New Markers for Separating Benign From Malignant Mesothelial Proliferations Are We There Yet?
A variety of immunohistochemical stains have been claimed to be useful in this context and 5 of them have been reported in multiple studies. Of these, glucose transporter 1 (GLUT-1), a putative marker of malignancy, probably makes the most mechanistic sense, since it is increased in a very wide variety of malignant tumors. Unfortunately, GLUT-1 staining of mesothelial cells is confounded by staining of red cells, making interpretation difficult; and, more important, although some authors (5-7) claim that GLUT-1 staining is never seen in benign mesothelial reactions, our experience and that of others (8-11) ed positive for GLUT-1.
p53 is a critical tumor suppressor; it has a role in genomic integrity, cell cycle arrest, and apoptosis. Many types of malignancies have mutated p53, suggesting, at first glance, that p53 immunostaining might be helpful in the diagnosis of mesothelioma. However, most of the reports describing p53 as a marker of mesothelioma predate the realization that some degree of p53 staining, typically fairly weak and patchy, can be seen in any process with proliferating cells, the so-called wild-type p53 staining pattern. Judging by other types of malignancies, the decision that abnormal p53 staining is present requires either strong staining of a very large proportion of cells (>50% or >75%) in a tumor, or staining of no cells at all. (12,13) Using these guidelines for interpretation, p53 immunohistochemistry is a strong predictor of p53 mutational status. (14)
In fact, p53 is infrequently mutated in mesotheliomas, (15) and what has been described as positivity for p53 in mesotheliomas is, in retrospect, probably a mixture of a (mostly) normal and an occasional abnormal immunophenotype. For example, in one older study (16) it was reported that 20 of 27 mesotheliomas (74%) showed staining of fewer than 25% of cells and the staining was of low intensity, which is the typical picture of normal p53 expression, while only 2 mesotheliomas demonstrated staining of more than 75% of cells. Attanoos et al (16) summarized the p53 immunostaining literature from 1992 to 2001. Seven of 9 reports (78%) failed to find p53 staining in benign reactions, while 2 found staining in 62% and 85% of cases.
In equivocal cases, overall survival can serve as a surrogate marker for the diagnosis of mesothelioma versus a benign reactive mesothelial proliferation. Our own experience is that, in a series of atypical mesothelial reactions, 30% of patients with greater than 10% of cells staining for p53 were alive 5 years after diagnosis, (2) implying that, at least as commonly interpreted, p53 staining is not helpful.
Insulin-like growth factor 2 messenger RNA-binding protein 3 (IMP-3) is an oncofetal protein found in fetal tissues and many types of malignant neoplasms. Some have reported that IMP-3 is only seen in mesotheliomas, (6,17) but we found, as have others, (7,8) that like GLUT-1, some proportion of benign reactions stain for this marker.
Two other stains that have been repeatedly examined are epithelial membrane antigen (EMA), claimed to mark mesotheliomas, and desmin, claimed to mark benign reactions. The use of these stains is purely empiric because there is no obvious underlying molecular or functional logic behind the results. Attanoos et al (16) reviewed the literature on desmin staining up to 2003; the summarized numbers indicate that while desmin shows positivity more frequently in benign reactions, it also shows positivity in a proportion of mesotheliomas, as much as 56% in 1 study. King et al, (18) summarizing the literature from 1979 to 2005, concluded that the specificity of desmin was 83%. More recently, Minato et al (7) found that while desmin stained mostly benign reactions, a small proportion of mesotheliomas also stained positively. When we looked at the 5-year survival of patients with a biopsy diagnosis of atypical mesothelial hyperplasia, only 50% of those with positive staining for desmin were alive, (2) suggesting that desmin staining fails to predict anything.
