Diffuse Malignant Mesothelioma
Sergio Pina Oviedo, MD; Philip T. Cagle, MD
? Diffuse malignant mesothelioma (DMM) is an uncom-
mon cancer with great clinical significance because it
currently remains an incurable disease, and most patients
die within months after diagnosis. Although DMM inci-
dence is leveling off or decreasing in developed countries
because of the strict control of asbestos use, it is increasing
in countries without adequate asbestos control. In some
settings, benign, reactive mesothelial hyperplasias and
organizing pleuritis can be difficult to differentiate from
DMM and vice versa, and the variety of DMM’s
histopathologic features generates an extensive list of
differential diagnoses with other malignancies, particular-
ly, metastatic malignancies, which are more frequent in
the pleura than are primary malignancies. These two issues
are the topic of discussion in this review, along with a brief
presentation of a case of DMM that presented in a 66-year-
old man with recurrent, right pleural effusions, and in
whom, diagnosis of DMM had not been suspected
clinically, radiographically, surgically, grossly, or initially,
on frozen section. It was not until focal invasion into the
skeletal muscle was discovered on permanent sections that
a diagnosis of DMM could be established.
(Arch Pathol Lab Med. 2012;136:882–888; doi: 10.5858/
REPORT OF A CASE
and the surgeon peeled ‘‘white-yellow fibrous plaque’’ from the
right parietal pleura and chest wall, which was sent for frozen
section. At frozen section, a diagnosis of ‘‘fibrous pleural plaques
with chronic inflammation’’ was made, and tissue was submitted
for permanent-section examination. On permanent sections,
fibrous pleural tissue, adipose tissue, and skeletal muscle were
present along with focal areas of proliferating epithelioid cells with
round nuclei, prominent nucleoli, and relatively abundant cyto-
plasm consistent with mesothelial cells. Focally, the epithelioid
cells were noted to infiltrate the skeletal muscle (Figure 1). A
diagnosis of diffuse malignant mesothelioma (DMM) was made
based on this unequivocal, focal invasion into skeletal muscle. The
diagnosis of DMM had not been suspected clinically, radiograph-
ically, surgically, grossly, or initially, on frozen section. It was not
until the focal invasion was discovered on permanent sections that
the diagnosis of DMM could be made.
66-year-old man presented with recurrent, right pleural
effusion. The patient underwent thoracoscopic examination,
Overview of DMM Diagnosis
Diffuse malignant mesothelioma is an uncommon cancer,
but it has great significance because (1) it is currently an
incurable disease, and most patients die within months after
diagnosis, thus diagnosis carries very severe implications;
(2) the close association of most traditional cases with
occupational asbestos exposure introduces a host of
medicolegal, regulatory, environmental, and government
policy issues, far beyond what is experienced with most
cancers; (3) although the incidence of DMM is leveling off or
decreasing in the United States and some other developed
countries because of the strict control on asbestos use,
DMM is increasing as a worldwide problem, both in
countries that delayed asbestos control relative to the
United States and in many developing countries where
burgeoning industrialization is not accompanied by ade-
quate asbestos control (there are also reports of an increase
of DMM in a younger population in developed countries
without evidence of asbestos exposure); and (4) DMM can
be notoriously difficult to diagnose for 2 primary reasons: (1)
benign, reactive mesothelial hyperplasias and organizing
pleuritis can be difficult to differentiate from DMM in some
settings and vice versa; and (2) the variety of DMM’s
histopathologic features generates an extensive list of
differential diagnoses with other malignancies, particularly
metastatic malignancies, which are more frequent in the
pleura than are primary malignancies.1–10
This fourth issue—the quandaries of diagnosis—is the
topic of this review. Historically, the difficulties in diagnos-
ing DMM led to the creation, decades ago, of national
panels of pathology experts for consultation, including the
United States–Canadian Mesothelioma Reference Panel.
