My approach to the diagnosis of mesothelial lesions
K J Butnor
............................................................... ............................................................... .
J Clin Pathol 2006;59:564–574. doi: 10.1136/jcp.2005.029652
Mesothelial lesions pose considerable diagnostic
challenges not only because benign tumours, reactive
proliferations and malignant mesothelioma can mimic one
another, but also because the morphological patterns
displayed by malignant mesothelioma can simulate a
variety of epithelial and non-epithelial malignancies.
Immunohistochemical markers can aid in distinguishing
epithelioid malignant mesothelioma from metastatic
adenocarcinoma, but because no single marker reliably
separates all cases, a panel of stains is recommended.
Immunohistochemical studies are of more limited value in
sarcomatoid malignant mesothelioma, and other features
often play an essential role. The separation of reactive
mesothelial proliferations from malignant mesothelioma on
small biopsy can be quite difficult, as distinguishing
features, such as stromal invasion, often cannot be
adequately assessed. In adequately sampled lesions,
however, the distinction between malignant mesothelioma,
benign mesothelial proliferations and other tumours can be
achieved in most cases by using a carefully intergrated
approach that incorporates clinical and radiographic data,
immunohistochemical studies and, in selected cases,
histochemical and ultrastructural techniques.
with the broad spectrum of morphological
appearances that malignant mesothelioma can
exhibit, and it is easy to understand why the
diagnosis of malignant mesothelioma is one of
the most challenging topics of surgical pathol-
approach to the diagnosis of mesothelial lesions
and their mimics and explores the role of
immunohistochemistry and other ancillary tech-
niques. The morphological patterns most prob-
ably encountered when evaluating suspected
mesothelial lesions include epithelioid pattern,
spindle cell or sarcomatoid pattern, biphasic
pattern and paucicellular or fibrotic pattern.
Table 1 lists the histological patterns seen in
K J Butnor, University of
Health Care, 111
Burlington, VT 05401,
Accepted for publication
7 November 2005
n immunohistochemical marker that is
both sensitive and specific for malignant
mesothelioma remains elusive. Couple this
As the epithelioid variant is the most common
histological subtype of malignant mesothelioma
and its principal differential consideration, meta-
static adenocarcinoma, is the most frequent non-
mesothelial neoplasm to involve the serosal
membranes, the epithelioid pattern is the most
likely pattern to be encountered in cases of
suspected malignant mesothelioma.
Epithelioid proliferations of the serosal mem-
branes can take the form of non-descript solid
sheets of neoplastic cells. Other architectural
arrangements can be more helpful in providing
clues to the diagnosis. A pure tubular configura-
tion, in which flattened-to-cuboidal cells encircle
hollow spaces, or a tubulopapillary configuration
of branching tubules admixed with papillae
and trabeculae, favours a diagnosis of epithe-
lioid malignant mesothelioma (EMM; fig 1).
Adenomatoid and microcystic configurations,
where the microcystic is characterised by cyst-
like spaces lined by attenuated cells and lakes of
basophilic extracellular material, can also be seen
in EMM (fig 1). In contrast, true acinar forma-
tions composed of columnar cells with eccentric
nuclei arranged around a central lumen are not
typical of EMM and should suggest a diagnosis
of adenocarcinoma. Papillary formations can be
seen in both reactive and malignant mesothelial
proliferations, as well as in adenocarcinoma
(fig 1). Both EMM and adenocarcinoma can also
exhibit an adenoid cystic configuration. Such
overlap emphasises the need to place architec-
tural features in the context of other findings.
Cytologically, EMM may be deceptively bland.
