 have suggested that bland collagen
necrosis and involvement of submesothelial adipose
tissue are features that help distinguish desmoplastic
mesothelioma from reactive fibrosis.
The spectrum of morphologic appearances in malignant mesothelioma is broad, making it difficult in many
cases to determine whether the process in question
is mesothelial and not a metastatic malignancy.39 The
main differential diagnosis with the epithelial pattern is
metastatic adenocarcinoma, and both can present with
a similar configuration. Furthermore, it is difficult to distinguish between the sarcomatous pattern and sarcoma.
Because of the histologic overlap between malignant
mesothelioma and other malignancies, additional analyses to clarify the diagnosis are often required.43 To this
end, immunohistochemistry markers are used mainly
to aid in distinguishing pleural mesothelioma from adenocarcinoma, but studies have also explored their role
in separating sarcomatous mesothelioma from sarcoma,
desmoplastic mesothelioma from reactive fibrosis, and
well-differentiated mesothelioma from reactive papillary hyperplasia.2 D2-40, a monoclonal antibody with
immunoreactivity for lymphatic endothelium, is a novel
marker with high sensitivity for cells of mesothelial origin and relatively high specificity for the differentiation
of epithelial malignant mesothelioma from pulmonary
adenocarcinoma. EMA and p-53 positivity suggests malignancy and helps differentiate benign from malignant
mesothelial processes.39 Several other immunohistochemistry markers are commonly used; however, none
of the markers has absolute sensitivity or specificity for
the diagnosis of malignant mesothelioma. Commonly, a
panel of markers will be employed.44
Staging
MPM rarely metastasizes to distant sites, but most patients present with locally advanced disease. As imaging
studies may provide inconclusive results, mediastinoscopy and video-assisted thoracoscopy are helpful preoperative staging procedures. The international staging system
for MPM emphasizes the extent of disease after surgery
and stratifies patients in prognostic categories according
to traditional tumor-node-metastasis system.45
Treatment
The 3 traditional modalities of treatment for MPM
are surgery, chemotherapy, and radiotherapy. They can
be used individually or in combination and with curative
intent or for palliation of symptoms. Several authors have
emphasized the importance of trimodality treatment for
a selected group of patients who present with early disease.46 Additionally, appropriate symptomatic treatment
of pain and shortness of breath is of paramount importance. Pleurodesis is an important procedure for palliation of shortness of breath in patients with MPM.
Surgery can accomplish 3 objectives: relief of dysp­
nea, debulking to increase efficacy of other treatments,
and radical resection to eradicate disease.47 One of the
commonly used radical surgery techniques consists of
extrapleural pneumonectomy, which is selected for patients with good performance status, early-stage disease
without mediastinal lymph node involvement, epithelial
histology, and adequate pulmonary function.45 Although
extrapleural pneumonectomy has been advocated as
the standard radical surgery for treatment of malignant
mesothelioma, some experts have expressed concern
that it has not been studied in a randomized trial and
has not been shown to confer benefit over debulking or
no surgery.47 In a series of 328 consecutive patients who
underwent extrapleural pneumonectomy, 60.4% had
complications and 3.4% died.48
In 85% to 90% of patients, the disease is unresectable at diagnosis, and chemotherapy is the mainstay of
treatment for most of these patients.49 Platinum-based
regimens have greater activity than non–platinum-based
combinations.49 Recently, 2 phase III trials showed that
the combination of a third-generation antifolate with
cisplatin provides survival benefit over cisplatin alone in
chemotherapy-naïve patients.50,51 Furthermore, the antifolate pemetrexed plus best supportive care as secondline chemotherapy in previously treated patients leads
to significant tumor response and delayed disease progression compared with best supportive care alone.52
Table 2 summarizes the 2 phase III trials evaluating the
combination antifolate and cisplatin in chemotherapynaïve patients with MPM.50,51
Radiotherapy is used for palliation of symptoms and
as adjuvant therapy after surgery. In the palliative setting, pain is the main indication for radiotherapy, and
pain relief can be achieved in at least 50% of patients
with radiotherapy.53 Due to the propensity of MPM to
spread along the tracks of chest tubes, surgical incisions, and biopsy needles, radiotherapy has also been
advocated as prophylactic therapy to prevent seeding
after invasive procedures. However, prophylactic radiotherapy after invasive procedures did not show benefit
in a recent randomized prospective trial.54
Experimental Therapies
Investigators have been exploring the role of new types
of treatment for MPM in animal studies or phase I and
II clinical trials. Potential therapies include intrapleural
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Table 2. Phase III Clinical Trials Evaluating the Combination Antifolate and Cisplatin
Author
Patients
Treatment
Vogelzang et al50 448 chemotherapyPemetrexed and
naïve patients with
cisplatin (n =
MPM not eligible for 226) versus ciscurative surgery
platin (n = 222)*
Primary RandomiOutcome zation
Blinding
Allocation
Concealment Results
Survival
Yes
Singleblinding
Not clear
Median survival: 12.1 mo in
pemetrexed/cisplatin group
versus 9.3 mo in cisplatin
group (P = 0.02)
van Meerbeeck 250 chemotherapyRaltitrexed and cis- Survival
et al51
naïve patients with
platin (n = 126)
MPM not eligible for versus cisplatin
radical surgery
(n = 124)
Yes
No
Not clear
Median survival: 11.4 mo in
raltitrexed/cisplatin group
versus 8.8 mo in cisplatin
group (P = 0.048)
MPM = malignant pleural mesothelioma.