The first chair of the United States–Canadian Mesothelioma
Reference Panel was the late Jacob Churg, MD, and the
current chair is his son, Andrew Churg, MD, of the
University of British Columbia (Vancouver, British Colum-
bia, Canada). In recent years, in addition to consulting on
medical cases referred by pathologists, this group has
published several articles on the differentiation of DMM
from benign mimics.11–12Since the late 1990s, the Interna-
tional Mesothelioma Panel has been headed by Francoise
Accepted for publication April 13, 2012.
From the Department of Pathology and Genomic Medicine, The
Methodist Hospital, Houston, Texas (Drs Oviedo and Cagle); and the
Department of Pathology and Laboratory Medicine, Weill Cornell
Medical College of Cornell University, New York, New York (Dr
The authors have no relevant financial interest in the products or
companies described in this article.
Presented at the New Frontiers in Pathology: An Update for
Practicing Pathologists meeting; University of Michigan; October 13,
2011; Ann Arbor, Michigan.
Reprints: Philip T. Cagle, MD, Department of Pathology and
Genomic Medicine, The Methodist Hospital, 6565 Fannin St, Ste
M227, Houston, TX 77030 (e-mail: email@example.com).
882Arch Pathol Lab Med—Vol 136, August 2012Diffuse Malignant Mesothelioma––Oviedo & Cagle
Galateau-Sall´ e, MD, of Caen, France, who is also chair of
the French Mesothelioma Reference Panel. This group,
supported by the French Ministry of Health, is composed of
experts from many countries and is particularly focused on
differentiation of early, including in situ, DMM from reactive
mesothelial hyperplasia.4Many of us (the same experts) also
serve on the pathology section of the International
Mesothelioma Interest Group, headed by Aliya Husain,
MD, of the University of Chicago, which has previously
published a consensus guideline on diagnosis of DMM in
the Archives of Pathology & Laboratory Medicine and will be
publishing an update in the near future.7,10The publications
of all of these expert panels are excellent sources for
information on DMM, particularly the pathologic diagnosis.
BENIGN PROLIFERATIONS VERSUS DMM
The pleural surface is lined by a single layer of flattened,
inconspicuous mesothelial cells that may show varying
degrees of reactive hyperplasia when the pleura is irritated
or inflamed. Reactive mesothelial hyperplasia is often, but
not always, seen in association with organizing fibrinous
and/or fibrous pleuritis (Figure 2). Pleuritis is often
accompanied by pleural effusion. Conditions that may cause
reactive mesothelial hyperplasia and/or organizing pleuritis
include, but are not limited to, infections (pleural infections
and subpleural pneumonias), collagen vascular diseases,
pulmonary infarcts, drug reactions, pneumothorax, sub-
pleural lung carcinomas, thoracic surgery, and chest trauma
as well as nonspecific or idiopathic cases. In some cases,
pleuritis with pleural thickening and pleural effusion of
unknown etiology is biopsied to rule out malignancy.
Whether malignancy is a clinical and radiologic consider-
ation, the pathologist may encounter florid, reactive
mesothelial hyperplasia and/or organizing pleuritis on
pleural biopsy or decortication specimens, for which DMM
is in the histopathologic differential diagnosis. The diag-
nostic question is not ‘‘what type of malignancy,’’ but rather,
‘‘is this cellular proliferation benign or malignant?’’1–7,9–17
Simple hyperplasia of reactive mesothelium is usually not
confused with malignancy and, as the name implies,
consists of a single row of regularly spaced, cytologically
bland, cuboidal mesothelial cells along the pleural surface
(Figure 3). Many florid, reactive mesothelial hyperplasia
cases, however, can exhibit one or more features suggestive
of malignancy, including high cellularity, cytologic atypia
with enlarged nuclei and prominent nucleoli, and the
presence of mitoses (Figure 4). In fact, some cases of florid,
reactive mesothelial hyperplasia can have greater cytologic
atypia than some cases of epithelioid DMM, which can be
very bland cytologically. Other histopathologic features
sometimes observed in florid, reactive mesothelial hyper-
plasia can appear even more ominous. These include
architectural changes, such as simple lumens or simple
papillary tufts (Figure 5); areas of necrosis (eg, leukocyto-
clastic necrosis occasionally seen in pleural infections); and,
Entrapment (Figure 6) occurs when organizing pleuritis
layers lie over a pleural surface lined by reactive mesothelial
hyperplasia, giving an initial impression of invasive meso-
thelial cells (see below). Closer examination discloses that
the hyperplastic mesothelial cells are arranged in a linear
pattern (which, in fact, is along the original pleural surface).