The cells in EMM are typically round, cuboidal or
polygonal, and have paracentric nuclei with
small nucleoli and a moderate amount of
acidophilic cytoplasm (fig 2). Paradoxically,
reactive mesothelial lesions often show more
cytological atypia than EMM and mitotic figures
are generally more abundant. In adenocarci-
noma, cells tend to exhibit eccentric nuclei,
prominent nucleoli, vesicular chromatin and a
greater degree of nuclear overlap and pleomorph-
ism than is seen in malignant mesothelioma
(fig 3). Intracytoplasmic vacuoles are seen in
both adenocarcinoma and malignant mesothe-
lioma, but unlike the crisp round borders seen in
the adenocarcinoma, mesothelial vacuoles are
usually degenerative in nature and appear
loculated with indistinct borders. Psammoma
bodies are occasionally seen in EMMs with a
papillary configuration, but when present in
abundance, a diagnosis of carcinoma, particu-
larly serous ovarian or primary peritoneal carci-
noma, should be strongly favoured.1 2
Abbreviations: BMM, biphasic malignant mesothelioma;
CEA, carcinoembryonic antigen; DMM, desmoplastic
malignant mesothelioma; EMM, epithelioid malignant
mesothelioma; SMM, sarcomatoid malignant
mesothelioma; TTF-1, thyroid transcription factor-1;
HBME-1, human mesothelial Cell-1; WT1, Wilms tumour
These cytological dissimilarities are not a constant feature
and EMM may occasionally show quite striking cytological
The degree of overlap between the morphological appearance
of EMM and its mimics warrants the use of ancillary
techniques such as immunohistochemical analyses in most
cases. As no singularly sensitive and specific immunohisto-
chemical marker for EMM exists, a panel of immunostains is
typically used. As there is not a single best panel, a well-
constructed panel includes a pan-cytokeratin, at least two
mesothelial markers and at least two carcinoma-associated
markers. The choice of antibodies depends largely on which
markers show consistently reliable results in the laboratory.
In my practice, I use a panel comprised of (1) pan-cytokeratin
AE1-AE3/Cam 5.2, (2) cytokeratin 5/6, (3) calretinin, (4)
monoclonal carcinoembryonic antigen (CEA) for pleural
tumours or B72.3 for peritoneal tumours and (5) thyroid
transcription factor-1 (TTF-1) for pleural tumours or Ber-EP4
for peritoneal tumours.
Diffuse staining with pan-cytokeratin is useful because it
confirms an epithelial process (fig 4). Cytokeratin 5/6 stains
more than 95% of EMMs (fig 4).3Occasional cytokeratin 5/6
expression has been reported in a variety of adenocarcino-
mas.3–5Cytokeratin 5/6 expression should be interpreted with
caution in cases with a squamoid morphology, as most
squamous cell carcinomas are positive.3The sensitivity of
calretinin varies depending on the clone used, but is in the
range of 73–100%.6 7Both the nuclear and cytoplasmic
compartments of malignant mesothelioma typically stain
pattern with lakes of basophilic material. (C) Papillary pattern. (D) Deciduoid pattern with plump polygonal cells with eosinophilic cytoplasm.
Histological patterns of epithelioid malignant mesothelioma. (A) Tubulopapillary pattern with branching tubules and papillae. (B) Microcystic
Histological patterns in malignant
leiomyosarcomatous or rhabdomyosarcomatous
Undifferentiated high-grade pleomorphic sarcoma
(malignant fibrous histiocytoma)-like
showing cuboidal cells with paracentric, bland nuclei, relatively
inconspicuous nucleoli and a moderate amount of cytoplasm.
