MESOTHELIOMA AND ITS DIFFERENTIAL
Thomas V. Colby MD
Clinical Features of Mesothelioma
? Males >> females thth? Age: 7 and 8 decades (with broad range)
? Signs and symptoms – shortness of breath, chest pain, recurrent effusions
? Sites: Pleura >> peritoneal >> other sites
? Majority associated with asbestos exposure
? Treatment: None proven; recent interest in extrapleural pneumonectomy and
? Prognosis: Survival 6 to 18 months (epithelioid greater than
Survival over five years is rare, but well documented.
Patterns of Presentation of Mesothelioma
? Diffuse process of pleura, peritoneum, or pericardium – by far the most
? Localized pleural, mediastinal, or intraabdominal mass (all rare)-see below
? Metastatic disease, usually as lymphadenopathy (also rare)
When confronted with a potential mesothelioma, one needs to know as much clinical and
radiologic information as is available. The gross findings at the time of surgery or
autopsy are extremely useful and these can often be inferred from radiologic studies. If
these features do not fit with the diagnosis that is being considered, then the pathologist
should go back and re-assess the problem.
The differential diagnosis of malignant mesothelioma depends on whether one is
1) An epithelial/epithelioid proliferation
2) A spindle cell/fibroblastic proliferation and the approach to these two
settings is entirely different.
The basic questions are whether the process is reactive or neoplastic, and if neoplastic is
it mesothelioma or some other neoplasm mimicking a mesothelioma? The diagnostic
approach, criteria of malignancy, and ancillary tests, particularly immunostains, for these
two groups are entirely different:
Reactive mesothelial hyperplasia vs. neoplasm
If neoplastic, mesothelioma vs. carcinoma (or melanoma, etc.)
For spindled/fibroblastic proliferations:
Fibrous pleurisy vs. neoplasm
If neoplastic, desmoplastic/sarcomatoid mesothelioma vs. other (sarcoma,
melanoma, sarcomatoid carcinoma, etc.)
1. The distinction of benign mesothelial proliferations from mesothelioma is covered by
Churg and recommendations summarized below:
2. The distinction between mesothelioma and metastatic carcinoma involving the pleura
is the most common problem and the one that has engendered the largest number of
papers in the literature and the situation in which immunohistochemical staining is
most useful. The following are some of the features that I personally have found
helpful over the years in distinguishing mesothelioma from carcinoma:
Fibrous stroma produced by the proliferation? This favors a neoplasm.
Stromal invasion? This favors a neoplasm; beware of entrapment of mesothelial cells
particularly in the pericardium.
Complex cellular proliferation or cohesive sheet-like proliferation? Favors neoplasm. Are papillae present? Favors a neoplasm.
Is necrosis present? Favors a neoplasm.
Cytologic features? Cytologically bland, cells can be seen in reactive mesothelial
proliferations and mesothelioma; marked nuclear atypia usually favors carcinoma.
Nuclear molding? Favors carcinoma.
Columnar cell shape? Favors carcinoma.
Mucous production? Faint mucicarmine positivity not uncommon in mesothelioma;
intracellular droplet positivity with PASd favors carcinoma (but rarely reported in
Cytokeratin stain: Good to confirm the cells actually stain; strong diffuse positivity
characteristic of mesothelioma (as well as, obviously, some carcinomas); CK may
highlight stromal invasion
Electron microscopy? Rarely helpful (to me!); cases that are diagnostic
ultrastructurally tend to be easy light microscopy diagnoses (my bias).
The issue of carcinoma versus mesothelioma remains the most common problem and the
vast majority of these cases are recognized with clinical history, knowledge of
gross/radiologic findings, knowledge of prior neoplasms, and careful attention to routine
histology. Carcinomas look like carcinomas and mesotheliomas look like mesotheliomas!
Immunohistochemistry is usually confirmatory.
Nevertheless, immunohistochemistry is considered by most to be the mainstay in this
differential diagnostic problem and the horizon is ever changing as new antibodies are
added and older ones are cast aside. The recommendation of an international
mesothelioma working group is that one use at least two positive markers for
mesothelioma and at least two positive markers for carcinoma in making this distinction.
Practically speaking most experts do at least 6 antibodies for the carcinoma vs
mesothelioma differential. In addition, sex and site of the biopsy are issues in selecting
antibody panels; ER/PR stains may be indicated in women and the differential for
carcinomas in the abdomen is different for that in the chest. I like a pancytokeratin, not
for its discriminatory value, but to highlight the architecture of the proliferation, help
highlight invasion, etc.
? Pankeratin to assess positivity and pattern
Markers favoring mesothelioma:
? Cytokeratin 5/6*
? Membrane pattern with EM
? D2-40 (new, and many are excited about this one)
? Podoplanin (new, and many are excited about this one)
Markers favoring carcinoma:
? MOC 31*
? TTF-1 (for lung ca)*
? EMA with cytoplastic pattern
? Surfactant (for lung ca)
? Others (e.g. ER/PR, CDX-2, PSA, etc. depending on situation)
None of these antibodies is perfect and occasional mesotheliomas stain positively (usually only a few cells focally) with carcinoma markers and carcinomas may stain with
mesothelioma markers. Squamous carcinoma, transitional carcinoma, and some others
are frequently positive with cytokeratin 5/6 and adenocarcinomas of the lung not
uncommonly stains with calretinin. It is said that cytoplasmic and nuclear staining with
calretinin is a good marker for mesothelioma. The greater number of antibodies that one
uses the greater the likelihood for discrepant staining and then one has to take a step back
and try to prioritize the findings and keep a mental tally sheet of the positive and negative features that favor one diagnosis over the other. In a small minority a confident diagnosis
is not possible.
