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Farkas et al. J Cancer Metastasis Treat 2022;8:37 https://dx.doi.org/10.20517/2394-4722.2022.89 Page 7 of 13

“panepithelial” markers have been proposed with staining in carcinomas but not mesotheliomas. Some of
these markers include CEA, B72.3, MOC-31, and Ber-EP4, and while these markers are more often positive
[28]
in carcinomas than mesotheliomas, these markers can be expressed, even strongly, in mesothelial lesions .
More recently, Claudin-4, an antibody raised against tight junctions of moderate to well-differentiated
epithelia, has emerged as the best marker to differentiate carcinoma from mesothelioma [31-33] . Current
recommendations to separate mesothelial lesions from carcinoma are to demonstrate reactivity for two
mesothelial markers (CK5/6, calretinin, WT-1, and/or D2-40) and show negativity for two carcinoma
[11]
markers (claudin 4, MOC-31, Ber-EP4, etc.) . It should be noted that the mesothelial markers are
nonspecific and imperfectly sensitive and that the sensitivity of these mesothelial markers typically drops in
[28]
sarcomatoid mesotheliomas . Also of note, the carcinoma/epithelial markers utilized will depend on the
carcinoma one is trying to exclude. For example, it would be perfectly reasonable to utilize TTF-1 and p40
immunohistochemical stains in the thoracic cavity, given how commonly non-small cell carcinoma is
encountered. It would make less sense to utilize these same markers in the peritoneal cavity, where other
carcinomas also need to be excluded (renal cell carcinoma, gynecologic malignancies, etc.) by utilizing
another set of immunohistochemical markers. In conclusion, for best results, sufficient yet judicious
immunohistochemical studies should be employed utilizing a panel of stains that are interpreted in light of
the clinical and radiographic settings.

Once a lesion is confirmed to be mesothelial in origin, the pathologist may still find it challenging to call the
lesion malignant, especially if there is limited tissue or a small biopsy and no invasion into underlying tissue
identified. Over the past few years, newer immunohistochemical markers have emerged that allow for the
separation of benign and malignant mesothelial proliferations. BRCA-associated peptide-1 (BAP1) has been
shown to be discriminatory when it comes to separating benign from malignant mesothelial
proliferations [34-36] . Nuclear loss of BAP1 staining [Figure 7] is currently reported as 100% specific for
malignancy in mesothelial proliferations. It has long been known that a frequent genetic alteration in
mesothelioma is the homozygous deletion of CDKN2A [37,38] . CDKN2A homozygous deletion can be reliably
detected by fluorescence in situ hybridization (FISH) [39-41] . While FISH testing for CDKN2A deletion is
useful, FISH testing is not always as readily available as immunohistochemistry in small laboratories.
Thankfully, methylthioadenosine phosphorylase (MTAP) is positioned near CDKN2A and is often co-
deleted [42,43] . Cytoplasmic loss of MTAP [Figure 8] has been shown to be 100% specific for malignancy in
mesothelial proliferations. While CDKN2A encodes the protein p16, p16 IHC has historically shown mixed
results when judging its utility at predicting homozygous deletion of CDKN2A in mesothelioma, but a
recent study shows some promise when evaluating p16 alongside MTAP IHC . While BAP1 and MTAP
[44]
are 100% specific for malignancy, unfortunately, BAP1 and MTAP IHC are not 100% sensitive in detecting
malignant mesothelial proliferations, but combining BAP1 and MTAP together does increase
sensitivity [45-47] . As data continues to emerge, it appears that a limited panel approach (BAP1, MTAP, NF2,
p53, among possible other markers) may be most useful in separating benign from malignant mesothelial
proliferations [36,48] . A possible decisional algorithm that one may follow based on the most commonly used
and accepted ancillary studies is provided [Figure 9]. While experts have not yet concluded what is the best
panel to utilize, it appears evident that combining multiple stains may eventually reach adequate sensitivity
for detection of mesothelioma; however, as new stains are proposed to help in this differential, the reader
should be warned that close attention should be paid to the specificity of these newly proposed markers.
The last word of caution on this topic pertains to the fact that one must confirm that the lesion is
mesothelial before interpreting these markers. For example, BAP1 nuclear loss can also be identified in
other malignancies (most notably, some melanomas and some renal cell carcinomas). Also, a recently
published study highlighted the lack of specificity of MTAP loss, which can be observed in a number of
intrathoracic malignancies .
[49]