*Dexamethasone was given the day before, day of, and day after pemetrexed dosing to reduce skin rash. During the study, the protocol was changed
to include folic acid and vitamin B12 supplementation to all enrolled patients after 3 deaths occurred in the experimental group.
gene transfer using an adenoviral vector, anti-mesothelin
immunotoxin, antibody against vascular endothelial
growth factor, and selective modalities of irradiation.55–58
Prognosis
The median survival from diagnosis was 8.9 months
in a recent population-based study in the United Kingdom.59 Shorter survival has been associated with pleural
involvement, lactate dehydrogenase level greater than
500 U/L, poor performance status, chest pain, platelet
count greater than 400,000 cells/µL, nonepithelial histology, and increasing age older than 75 years.60 Surgical predictors of poor prognosis include positive resection margins and metastatic extrapleural nodes.61 More
recently, new serum biomarkers and gene expression
data have been identified and shown to correlate with
clinical outcome.62
surveillance. Chest radiograph reveals a localized area of
increased density along the peripheral chest wall. When
visualized en face rather than in profile, pleural plaques
may appear as a lung nodule. Oblique films usually reveal the pleural location. In 15% of cases, calcification
is present on plain radiographs.69 CT is especially useful
in eliminating false-positive diagnoses of noncalcified
plaques caused by subpleural fat and prominent intercostal muscles.70 Figure 3 shows a chest CT scan of a
patient with pleural plaque. In a longitudinal study, the
presence of pleural plaques in workers with previous
asbestos exposure did not predict loss of lung function.71
However, the presence of pleural plaques has been independently associated with abnormal lung function.72,73
Pleural plaques indicate increased risk for asbestosis and
should therefore prompt monitoring for development of
interstitial fibrosis or MPM.65
PLEURAL PLAQUES
DIFFUSE PLEURAL THICKENING
Pleural plaques are characterized by thickening of
the parietal pleura and are the most common asbestosrelated disorder. For example, a field-based, crosssectional study in villages from Turkey found pleural
plaques in 14.4% of the villagers.63 Pleural plaques are
a useful surrogate of past asbestos exposure; however,
the extent of their surface does not seem to correlate
with cumulative asbestos exposure.64 They typically follow the ribs on the lower posterior thoracic wall or are
located over the central tendons of the diaphragm.65
The visceral pleura, costophrenic angles, and lung apices are usually spared.66
Patients with pleural plaques can be asymptomatic
or manifest with shortness of breath and chest pain.67,68
Asymptomatic pleural plaques are found incidentally
or when asbestos-exposed individuals undergo imaging
In most cases, diffuse pleural thickening is the sequela
of previous benign asbestos effusion or the result of multiple confluent plaques. Extension of pulmonary fibrosis to
the visceral and parietal pleura, previously thought to be
the main cause of diffuse pleural thickening, was responsible for only 10% of the cases in a series of 185 cases.74
Common differential diagnosis includes the residue of
malignant effusion, previous infection, or trauma.74
The pathogenesis of diffuse pleural thickening depends on its cause. In the case of pleural fibrosis
induced by asbestos exposure, it has been postulated
that inhaled fibers can accumulate in the pulmonary
interstitial space and be transported to the subpleural
space by means of lymphatic flow. Then, there is perturbation of fibroblasts, which produces extracellular
matrix proteins and respond to injury by producing
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Mesothelioma and Other Asbestos-Related Pleural Diseases
scar tissue, manifested as pleural fibrosis. That many
patients develop pleural fibrosis without evident lung
parenchymal disease suggests that the fibrogenic drive
has an underlying genetic component.75
On chest radiograph, McLoud et al74 defined diffuse pleural thickening as a smooth, noninterrupted
pleural density over at least one fourth of the chest
wall. On chest CT, Lynch et al66 defined diffuse pleural
thickening as a continuous sheet of pleural thickening
more than 5 cm wide, more than 8 cm in craniocaudal
extent, and more than 3 mm thick.