Close-up view of epithelioid malignant mesothelioma,
Diagnosis of mesothelial lesions565
with calretinin, although nuclear staining is considered far
more specific (fig 4).4Staining limited to the cytoplasm
should not be interpreted as unequivocal evidence of
mesothelial differentiation, as it can be occasionally seen in
Monoclonal CEA serves the dual function of being a
reliable negative marker for EMM and a positive marker in
most pulmonary adenocarcinomas (fig 5).11Monoclonal CEA
is preferred to polyclonal CEA because polyclonal CEA has a
propensity for non-specific background staining.12For pleural
biopsies, a second sensible carcinoma-associated marker is
TTF-1. Thyroid transcription factor-1 shows nuclear staining
in 75% or more of pulmonary adenocarcinomas and is
consistently negative in EMM (fig 5).13 14Cytoplasmic TTF-1
staining is non-specific and has been reported in carcinomas
from several sites.15
Although CEA is a sensitive marker for pulmonary
adenocarcinoma, it detects ,20% of primary peritoneal or
ovarian serous carcinomas.16A more suitable choice for
peritoneal biopsies is B72.3, which diffusely stains around
70–80% of adenocarcinomas, including ovarian carcinoma,
and is negative in most EMMs.1 10As thyroid transcription
factor-1-positive tumours do not generally enter the differ-
ential diagnosis of peritoneal tumours, Ber-EP4 can be
substituted as a second carcinoma-associated marker in
peritoneal biopsies. Similar to B72.3, Ber-EP4 is diffusely
positive in a high proportion of adenocarcinomas.17Ber-EP4
staining occurs in a minority of malignant mesotheliomas
and when present, is typically restricted to a few cells.8 17 18
In tumours that are positive for only one of the two
only pan-cytokeratin-positive, or show conflicting results,
additional markers may be helpful (table 2). The newly
developed markers D2-40 and anti-podoplanin show mem-
branous staining in 86–96% of EMMs (fig 4).19 20Both
antibodies have been recently shown to recognise the same
protein, the human mucin-type glycoprotein podoplanin.21
Carcinomas from several sites, such as lung, breast and
kidney, are negative for these markers. D2-40, however, must
be used with caution in peritoneal biopsies, as staining was
observed in some ovarian serous carcinomas.19As D2-40 and
podoplanin also highlight lymphatic endothelial cells, care
must be taken not to misinterpret staining of lymphatic
channels as evidence of mesothelial differentiation. The list
of vascular tumours that are recognised by these markers
continues to grow. The Wilms tumour gene 1 protein (WT1)
shows nuclear staining in about of 80% of EMMs.14 22–24
Although this is a useful marker in pleural biopsy, in which
the main distinction is between EMM and pulmonary
adenocarcinoma, it is of limited utility in peritoneal biopsies,
as a substantial number of renal, ovarian and endometrial
carcinomas stain for this marker.25–27Thrombomodulin is also
positive in a high proportion of EMM, but like cytokeratin
5/6, this marker stains most squamous cell carcinomas and,
forming columnar cells with nucleoli.
Adenocarcinoma metastatic to the pleura, showing gland-
cytokeratin 5/6 staining. (C) Calretinin stains both the nuclei and cytoplasm. (D) D2-40 exhibits a membranous staining pattern.
Case (D) a kind gift from James Burchette, Duke University, Durham, North Carolina, USA.
Immunohistochemical staining in epithelioid malignant mesothelioma. (A) Diffuse, strong staining for pan-cytokeratin. (B) Cytoplasmic
in addition, is often positive in urothelial and renal cell
carcinomas.28–30Despite initial enthusiasm, human mesothe-
lial cell-1 (HBME-1), mesothelin and an array of other
purported mesothelial markers have subsequently been
shown to lack specificity for EMM.31–33
Additional exclusionary markers for EMM include MOC-
31, which diffusely stains a very high proportion of
carcinomas and is only focally immunoreactive in rare
EMMs, and BG-8, which shows comparable results.10 34
CD15 (Leu-M1) stains around 60–70% of adenocarcinomas
and is negative in most EMMs, with most of the rare positive
cases occurring in the peritoneum.1 10 32 35 36
With the proliferation of sophisticated immunohistochemical
markers, interest in histochemical stains for the diagnosis of
malignant mesothelioma has waned. Histochemical techni-
ques, however, should not be overlooked, particularly when
immunostains produce conflicting or equivocal results.
