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Page 4 of 13 Farkas et al. J Cancer Metastasis Treat 2022;8:37 https://dx.doi.org/10.20517/2394-4722.2022.89

BIPHASIC MESOTHELIOMA
Mesotheliomas in which both epithelioid and sarcomatoid morphology are present should be classified as
biphasic mesothelioma (approximately 20% of all mesotheliomas; Figure 3), and the specific ratio of
epithelioid to sarcomatoid components should be noted. While rather arbitrarily assigned, at least 10% of
each component (epithelioid and sarcomatoid) is required for diagnosis in the most recent WHO
[8]
classification . This 10% cutoff is only applied to resected mesothelioma. According to the most recent
classification schemes, a small biopsy with any amount of both epithelioid and sarcomatoid mesothelioma
[10]
should be classified as biphasic . It is known that approximately 20% of biopsies showing epithelioid
mesothelioma will, in fact, show biphasic morphology in resection specimens [20,21] . Biphasic and sarcomatoid
morphology on a small biopsy are quite predictive of the tumor having a significant proportion of
sarcomatoid morphology at the time of resection [20,21] . The ratio of each constituent, especially with regard to
the sarcomatoid component, may be prognostic. Data is limited, but it is suggested that sarcomatoid
predominant biphasic mesotheliomas have worse outcomes, with prognostic cutoffs reported from
20%-50% sarcomatoid morphology [19,22] . Given that there is some data to suggest a prognostic cutoff around
50% for sarcomatoid morphology, it may be helpful for the patient’s treatment team to be aware that 95% of
biopsies with pure epithelioid morphology showed at least 50% epithelioid morphology at the time of
[20]
resection . While biphasic mesothelioma has an overall survival in between epithelioid and sarcomatoid
mesothelioma, the exact prognostic significance of percent epithelioid and sarcomatoid morphology in
biphasic mesothelioma is unclear; nonetheless, pathologists are now encouraged to report these findings on
resected mesotheliomas .
[12]

HISTOLOGIC GRADING
Pathologic grading systems have been described and most robustly studied in epithelioid mesothelioma.
The original grading system was developed at Memorial Sloan Kettering and consisted of a nuclear grade
score, calculated as a sum of nuclear atypia and mitotic count . Briefly, nuclear atypia is scored as 1
[14]
[Figure 4] for mild cytologic atypia with occasional small nucleoli (mesothelial cells are similar to benign
resting or benign reactive mesothelial cells); score 2 [Figure 5] shows increased cytologic atypia with
moderate pleomorphism and occasional nucleoli; score 3 [Figure 6] shows marked cytologic atypia with
enlarged and highly pleomorphic nuclei and prominent nucleoli. Mitotic count score (per 2 mm ) is scored
2
as 1 (0 to 1 mitotic figures), 2 (2 to 4 mitotic figures), or 3 (≥ 5 mitotic figures). The nuclear atypia and
mitotic count scores are added together to yield a three-tier nuclear grade; nuclear grade 1 (sum of nuclear
atypia and mitotic count = 2-3), nuclear grade 2 (sum = 4-5), and nuclear grade 3 (sum = 6). This grading
scheme was shown to be highly predictive of overall survival. Subsequently, studies from the University of
Chicago showed that the addition of necrosis further stratified patients into prognostic groups . This
[13]
[10]
finding was then incorporated into the most recently proposed grading system . This grading system, not
only recommended by expert consensus but included in the WHO and CAP synoptic reporting for
mesothelioma, is a combination of the three-tiered system with the addition of necrosis. This yields a two-
tiered (low and high grade) classification scheme in which the mesothelioma is designated as a low grade if
it is nuclear grade 1 or nuclear grade 2 without necrosis and designated as a high grade if it is nuclear grade
2 with necrosis or nuclear grade 3. While this system has yet to be seen in widespread clinical use, as it is
now a part of the routine classification of epithelioid mesothelioma, one would anticipate it becoming more
commonly reported. Nuclear grading in epithelioid mesothelioma can be applied to specimens obtained via
biopsy or resection [23,24] .

At present, there is no consensus on the need to grade sarcomatoid or biphasic mesotheliomas as tumors
with sarcomatoid morphology behave aggressively. A number of studies have proposed grading non-
epithelioid mesotheliomas, but these are not recommended at present to be utilized in clinical practice [15,19,25] .