Diffuse pleural thickening is associated with restrictive lung function.76 Additionally, total lung capacity has
a strong negative association with the extent of diffuse
pleural thickening.77 Although trapping of the lung has
been postulated as the cause of restrictive physiology in
diffuse pleural thickening, early parenchymal fibrosis
likely contributes to it, especially when low carbon
monoxide diffusing capacity is present.76
ROUNDED ATELECTASIS
Rounded atelectasis is a distinct form of subpleural
collapse characterized by adjacent pleural thickening
and invagination of the lung parenchyma. In most cases,
it is secondary to asbestos exposure, but other causes
have also been implicated, including lymphangioleiomyomatosis, post–coronary artery bypass surgery, and
end-stage renal disease.78–80 In a series of 74 patients with
rounded atelectasis, 64 (86.5%) had been occupationally exposed to asbestos, with an overall mean length of
exposure of 24.6 years; all of those exposed to asbestos
were male, and their mean age was 62.6 years.81
At least 3 theories have been formed to explain
the pathogenesis of rounded atelectasis: the folding
(pleural effusion), fibrosing (pleural injury), and microbronchial distortion theories.82,83 The folding theory
claims that a pleural effusion causes the lung to float,
collapse, and eventually fold about itself. The fibrosing
theory holds that an initial injury to the pleura leads to
an inflammatory reaction and subsequent fibrosis in its
most superficial layer. The contraction of the fibrous
tissue pulls the underlying pleura with resulting invagination to the lung parenchyma. Since the elastic tissue
framework is closely connected with the pleural internal elastica lamina, the invagination leads to collapse
of the lung parenchyma.82,84 The newly proposed microbronchial distortion theory assimilates the previous
2 mechanisms by suggesting that increasing pleural
fluid pressure or visceral pleural fibrotic plaque con-
Figure 3. Transverse section chest computed tomography scan
(5-mm collimation) without contrast showing calcified pleural
plaque along the right diaphragmatic pleural surface.
traction cause displacement of underlying lung parenchyma and distortion of small bronchi with subsequent
peripheral gas absorption.83
Rounded atelectasis can be asymptomatic or produce
shortness of breath, cough, and chest pain.85 On chest
radiograph, it appears as a focal lung nodule or mass
in a subpleural location, with curvilinear opacities connecting the mass to the hilum. The so-called “comet-tail
sign” represents blood vessels and bronchi converging
in a whirling pattern toward the base of the lung and
then curving up to enter the mass along its anteriorinferior margin. The lesion is characteristically located
at the lung base and measures 2.5 to 5 cm in greatest
di­ameter. Chest CT typically shows a rounded or oval peripheral lung mass abutting a pleural surface, a comettail sign, volume loss in the affected lobe, and associated
pleural thickening with or without calcification.86 Hilar
or mediastinal lymphadenopathy is not associated with
rounded atelectasis; the presence of lymphadenopathy
should prompt further consideration of malignancy. In
a study evaluating the accuracy of chest CT criteria for diagnosing rounded atelectasis, the presence of a pleuralbased mass and pleural thickening adjacent to the mass
were present in all cases of rounded atelectasis but
lacked specificity. The best discriminating criterion was
the comet-tail sign, with a specificity of 92%.87 Figure 4
shows typical CT findings of rounded atelectasis.
Although chest CT is a useful tool for the diagnosis
of rounded atelectasis, there is no perfect imaging discriminator between rounded atelectasis and other similar lesions. Since malignancy is the main differential
diagnosis, close follow-up is necessary when lung biopsy
in not performed.87 In the absence of classic features,
biopsy should be entertained.88
www.turner-white.comPulmonary Disease Volume 13, Part 5 Mesothelioma and Other Asbestos-Related Pleural Diseases
Figure 4. Transverse section chest computed tomography scan without contrast
(5-mm collimation) showing typical findings
of rounded atelectasis: an oval pleural based
lung lesion, comet-tail sign, adjacent pleural
thickening, and pleural plaques. Follow-up
over 4 years revealed stability of the lesion.
BENIGN PLEURAL EFFUSION
Benign pleural effusion is common in individuals exposed to asbestos. One study showed a 3.1% prevalence
of benign pleural effusion in individuals exposed to
asbestos. Moreover, effusions of any cause were 5 times
more common in individuals exposed to asbestos than
in a nonexposed group.89 It is a frequent cause of effusions without immediate apparent cause, emphasizing
the importance of obtaining a comprehensive social
and occupational history. In a series of 22 patients, the
time from initial asbestos exposure to development of a
pleural effusion varied broadly, but the mean duration
was 16.3 years.90
The most common presenting symptom is pleuritic
chest pain followed by fever sensation and shortness of
breath. In almost half of the cases, the effusion is asymptomatic and discovered incidentally.91 Chest radiograph
usually shows unilateral pleural effusion with associated pleural thickening.90 The effusion is an exudate
and is grossly bloody in approximately half of cases.91
While the effusion recurs in a minority of patients, the
large majority of effusions spontaneously resolve within
12 months of diagnosis.90
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