Intense staining of intracytoplasmic vacuoles or luminal
secretions for periodic acid-Schiff after pretreatment with
diastase or Alcian blue after hyaluronidase, which is
indicative of neutral acid mucin production, favours a
diagnosis of adenocarcinoma, whereas absent or markedly
decreased staining after pretreatment is more consistent with
malignant mesothelioma (table 2; fig 6).37Mucicarmine
should not be used, as it occasionally cross reacts with
hyaluronic acid. Histochemical stains are generally not useful
for the diagnosis of non-epithelioid malignant mesothelio-
When immunohistochemical and histochemical results are
inconclusive, detecting characteristic ultrastructural features
by electron microscopy may facilitate the diagnosis of
malignant mesothelioma. Although a detailed discussion of
the ultrastructure of malignant mesothelioma is outside the
scope of this review, a key ultrastructural element of EMM is
the presence of long, slender microvilli.38 39Unfortunately,
distinguishing features may not be present in all cases,
particularly in poorly differentiated tumours.40
The main entity to exclude when considering a diagnosis of
EMM is metastatic carcinoma; ancillary techniques provide
considerable support in this distinction. Accurate diagnosis,
however, requires the integration of clinicoradiographic
information. In some instances, there is a pre-existing
diagnosis of carcinoma at an extraserosal site. Comparison
of the histological features of a serosal biopsy specimen with
those of the primary tumour may obviate the need for
immunohistochemical stains or prompt the use of site-
specific carcinoma-associated markers, such as thyroglobulin
or prostate specific antigen.
It is also essential to confirm that the gross distribution of
tumour is compatible with the histological impression. In
cases of metastatic carcinoma, an extraserosal mass is usually
apparent and the serosa is typically studded by multiple small
nodules or is irregularly thickened by discrete masses. By
contrast, malignant mesothelioma usually features confluent
nodules or forms a diffuse thick rind-like growth that encases
the subjacent organs. Not all tumours that diffusely involve
the serosa, however, represent malignant mesothelioma, nor
are all malignant mesotheliomas diffusely distributed. Rarely,
carcinomas and other non-mesothelial tumours can exhibit a
growth pattern similar to that of malignant mesothelioma,
Malignant mesothelioma uncommonly manifests as a sharply
mesothelioma seems to have a much better prognosis than
the diffuse form of malignant mesothelioma.45
Several rare variants of EMM deserve special mention
because of their propensity to be confused with other
Immunohistochemical staining of lung adenocarcinoma metastatic to the pleura. (A) Monoclonal carcinoembryonic antigen. (B) Thyroid
histochemical staining reactions in epithelioid malignant
mesothelioma and adenocarcinoma
Expected immunohistochemical and
with diastase (PAS-D)
Alcian blue with
+ or 2
If + without digestion,
remains + after digestion
+, positive; 2, negative.
*Positive in a small proportion of non-pulmonary adenocarcinomas.
?Nuclear staining in pulmonary adenocarcinoma and thyroid
`Positive in some renal, ovarian and endometrioid carcinomas.
1Positive in most renal and urothelial carcinomas.
CEA, Monoclonal carcinoembryonic antigen; TTF-1 thyroid transcription
factor-1; WT1, Wilms tumour gene 1; PAS-D, periodic acid-Schiff-D.
Diagnosis of mesothelial lesions567
tumours. Clear cell malignant mesothelioma can histologi-
cally mimic conventional
Distinguishing renal cell carcinoma from clear cell malignant
mesothelioma can be quite challenging, not only because
renal cell carcinoma has the propensity to metastasise long
before the primary tumour is discovered but also because
renal cell carcinoma does not consistently stain with some
carcinoma-associated markers, such as CEA. The most
reliable markers for distinguishing clear cell malignant
mesothelioma from renal cell carcinoma seem to be
calretinin, cytokeratin 5/6 and CD15.47 48
Deciduoid malignant mesothelioma is comprised of sheets
of plump round-to-polygonal cells with eosinophilic cyto-
plasm (fig 1). Deciduoid malignant mesothelioma has been
confused with ectopic decidual reaction and may also be
mistaken for other oncocytoid tumours, such as hepatocel-
lular carcinoma and adrenocortical carcinoma.49Hep-Par1
and inhibin, markers that are positive in hepatocellular
carcinoma and adrenocortical carcinoma, respectively, are
negative in EMM.50
EMM with a predominantly papillary configuration must
be distinguished not only from adenocarcinomas such as
ovarian and primary peritoneal serous carcinoma but also
from well-differentiated papillary mesothelioma, a generally
indolent tumour characterised by serosal plaques or small
nodules composed histologically of fibrovascular cores lined
by bland cuboidal mesothelial cells (fig 7). Although it is
debatable whether focal invasion is acceptable in well-
differentiated papillary mesothelioma, tumours with diffuse
hyaluronic acid. (B) Staining is markedly reduced in a serial section pretreated with hyaluronidase. (C) Periodic acid-Schiff staining of neutral mucin is
unaffected by diastase digestion, as is shown in the cytoplasmic vacuoles (arrows) of this adenocarcinoma metastatic to the pleura.