The hyperplastic mesothelial cells may exhibit the reactive
changes mentioned in the previous paragraph. However, no
round nuclei, prominent nucleoli, and relatively abundant cytoplasm
infiltrating between skeletal muscle fibers on pleural biopsy, consistent
with a diagnosis of diffuse malignant mesothelioma (hematoxylin-eosin,
original magnification 3300).
High-power magnification shows epithelioid cells with
fibroblastic granulation tissue in this organizing fibrinous and fibrous
pleuritis (hematoxylin-eosin, original magnification 3300).
Eosinophilic fibrin mixed with red blood cells is organized by
mesothelial cells lines the pleural surface in simple mesothelial
hyperplasia (hematoxylin-eosin, original magnification 3300).
A single row of regularly spaced, reactive, cuboidal
Arch Pathol Lab Med—Vol 136, August 2012Diffuse Malignant Mesothelioma––Oviedo & Cagle883
invasion into the underlying pleural or subpleural tissues is
observed, and the ‘‘lumen’’ or ‘‘lumens’’ are simple, linear
spaces between mesothelial lined surfaces and not complex,
branching tubules. Cytokeratin immunostain will disclose
cytokeratin-positive mesothelial cells along the original
pleural surface and, perhaps, scattered within the organizing
pleuritis, but there should be a sharp demarcation with no
cytokeratin-positive cells infiltrating the underlying pleural
connective tissue or subpleural tissues (Figure 7).2–7,10,11,14–17
The proliferating fibroblasts, endothelial cells, and spin-
dled mesothelial cells of organizing pleuritis may mimic
sarcomatoid DMM, and fibrocytes and spindled mesothelial
cells within mature, dense, fibrous pleuritis may mimic
desmoplastic DMM. The storiform pattern that may be seen
in sarcomatoid DMM is lacking in benign pleuritis.
Zonation of the proliferating cells, with more toward the
surface and tapering off in the deeper tissues, is character-
istic of benign pleuritis and can be confirmed with
cytokeratin immunostaining of the reactive spindle meso-
thelial cells, if needed (Figure 8). The orientation of the
tissue may be important because tangential or en face
preparation show increased cellularity, enlarged nuclei, and prominent
nucleoli (hematoxylin-eosin, original magnification 3300).
The benign, reactive mesothelial cells in this touch
observed in this example of benign, reactive mesothelial hyperplasia
(hematoxylin-eosin, original magnification 3300).
Simple, papillary tufts lacking fibrovascular cores are
mesothelial cells lining the pleural surface causing entrapment of the
benign mesothelial cells, which can cause a false impression of invasion
(hematoxylin-eosin, original magnification 3200).
Organizing pleuritis overlies a single row of reactive
plastic mesothelial cells along the pleural surface with scattered
mesothelial cells in the overlying organized pleuritis in this example of
entrapment of benign mesothelial cells (original magnification 3150).