Epithelial membrane antigen is just as problematic. Attanoos et al (16) reviewed 6 studies and, adding their own, found that some proportion of benign reactions were reported to stain in all but 1 report. King et al (18) concluded that the specificity of EMA was 89%. Reports that support or refute the specificity of EMA continue to be published. (6,7) We found that approximately 30% of patients with a diagnosis of atypical mesothelial hyperplasia and positive EMA staining were alive at 5 years after diagnosis. (2)
Our point here is not to completely review the now rather extensive literature on these markers, but to point out that, for any of them, it is easy to find reports of "wrong" staining. Interpretation issues aside, the real problem with all of these stains is that, when they work at all, they work in a statistical sense; that is, overall, a greater proportion of mesotheliomas than benign reactions stain positively for GLUT-1, p53 (but that staining may be wrongly interpreted), IMP-3, and EMA, and the reverse is true for desmin. Were this a matter of dealing with one type of malignancy versus another, some of these markers might be useful. But there are too many benign or malignant processes that stain the "wrong" way to use them in an individual case when the distinction is between a tumor that in the pleura is rapidly and universally fatal and in the peritoneum requires extensive debulking and hot intraperitoneal chemotherapy, (19) and a benign reaction that necessitates only watchful waiting and patient reassurance.
Against this background, 2 new markers have emerged that have molecular logic, and thus far, appear to have 100% specificity for separating benignity from malignancy. [p16.sup.INK4a] (also known as cyclin-dependent kinase inhibitor 2A [CDKN2A], referred to here as "p16") is a member of the inhibitor of cyclin-dependent kinase 4 (INK4) family of cell cycle regulatory proteins that bind to and usually inhibit D-type cyclin-dependent kinases. p16 is a tumor suppressor gene; the normal action of its gene product is to arrest the cell cycle in G1. (20,21) Conversely, the functional result of p16 deletion is enhanced cell proliferation. Loss of function via homozygous deletion, hypermethylation, or mutation of p16 has been described in a variety of human tumors. (22,23)
Deletion of the 9p21 region is very common in malignant mesotheliomas, typically resulting in loss of p16 (CDKN2A) and its splice variant p14, p15 (CDKN2B), and methylthioadenosine phosphorylase (MTAP). (24,25) Illei et al (26) reported that loss of p16 gene could be detected by fluorescence in situ hybridization (FISH) in effusion cytology specimens of mesotheliomas, and Chiosea et al (27) were the first to show that the same phenomenon could be observed in formalin-fixed, paraffin-embedded tissue.
Table 1 lists reports that have examined mesotheliomas and/or benign mesothelial reactions, using FISH for p16 in tissue sections and/or effusion cytology specimens. Thus far, with roughly 220 benign reactions reported, there are no instances of benign reactions that show homozygous loss, so the specificity of this approach is 100%, which makes it a very attractive test. An additional benefit of p16 FISH analysis is that it conveys prognostic information: loss of p16 is associated with more aggressive disease. (28,29)
The 2 major drawbacks of p16 are the requirement to use FISH, because p16 immunohistochemistry does not give the same results, (27) and, more problematic, the issue of sensitivity. As shown in Table 1, for pleural epithelial mesotheliomas, sensitivity ranges from approximately 45% to 85% (average, 64%). For peritoneal epithelial mesotheliomas sensitivity is worse, ranging from approximately 14% to 50% (mean, 38%). In some reports sarcomatous mesotheliomas fare better, with deletion reported in up to 100% of cases, but in other reports the proportion of p16-deleted sarcomatous tumors is much lower. Thus, while homozygous loss of p16 by FISH is diagnostic of malignancy in this context, failure to find loss of p16 does not rule out a mesothelioma.
BRCA1-associated protein 1 (BAP1) is a nuclear ubiquitin hydrolase that is believed to function as a tumor suppressor. It controls a number of functions including DNA repair and expression of genes related to cell cycle and cell proliferation; it can also induce cell death. (30,31) Bott et al (32) were the first to report BAP1 somatic mutations in mesotheliomas. At the same time, Testa et al (33) described families with mesothelioma and germline mutations of BAP1. Further investigation of kindreds with germline mutations have shown an increased incidence of cutaneous and ocular melanomas, as well as benign melanocytic skin tumors, renal cell carcinomas, and probably other types of cancers as well.33-35 The exact incidence of germline BAP1 mutation-associated mesotheliomas is uncertain, but it is probably on the order of 1% to 2% of cases. (36)
BAP1 somatic mutations appear to be common in mesotheliomas, (30) and, most important from the point of view of diagnosis, the presence of biallelic mutations in BAP1 determined by molecular analysis correlates with loss of immunohistochemical staining, while cells expressing at least 1 wild-type copy of BAP1 retain immunohistochemical staining. (31,33,37) Thus far, there is considerable variability in the reported frequency of BAP1 protein loss but it appears that epithelial mesotheliomas lose BAP1 more frequently than do mixed or sarcomatous forms (Table 2), a point that needs to be kept in mind in deciding whether p16 FISH or BAP1 immunohistochemistry is more likely to be productive in a morphologically problematic case.