(A) Alcian blue staining of epithelioid malignant mesothelioma highlights intracytoplasmic (arrowhead) and intraluminal (arrow) droplets of
fibrovascular cores lined by a single layer of bland cuboidal mesothelial
Well-differentiated papillary mesothelioma with broad
packed sheets within the peritoneum cavity or pleural space (top). This
case is from a patient with spontaneous pneumothorax. Stromal invasion
Exfoliated reactive mesothelium sometimes forms densely
invasion should be designated as EMM.51–55The superficial
portion of some EMMs can exhibit a well-differentiated
papillary mesothelioma-like pattern, which can create diag-
nostic difficulties in small biopsy specimens in which stromal
invasion cannot be definitively assessed.
Diffuse stromal invasion is also helpful in differentiating
EMM from reactive mesothelial proliferations, although care
must be taken not to overinterpret reactive mesothelial cells
entrapped within granulation tissue or organising serositis as
true stromal invasion.56Sheets of mesothelial cells packed
within the pleural or peritoneal space seen in reactive
conditions and without stromal invasion, should not be
diagnosed as malignant (fig 8). Occasionally, nodular prolifera-
tions along the serosal membranes are actually composed of
histiocytes rather than mesothelial cells, which is termed
nodular histiocytic hyperplasia.57
EMA and p53 seem to be preferentially expressed in malignant
mesothelioma, whereas desmin immunoreactivity is more
common in the reactive mesothelium.58 59As overlap exists,
however, the US–Canadian Mesothelioma Reference Panel
recommends that these markers not be routinely used in
individual cases.56The distinction of reactive pleuritis from
malignant mesothelioma is discussed later (see desmoplastic
Benign tumours of mesothelial origin also have the
potential to pose diagnostic problems in small biopsy
samples. Adenomatoid tumours are composed of flat-to-
cuboidal cells arranged in cords and tubules, but unlike most
EMMs, aresolitary, sharply
Multiloculated peritoneal inclusion cysts, or benign multi-
cystic mesothelioma, typically feature multiple translucent
peritoneal cysts lined by bland flattened mesothelium.60The
gross appearance and lack of stromal invasion distinguishes
this entity from the microcystic variant of EMM.
Thymoma, which can be metastatic to or arise primarily in
the pleura, variably expresses antimesothelial antibodies.61
haemangioendothelioma of the pleura composed of plump epithelioid cells, some of which feature intracytoplasmic lumens with red blood cells
(A) Thymoma directly extending the pleura showing an organoid growth pattern and perivascular lakes. (B) Epithelioid
(B) Malignant fibrous histocytoma-like pattern featuring anaplastic and bizarre multinucleated tumour cells. (C) Heterologous elements are sometimes
present, as in this sarcomatoid malignant mesothelioma with osteoid differentiation.
Histological spectrum of sarcomatoid malignant mesothelioma. (A) Spindle cells with a storiform arrangement resembling fibrosarcoma.