Cytokeratin immunostain demonstrates the row of hyper-
884Arch Pathol Lab Med—Vol 136, August 2012Diffuse Malignant Mesothelioma––Oviedo & Cagle
sections may be misleading about the distribution of the
Another feature that is suggestive of organizing pleuritis,
as opposed to DMM, is the presence of parallel capillaries
perpendicular to the pleural surface within the granulation
tissue. Infiltrating malignant cells would presumably cause
disarray of the capillaries, although this is not definitive
evidence of malignancy.7,10,15,17
A few significant features are considered confirmatory of
DMM on pleural biopsy and decortication specimens and
into underlying tissues, specifically adipose tissue and/or
skeletal muscle under the parietal pleura and lung tissue
under the visceral pleura, is diagnostic of DMM. Cytokeratin
immunostain may be useful in confirming the infiltration of
cytokeratin-positive cells within adipose tissue, skeletal
muscle, or lung tissue (Figure 9). Once again, tangential or
en face sections may be misleading.2–7,10,11,14–17Care should
also be taken not to mistake spaces within organizing
pleuritis (so-called fake fat; Figure 10) for infiltration of
desmoplastic DMM around adipose tissue (the so-called
Swiss cheese effect).12
Proliferating cellular nodules that expand the surrounding
stroma are confirmatory of a neoplasm rather than a reactive
process. In addition, cancer can be diagnosed if there are
unequivocal histopathologic features of malignancy, such as
severe pleomorphism and atypical mitoses. A lack of
zonation with high cellularity of atypical cells throughout
the thickness of the pleura suggests malignancy if the
specimen is properly oriented and not a tangential or en face
section.2–7,10,11,14–17Bland necrosis with foci of ‘‘clean,’’
ischemic-type necrosis of the proliferating cells is charac-
teristic of DMM (Figure 11) and differs from the ‘‘dirty,’’
leukocytoclastic necrosis often seen with infections and
other types of cancer, such as colon cancer. Although bland
necrosis is not diagnostic of DMM by itself, its presence in a
biopsy or decortication specimen may bring attention to a
desmoplastic DMM that might otherwise be overlooked.13
We recommend the term atypical mesothelial proliferation
when it cannot be determined whether a mesothelial
proliferation is benign or malignant in a given specimen
based on the histopathologic criteria discussed above, for
example, during frozen section or when a biopsy is
inconclusive. No doubt, some atypical mesothelial prolifer-
ations are florid, reactive mesothelial hyperplasias, and
others are DMM, but the histopathologic features in the
biopsy may not be definitive for either diagnosis. Therefore,
malignancy is neither confirmed nor ruled out when a
diagnosis of atypical mesothelial proliferation is made. In
these circumstances, the patient’s treating physician may
elect to observe the patient, attempt to obtain diagnostic
tissue, or make another decision, based on clinical suspicion
and other circumstances.2–7,10–17
DMM VERSUS OTHER TYPES OF CANCER
Most cancers involving the pleura are metastatic cancers,
and DMM, as a primary malignancy of the pleura, is actually
uncommon, with fewer than 2000 cases per year in the
United States. Diffuse malignant mesotheliomas have a
variety of histopathologic patterns, which means that many
different types of cancer potentially enter into the differen-
tial diagnosis of DMM and vice versa.
Diffuse malignant mesothelioma is divided into epithe-
lioid (the most common), sarcomatoid, and mixed or
biphasic patterns. In the mixed or biphasic pattern, both
epithelioid and sarcomatoid patterns are observed in the
Epithelioid DMMs are composed of cuboidal to polygonal
cells that histologically resemble mesothelial cells in well-
differentiated DMM, and the correct diagnosis of DMM is
strongly suspected on the basis of the hematoxylin-eosin
histology, in many cases. Secondary patterns of DMM
include well-differentiated solid (Figure 12), tubulopapillary
(Figure 13), or acinar (Figure 14) patterns; less-frequently
adenomatoid or poorly differentiated solid patterns are
seen, and deciduoid, adenoid cystic, signet ring, clear cell, or
small cell patterns are seen infrequently.1–7,9,10,16–22
Although most of the literature focuses on differentiation
of epithelioid DMM from pulmonary adenocarcinoma, that
differential, although important, is not the only differential
to consider for epithelioid DMM. Metastatic adenocarcino-
mas from organs other than the lungs, for example, the
gastrointestinal tract or kidney, may need to be considered
for the solid, tubulopapillary, acinar, adenomatoid, decid-
uoid, adenoid cystic, signet ring, and clear cell patterns.