An added attraction of BAP1 immunohistochemistry is that stromal and inflammatory cells will always stain, thus providing a built-in control. Even in mesotheliomas arising in the setting of germline BAP1 mutation, nontumor cells will express a single wild-type copy and hence produce a positive immunohistochemistry result. To show loss of BAP1 immunoreactivity, both copies of BAP1 must be mutated, either by a combination of germline and somatic events as in BAP1 cancer syndrome, or by 2 somatic events in sporadic cancers.
There are relatively little data on BAP1 in benign reactions, but the data that exist are encouraging (Table 3). We found that none of 53 reactive mesothelial proliferations showed loss of BAP1 by immunohistochemistry. Similarly, none of 23 benign cases stained by the French Mesothelioma Panel had loss of BAP1. Cigognetti et al (38) reported that 2 of 27 apparently benign reactions (7%) showed loss of BAP1, which at first glance would decrease the value of the test, but on follow-up these 2 cases turned out to be mesotheliomas, whereas 0 of 25 truly benign reactions had BAP1 loss. More data are obviously needed, but at least at this point, the specificity of BAP1 loss is 100%.
As is true of p16 FISH, the major drawback of BAP1 immunohistochemical staining relates to sensitivity (Table 2), so that a mesothelial proliferation that retains BAP1 expression may still be malignant. It is possible that a combined approach of both p16 FISH and BAP1 immunohistochemistry will at least partially solve this problem. We found, using a tissue microarray and taking all tumor morphologies and sites, that BAP1 was lost in 7 of 26 cases (27%), p16 was deleted in 14 of 27 (52%), and one or the other was lost in 14 of 24 (58%), only a very modest improvement. (39) However, when the analysis was confined to pleural epithelial mesotheliomas, BAP1 was lost in 5 of 9 (56%), p16 in 7 of 12 (58%), and one or the other was lost in 7 of 9 (78%) cases.
Are we there yet? For BAP1 clearly more information is needed on staining of benign reactions, but the data that exist suggest that homozygous loss of p16 by FISH or loss of BAP1 by immunohistochemistry is never seen in benign reactions. The downside of both markers is that they are only deleted/lost in a proportion of mesotheliomas, but if either p16 FISH or BAP1 immunohistochemistry is run and results are not abnormal, addition of the second test may improve sensitivity. We propose that, as a matter of efficiency and cost containment, BAP1 test be run first, even in sarcomatous mesotheliomas where BAP1 loss is less frequent, and if it is not lost, then p16 FISH should be tried.
One important caveat must also be kept in mind. Loss of BAP1 staining or deletion of p16 by FISH is not specific to mesotheliomas, but can be seen in a variety of malignancies. Thus, it is crucial to confirm, using established immunohistochemical stains, that the process in question is mesothelial before proceeding to BAP1 testing and/or p16 FISH.
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Andrew Churg, MD; Brandon S. Sheffield, MD; Francoise Galateau-Salle, MD
Accepted for publication July 6, 2015.
Published as an Early Online Release August 19, 2015.
From the Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada (Drs Churg and Sheffield); and Service Anatomie Pathologique, Centre National Referent MESOPATH, CHU du Caen, Caen, France (Dr Galateau-Salle). Dr Galateau-Salle is now with the Department of Pathology, Centre Leon Berard, Lyon, France.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Andrew Churg, MD, Department of Pathology JPPN 1401, Vancouver General Hospital, 910 W 10th Ave, Vancouver, BC V5Z 1M9, Canada (email: email@example.com).