Diagnosis of mesothelial lesions569
The possibility of thymoma should be considered in tumours
with a lobulated architecture, perivascular lakes or organoid
growth (fig 9). The expression of immature lymphocytes by
terminal deoxynucleotide transferase (TdT) or CD1a staining
can further help in the distinction from EMM. Germ cell
tumours occasionally involve the serosa, but are negative for
calretinin and stain for placental alkaline phosphatase.62 63
Vascular tumours, such as epithelioid hemangioendothe-
lioma and angiosarcoma, rarely involve the pleura (fig 9).
Although they may show aberrant cytokeratin expression, in
contrast with that in EMM, staining is typical patchy or
weak, and expression of mesothelial-associated markers,
such as calretinin and cytokeratin 5/6, is absent.64 65The
vascular nature of these tumours can be highlighted by
staining for CD31, CD34 and factor VIII. Other non-epithelial
tumours that can mimic EMM include malignant melanoma
and lymphoma, which can be excluded by diffuse staining for
SPINDLE CELL OR SARCOMATOID PATTERN
Occasionally, tumours involving the serosal membranes
feature a spindle cell or frankly sarcomatoid pattern.
Sarcomatoid malignant mesotheliomas (SMMs), which
constitute about 15–20% of malignant mesotheliomas, range
from fibroblast-like spindle cells arranged in a storiform,
fascicular or haphazard pattern reminiscent of fibrosarcoma
to malignant fibrous histiocytoma-like tumours with ana-
plastic and sometimes multinucleated cells (fig 10).66Rarely,
SMMs show leiomyoid, chondroid, osseous or rhabdomyo-
blastic differentiation (fig 10).37 67–69
The mesothelial markers so often useful in the diagnosis of
EMM are of limited value in SMM. Calretinin immunor-
eactivity is seen in only 39–70% of SMMs, whereas
cytokeratin 5/6 stains 0–29% of cases.70 71Spindle cell
neoplasms that mimic SMM occasionally stain for antime-
sothelial antibodies.70 71Mesenchymal differentiation can
sometimes be shown immunohistochemically in SMMs in
the form of smooth muscle actin, desmin or S-100 expres-
Because of the inconsistent staining of SMMs for
mesothelial markers, in cases of suspected SMM, I generally
carry out staining with a limited panel consisting of pan-
cytokeratin and vimentin. Expression of vimentin, which is
present in most malignant mesotheliomas, assures that the
tissue has undergone proper fixation.39Pan-cytokeratin stains
around >70% SMMs, often intensely and diffusely.70 71In
contrast, most sarcomas are non-immunoreactive or only
SMMs often lack the more helpful features generally
associated with malignant mesotheliomas and instead ultra-
structurally resemble soft tissue fibrosarcomas.37
SMMs, especially those displaying heterologous elements,
may simulate sarcomas. A wide variety of sarcomas can
metastasise or directly invade the serosa from adjacent
organs and a few sarcomas may arise as primary serosal
usually helps in the distinction, the separation of SMM from
sarcoma requires the integration of clinical and radiographic
information. Serosal involvement by metastatic sarcoma is
typically a late manifestation. Comparison of the histological
features of the serosal and primary tumours can facilitate
It is more difficult to distinguish SMM from sarcoma-
toid carcinoma, as pan-cytokeratin cannot be used as a
discriminator. As with sarcomas, careful attention to whether
there is radiographic evidence of an extraserosal mass is
essential. As for EMM, malignant melanoma, particularly the
spindle cell variant, is in the differential for SMM.
The biphasic pattern, although less common than the
epithelioid pattern, is more common than a purely sarcoma-
toid pattern in serosal biopsies. About 30% of malignant
mesotheliomas exhibit both epithelioid and sarcomatoid
components (fig 11).54The minor component should com-
prise .10% of the tumour to be designated as biphasic, or
mixed-type, malignant mesothelioma (BMM).54The detec-
tion of a sarcomatoid component in an otherwise epithelioid
tumour, or vice versa, is dependent on the extent of sampling,
as shown by a recent study in which 20% of tumours
diagnosed as EMM at pleural biopsy were reclassified as
BMM at extrapleural pneumonectomy.73In some cases, there
is a gradual transition between epithelioid and sarcomatoid
components, although others are sharply demarcated.