Beyond metastatic adenocarcinomas from various sites,
metastatic squamous cell carcinomas, melanomas, and
urothelial carcinomas may also enter into the differential
diagnosis of solid-pattern DMM, particularly, if poorly
differentiated, and metastatic squamous cell carcinoma or
melanoma might enter into the differential diagnosis of
clear cell pattern DMM. Small cell DMMs are extremely
rare, but, if encountered, must be differentiated from
pleuritis with mesothelial cells thickest toward the surface and tapering
off in the deeper tissues (original magnification 3200).
Cytokeratin immunostain confirms zonation in this benign
Arch Pathol Lab Med—Vol 136, August 2012Diffuse Malignant Mesothelioma––Oviedo & Cagle885
early diffuse malignant mesothelioma (original magnification 3300).
Cytokeratin immunostain demonstrates infiltration of cytokeratin-positive mesothelioma cells infiltrating into adipose tissue in a case of
organizing pleuritis (hematoxylin-eosin, original magnification 3300).
Vacuoles in the midst of mesothelial cells create the false impression of invasion into the adipose tissue in this example of ‘‘fake fat’’ in
886 Arch Pathol Lab Med—Vol 136, August 2012 Diffuse Malignant Mesothelioma––Oviedo & Cagle
metastatic small cell carcinoma of the lung or other
Sarcomas, metastatic to the pleura and, much less-
frequently, primary in the pleura, enter into the differential
diagnosis of sarcomatoid DMM, as do sarcomatoid carci-
nomas and spindle cell melanomas. Sarcomatoid DMM may
sometimes have heterologous elements (osteosarcomatous
or chondrosarcomatous) or be pleomorphic.1–7,9,10,16–32The
rare lymphohistiocytoid DMM (Figure 15) must be differ-
entiated from lymphoma, in addition to inflammatory
The differentiation of these patterns of DMM from
metastatic cancers from other sites depends on the clinical
history and imaging observations as well as the immuno-
staining patterns of the cancer. The immunohistochemical
traits of the entire range of malignancies that might
metastasize to the pleura and mimic DMM is beyond the
scope of this review, and there are a number of other
sources on this subject.1–7,9,10,25,27,28However, as noted
earlier, for all the focus in the literature on pulmonary
adenocarcinoma versus epithelioid DMM, the pathologist
should not omit consideration of primary sites other than
the lungs and cell types of cancer other than adenocarci-
noma, depending on the context of the case and the
histopathologic pattern observed. Because the immuno-
stains that distinguish pulmonary adenocarcinoma from
epithelioid DMM may not apply to these other cancers,
other immunostains may be warranted, depending on the
diagnostic considerations. Some of these other cancers may
be immunopositive for markers traditionally used to
separate DMM from pulmonary adenocarcinoma. For
example, squamous cell carcinoma is often immunopositive
for CK 5/6, which was once used as a DMM marker, and
ovarian carcinoma is often immunopositive for WT1,
another marker used to distinguish DMM from pulmonary
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(hematoxylin-eosin, original magnification 3300).
Bland necrosis consists of a ‘‘clean,’’ ischemic necrosis in the upper left of this sarcomatoid diffuse malignant mesothelioma
round nuclei, prominent nucleoli, abundant cytoplasm, and distinct cell borders (hematoxylin-eosin, original magnification 3300).
The malignant cells in this well-differentiated, solid diffuse malignant mesothelioma have features of mesothelial cells, including relatively
diffuse malignant mesothelioma (hematoxylin-eosin, original magnification 3300).
Papillae with fibrovascular cores lined by malignant cells that cytologically resemble mesothelial cells are seen in this tubulopapillary
(hematoxylin-eosin, original magnification 3300).
Malignant cells that cytologically resemble mesothelial cells line lumens in this case of acinar diffuse malignant mesothelioma
nant cells that cytologically resemble mesothelial cells and can be
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