Table 1. Sensitivity of p16 Fluorescence In Situ Hybridization for Homozygous Deletions by Mesothelioma Type and Site and in Benign Reactions (a) Mesothelioma Source, y Morphology Pleural, No. (%) Illei et al, (26) 2003 (b) Epithelial 6/7 (86% not broken down by site) Chiosea et al, (27) 2008 (c) Epithelial 35/52 (67) Monaco et al, (9) 2011 (d) Epithelial 19/27 (70) Krasinskas et al, (25) 2010 Epithelial Chung et al, (29) 2010 Epithelial 19/42 (45) Takeda et al, (40) 2010 Epithelial 24/28 (86) (e) Wu et al, (41) 2013 Epithelial 10/18 (56) Hwang et al, (42) 2014 Epithelial 5/11 (45) Sheffield et al, (39) 2015 Epithelial 7/12 (58) Ito et al, (43) 2015 Epithelial Chung et al, (29) 2010 Mixed/sarcomatous 4/12 (33) Takeda et al, (40) 2010 Mixed (e) 6/7 (86) Sarcomatous 5/5 (100) Tochigi et al, (22) 2013 Sarcomatous 26/32 (81) Wu et al, (41) 2013 Sarcomatous 22/22 (100) Sheffield et al, (39) 2015 Sarcomatous 4/8 (50) Peritoneal, Benign Reactions, Source, y No. (%) No. (%) Illei et al, (26) 2003 (b) 0/19 (0) Chiosea et al, (27) 2008 (c) 5/10 (25) 0/40 (0) Monaco et al, (9) 2011 (d) 21/41 (51) 0/70 (0) Krasinskas et al, (25) 2010 9/25 (36) Chung et al, (29) 2010 0/11 (0) Takeda et al, (40) 2010 Wu et al, (41) 2013 0/10 ("fibrous pleuritis," 0%) Hwang et al, (42) 2014 1/7 (14) Sheffield et al, (39) 2015 0/40 (0) Ito et al, (43) 2015 9/19 (48) 0/30 (0) Chung et al, (29) 2010 Takeda et al, (40) 2010 Tochigi et al, (22) 2013 Wu et al, (41) 2013 Sheffield et al, (39) 2015 (a) Empty cells indicate test not performed. (b) All effusion cytology specimens. (c) Assumed all epithelial. (d) Includes effusion cytology specimens. Sixty-one tumors were epithelial, 3 mixed, 4 sarcomatous, but results by subtype were not broken out in the article. (e) Specific site breakdown not provided, but 37 of 40 tumors (92%) were pleural. Table 2. Frequency of BAP1 Loss by Immunohistochemistry in Mesotheliomas Source, y Epithelial, No. (%) Nasu et al, (31) 2015 (a) 50/63 (79) Farzin et al, (36) 2015 75/120 (63) Yoshikawa et al, (37) 2012 10/12 (81) Sheffield et al, (39) 2015 (b) 5/9 (56) Cigognetti et al, (38) 2015 128/184 (70) Source, y Mixed, No. (%) Sarcomatous, No. (%) Nasu et al, (31) 2015 (a) 9/16 (56) 5/8 (63) Farzin et al, (36) 2015 19/42 (45) 12/67 (18) Yoshikawa et al, (37) 2012 1/5 (20) Sheffield et al, (39) 2015 (b) 2/12 (15) Cigognetti et al, (38) 2015 9/15 (60) 2/13 (15) Abbreviation: BAP1, BRCA1-associated protein 1. (a) A few tumors showed a mixture of cells with BAP1 loss and BAP1 retention. These have been counted here as BAP1 lost. (b) Pleural mesotheliomas. Table 3. Frequency of BAP1 Loss by Immunohistochemistry in Benign Reactions BAP1 Loss in Benign Source, y Reactions, No. (%) Sheffield et al, (39) 2015 and 0/53 (0) Churg (unpublished data, June 2015) Galateau-Salle (unpublished 0/23 (0) data, June 2015) Cigognetti et al, (38) 2015 0/25 (0) Abbreviation: BAP1, BRCA1-associated protein 1.
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|Author:||Churg, Andrew; Sheffield, Brandon S.; Galateau-Salle, Francoise|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Apr 1, 2016|
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