As may be expected, the utility of ancillary techniques in
BMM falls between that which is reported for EMM and
SMM. It is not uncommon for BMMs to show strong
immunoreactivity for mesothelial markers in the epithelioid
component and weak or absent staining in the sarcomatoid
BMM must be distinguished from metastatic pleomorphic
carcinoma from several sites, most commonly from the lung.
This distinction can usually be achieved by assessing the
immunostaining characteristics of the epithelioid areas of a
tumour for mesothelial-associated and carcinoma-associated
markers. Non-pleomorphic carcinomas metastatic to the
serosa can incite such an exuberant desmoplastic response
as to also simulate BMM. Other considerations include
metastatic malignant melanoma and biphasic synovial
sarcoma. Biphasic synovial sarcoma can be metastatic or
occur as a primary tumour of the pleura (fig 12). Synovial
sarcoma often stains at least focally for pan-cytokeratin and
calretinin, but unlike BMM, is usually at least focally positive
for Ber-EP4, negative for thrombomodulin and negative for
WT1.71 74BMM lacks the (X;18) chromosomal translocation
that can be detected through molecular techniques in
component comprising of tubules (top) merging with a sarcomatoid
component of spindled cells arranged in fascicles (bottom).
Biphasic malignant mesothelioma showing an epithelioid
PAUCICELLULAR OR FIBROTIC PATTERN
The paucicellular or fibrotic pattern is arguably the most
challenging pattern to evaluate in serosal biopsy samples
because of the potential for misdiagnosing benign processes
as malignant and, conversely, malignant tumours as benign.
Desmoplastic malignant mesothelioma (DMM) is an under-
recognised variant of malignant mesothelioma that can be
deceptively bland. This subtype, which accounts for 5–10% of
malignant mesotheliomas, most commonly affects the
pleura.76–78Its banal appearance belies the aggressive nature
of this tumour.
DMMs are characterised by dense paucicellular hyalinised
collagen amid which spindle or stellate tumour cells, often
associated with slit-like spaces, are arranged in a storiform or
patternless arrangement (fig 13).76 79This appearance should
comprise at least 50% of a tumour to be designated as
DMM.54Sarcomatoid foci are usually present, but may be
quite small and difficult to detect without adequate
sampling. Epithelioid foci can be occasionally seen. The
presence of frankly sarcomatoid areas, in conjunction with
one or more of the following, is considered highly specific for
DMM: bland infarct-like necrosis, invasion of chest wall
epithelioid cells interspersed with sarcomatoid foci.
Biphasic synovial sarcoma metastatic to the pleura showing
pleurisy. The invasion of chest wall adipose tissue by spindled tumour cells is seen at the bottom of the field. (B) Higher-power view of (A) showing
fascicular arrays of hyalinised collagen amid which mildly atypical spindle cells infiltrate fat. (C) Sarcomatoid region of a desmoplastic malignant
mesothelioma showing diffuse invasion of chest wall skeletal muscle. (D) Desmoplastic malignant mesothelioma invading pulmonary parenchyma. In
this example, tumour spreads into the lung as intra-alveolar plugs in a peculiar bronchiolitis obliterans-organising pneumonia-like pattern. (E) Pan-
cytokeratin staining of the tumour in (A) highlights invading tumour cells within adipose tissue of the chest wall.
(A) At low magnification, this desmoplastic malignant mesothelioma appears deceptively bland with features reminiscent of fibrous
Diagnosis of mesothelial lesions571
adipose tissue or skeletal muscle or lung, and distant
metastases (fig 13).80
Traditional mesothelial markers do not typically stain DMM.
The opposite problem is seen with pan-cytokeratin, which
stains both neoplastic mesothelial cells in DMM and
entrapped reactive mesothelial cells in fibrous pleuritis. The
utility of immunohistochemistry analyses in the diagnosis of
DMM instead lies in ability of pan-cytokeratin to highlight
invasive tumour cells within pulmonary parenchyma or chest
wall skeletal muscle or adipose tissue (fig 13).
