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Page 2 of 13 Farkas et al. J Cancer Metastasis Treat 2022;8:37 https://dx.doi.org/10.20517/2394-4722.2022.89

[7]
[5,6]
and 5-year survival of 5% or less , though patients with localized disease may have better outcomes . The
main diagnostic features of mesothelioma are published in the World Health Organization Classification of
[8]
Thoracic Tumours . Mesothelioma remains a challenging entity to diagnose, especially when the
pathologist is given a small biopsy. Currently, mesothelioma is divided histologically into three major
subtypes (epithelioid, sarcomatoid, and biphasic), which can be further categorized into prognostic groups
based on nuclear grade and cytologic and stromal features [9,10] . The gold standard for the diagnosis of
mesothelial lesions as malignant is tissue invasion, which is not always possible on small biopsies . The
[11]
diagnosis of mesothelioma can be achieved using ancillary testing, specifically BAP1 and MTAP
immunohistochemistry or CDKN2A fluorescence in situ hybridization; furthermore, these markers can also
facilitate the identification of mesothelioma in situ prior to the invasive phase of the disease.

EPITHELIOID MESOTHELIOMA
The majority of mesotheliomas (approximately 55%) exhibit an epithelioid growth pattern [Figure 1], and
these are further subclassified based on secondary architectural patterns, cytology, and stromal features [10,12] .
While data may be limited with only a few published articles in the literature, studies show that some of
these features stratify patients into prognostic groups within epithelioid mesothelioma. Architectural
patterns that have been described in epithelioid mesothelioma include tubulopapillary, trabecular,
adenomatoid, microcystic, solid, and micropapillary. Cytologic features described in epithelioid
mesothelioma include rhabdoid, deciduoid, small cell, clear cell, signet ring, lymphohistiocytoid, and
pleomorphic. A subset of mesotheliomas may show myxoid stroma. The pathologist is encouraged to report
these features to improve diagnostic accuracy and potentially help with risk stratification [10,12] . Features
associated with a more favorable prognosis in epithelioid mesothelioma include tubulopapillary, trabecular,
and adenomatoid architectural patterns, as well as lymphohistiocytoid cytologic features and the presence of
myxoid stroma (50% or greater of total tumor) [10-12] . Unfavorable features that portend a worse prognosis in
epithelioid mesothelioma include solid and micropapillary architecture, as well as rhabdoid and
pleomorphic cytologic features [8,10-12] . Grading systems that incorporate nuclear features (atypia, mitotic
index) into classification have been shown in medium to large cohorts to determine prognosis [13,14] . While
these grading studies have not been shown to uniformly predict disease performance across histologic
subtypes, they are a powerful prognostic tool in epithelioid mesothelioma, and recently proposed high- and
low-grade grouping of epithelioid mesothelioma is now recommended [13-15] . The grading of epithelioid
mesotheliomas will be discussed in greater detail below.

SARCOMATOID MESOTHELIOMA
Sarcomatoid mesothelioma [Figure 2] is characterized by the haphazard proliferation of malignant spindled
mesothelial cells resembling sarcoma . The less cellular and densely fibrotic desmoplastic variant has long
[8]
been recognized as a pattern of sarcomatoid mesothelioma . Sarcomatoid mesotheliomas are rare,
[8]
comprising only around 10% of all cases, ranging from 7%-22% [16,17] . More recently, the application of
specific cellular features to the diagnostic classification of sarcomatoid mesothelioma has been proposed,
similar to epithelioid mesothelioma [10,12] . These cytologic features include noting whether cells are
pleomorphic, lymphohistocytoid, or transitional; lymphohistiocytoid has been associated with a more
[12]
favorable prognosis (transitional will be discussed below) . Pleomorphic features have been observed in
both epithelioid and sarcomatoid mesotheliomas, and are genomically similar enough to be classified as
[10]
either, based upon the cytomorphology of the tumor (epithelioid or sarcomatoid) . Desmoplasia is
classified as a stromal feature .
[12]
Transitional mesothelioma (transitional features) presents as a proliferation of elongated epithelioid
mesothelial cells with sheet-like, yet discohesive growth and, as previously mentioned, is now considered a