My approach to the diagnosis of mesothelial lesions
K J Butnor
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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,
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