Adherence to the four previously mentioned criteria permits
separation of DMM from its main differential consideration,
chronic fibrous pleuritis, in most cases. Other features that
may aid in the distinction include elongated capillaries
perpendicular to the pleural surface and zonation, both of
which are seen in reactive pleuritis but not in DMM (fig 14).80
Zonation refers to the phenomenon in which the degree of
cellularity and atypia is highest near the serosal surface and
trails off toward the chest wall.
Desmoplastic malignant mesothelioma can occasionally
show basketweave-like areas reminiscent of pleural plaque.
Storiform growth, which is common in DMM, is not a feature
in pleural plaque.39
Localised fibrous tumour of the pleura, with its whorls and
haphazard arrays of keloid-like collagen, may be potentially
confused with DMM, particularly in small biopsy specimens.
Localised fibrous tumour, however, typically has a distinctive
pedunculated appearance and, contrary to DMM, is usually
CD34 positive and cytokeratin negative.81The rare entity
known as calcifying fibrous pseudotumour of the pleura also
shows densely hyalinised collagen, but unlike DMM,
additionally features psammomatous or dystrophic calcifica-
Several unusual forms of malignant mesothelioma have been
described. Small-cell malignant mesothelioma bears a resem-
blance to small cell carcinoma and other small round cell
tumours, such as primitive neuroectodermal tumour (Askin’s
tumour) and lymphoma.83 84A targeted immunohistochem-
ical approach using markers such as TTF-1, LCA and CD99
may aid in the distinction.
large histiocytoid cells with moderately abundant pale
cytoplasm and a dense accompanying lymphoplasmytic
infiltrate.85–87Although this entity may be confused with
lymphoma and inflammatory pseudotumour, careful exam-
ination will usually show cytokeratin-positive sarcomatoid
tumour cells in the background or areas more typical of
CAVEATS TO THE DIAGNOSIS OF MESOTHELIAL
With the availability of immunostains, the problem in
evaluating cytological specimens lies not so much in the
distinction between malignant mesothelioma and metastatic
carcinoma but in the separation of malignant mesothelioma
from reactive mesothelial proliferations. As there is signifi-
cant overlap between the cytological appearance of reactive
and neoplastic mesothelium, it remains my practice, and that
of a number of others, not to render a diagnosis of malignant
mesothelioma solely on the basis of cytology specimens.39 88
Given the prognostic and potential medicolegal implica-
tions of a diagnosis of malignant mesothelioma, a lack of
certainty as to the diagnosis on small biopsy specimens
should prompt a request for a larger tissue sample, preferably
one which allows for assessment of invasion of subjacent
tissues, such as chest wall or omental fat. A small percentage
of tumours remain indeterminate even after extensive
examination with ancillary techniques. In most cases,
however, by using an integrated approach of clinicoradio-
graphic, histopathological and ancillary techniques, the
distinction between malignant mesothelioma and its mimics
can be made with confidence.
1 Ordonez NG. The diagnostic utility of immunohistochemistry and electron
microscopy in distinguishing between peritoneal mesotheliomas and serous
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capillaries (arrows) oriented perpendicularly to the pleural surface.
Organising pleuritis showing chronic inflammation and
N Given the histological overlap between malignant
mesothelioma and other malignancies that involve the
serosal membranes, the use of ancillary techniques
such as immunohistochemistry is warranted.
N As there is no single uniformly sensitive and specific
immunomarker for malignant mesothelioma, it is a
good practice to use a panel of immunostains that
includes both mesothelial-associated and carcinoma-
N Desmoplastic malignant mesothelioma can be decep-
tively bland. Foci of sarcomatoid growth, bland
necrosis, invasion of chest wall tissue and a lack of
zonation are features that help to distinguish desmo-
plastic malignant mesothelioma from reactive pleuritis.
N Because of the therapeutic, prognostic and potential
medicolegal implications of a diagnosis of malignant
mesothelioma, a conservative approach is best,
especially when interpreting small biopsies.
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