There have been a number of studies suggesting specific panels to use in the differential
diagnosis of mesothelioma and adenocarcinoma. Again, no panel is perfect and the
antibodies suggested vary from study to study since some labs have their own favorite
antibodies. In the study by Yaziji, et al. a three antibody panel, including calretinin, BG8, and MOC 31 provided 96% sensitivity and specificity for distinguishing epithelioid
mesothelioma from adenocarcinoma. In clinical practice, the senior author (Dr. Gown)
said that he would rarely follow this recommendation and usually did at least six
antibodies as mentioned above.
Ordonez has reviewed immunohistochemistry and electron microscopy in the distinction
of peritoneal mesothelioma and serous carcinoma and concluded that BerEp-4 and MOC
31 are the best negative mesothelioma markers in this situation and that the best positive
markers are D2-40, podoplanin, and calretinin.
3. Desmoplastic mesothelioma versus fibrous pleuritis. As defined above, a
desmoplastic mesothelioma is a sarcomatoid mesothelioma that has greater than 50%
dense collagenized stroma sometimes with a vague storiform appearance. These
regions are not overtly sarcomatous. Since desmoplastic mesotheliomas may over
grow hyaline pleural plaques it is sometimes difficult, if not impossible, to separate
the pre-existing benign fibrotic reaction of the pleura from a desmoplastic
mesothelioma since the latter may produce regions that are nearly indistinguishable
from hyaline pleural plaque. Abrupt transitions in cellularity are one of the most
useful clues that the process is neoplastic. The separation of desmoplastic
mesothelioma from fibrous pleurisy is summarized as follows (from Churg):
The series by Mangano et al. nicely showed that desmoplastic mesothelioma could be
separated from fibrous pleurisy on the basis of the presence of a diffuse storiform
proliferation of the pleura and one or more of the following features:
? Invasion of the chest wall or lung
? Foci of bland necrosis
? Frankly sarcomatoid foci
? Distant metastases
Immunostaining in the setting of desmoplastic mesothelioma vs. fibrous pleurisy is
helpful in highlighting invasion of cytokeratin positive cells into structures adjacent to the
pleura such as lung or chest wall. Doing carcinoma markers in this setting is
While rarely a problem, desmoid tumors may present as pleural masses and could mimic
a desmoplastic mesothelioma. In general these are more localized and have a more
extensive soft tissue component. These have recently been reviewed by Andino, et al.
4. Sarcomatoid mesothelioma versus other sarcoma. Distinguishing sarcomatoid
mesotheliomas from other sarcomas involving the pleura is such an uncommon
scenario that it is rarely encountered by the surgical pathologist. In such cases careful
attention to any prior history of sarcoma, the pattern of growth in the pleural space
(sarcomas tend to be multiple nodules rather than more diffuse growth) and selected
immunostains based on the histology of the process should allow resolution of most
cases. The only sarcomas seen in the pleura with any frequency, and ones which not
uncommonly closely mimic a mesothelioma, are malignant vascular tumors. When
synovial sarcoma is in the differential, molecular studies for the X:18 translocation
Localized Malignant Mesotheliomas
The US & Canadian Mesothelioma Panel has put together a series of 22 cases that
included both pleural and peritoneal locations (see Allen ref.).
? 15 men, 7 women; age 37-83 years; mean 62.4
? 20 pleural, 2 peritoneal
? Mean size: 6.1 cm
? 15 epithelial, 6 biphasic, 1 sarcomatous
? Immunohistochemistry and ultrastructural studies as for diffuse mesothelioma
? Follow-up in 11 cases; 7 dead of disease at 7 months to 6 years, 1 dead of
unrelated causes, 3 (27%) alive at 6-18 months. Those who died tended to die of
metastatic disease as opposed to local spread.
Based on these studies, localized malignant mesothelioma is now recognized as an
unusual variant of malignant mesothelioma. These appear as localized masses that are
usually pleural based. In the peritoneum they may involve adjacent structures and
simulate primary tumors of the colon, stomach, liver, etc.
ASBESTOS AND MESOTHELIOMAS
While the vast majority of mesotheliomas are associated with asbestos exposure (the
exact percent varies with the series) one essentially never encounters asbestos bodies in
routine histologic sections of the pleura and the tumors that arise therein. The search for asbestos bodies should be in lung tissue if it is included with the pleural biopsy. The
identification of asbestos bodies (even a single body) in routine histologic material of the lung suggests significant prior exposure and can be used to support an asbestos-
associated mesothelioma. An attribution of cause or association between a mesothelioma
and asbestos exposure can also be made if there is sufficient documentation of exposure
in the clinical history.
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