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Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations.

To the Editor.--The separation of benign from malignant mesothelial proliferations remains a difficult problem in diagnostic pathology. Recent molecular studies have demonstrated that mesotheliomas commonly show mutation or deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A, p16) and BRCA-associated protein-1 (BAP1), and this information has been exploited through the use of p16 fluorescence in situ hybridization (FISH) analysis and BAP1 immunohistochemistry, where loss of either marker is a reliable indicator that a mesothelial proliferation is malignant. (1,2)

Next-generation sequencing has also identified frequent alterations in the tumor suppressor genes neurofibromin 2 (NF2), large tumor suppressor kinase 1 and large tumor suppressor kinase 2 (LATS1/2) in mesotheliomas, (3,4) but the potential diagnostic utility of this information has not been extensively explored. Singhi et al (5) recently showed that a proportion of mesotheliomas exhibit hemizygous loss of NF2 by FISH analysis, and that such loss is associated with an inferior prognosis. We asked whether immunohistochemistry directed toward NF2 (merlin), LATS2, and their downstream effector YAP/TAZ (a complex of Yes-associated protein and transcriptional coactivator with PDZbinding motif) (6) could serve as adjunctive tests when a question of mesothelioma versus a benign reaction arises.

We undertook in-house validation of immunohistochemical assays for NF2 (1:200; catalog No. HPA003097, Sig ma-Aldrich, St Louis, Missouri), LATS2 (1:20; catalog No. HPA039191, Sigma-Aldrich), and YAP/TAZ (1:150; catalog No. 8418, Cell-Signaling Technology, Danvers, Massachusetts). All 3 markers were applied to a previously characterized tissue microarray containing both mesotheliomas and benign mesothelial proliferations. (1) Two additional published cases of mesothelioma with available comprehensive sequencing (7) were stained for NF2.

LATS2 staining showed frequent loss in both benign proliferations and mesotheliomas (Table). YAP/ TAZ showed frequent nuclear staining (activated phenotype) in both benign proliferations and mesotheliomas (Table). NF2 staining was detected in all cases of benign mesothelial proliferations, and loss was identified in only a single mesothelioma (1 of 25, 4%) (Table). The 2 cases with comprehensive genomic profiling were stained for NF2: the first ([NF2.sup.Y177FS]) showed positive staining for NF2, and the second ([NF2.sup.R466*]) also showed positive staining for NF2. Both cases harbored somatic loss-of-heterozygosity events and were not predicted to express any wild-type NF2. (7) Since the incidence of NF2 mutations in mesothelioma is estimated at 50%, (4) these results indicate that many mesotheliomas with mutated NF2 retain NF2 immunoreactivity, here including 2 tumors with frameshift and nonsense mutations.

These data suggest that, at least using the antibodies used here, NF2, LATS, and YAP/TAZ immunohistochemical stains are not helpful for the diagnosis of mesothelioma versus a benign proliferation.

Brandon S. Sheffield, MD [1]; Julie Lorette, MLT2; Yaoqing Shen, MD [3]; Marco A. Marra, PhD [3,4]; Andrew Churg, MD [1,5]

[1] Departments of Pathology and Laboratory Medicine and [4] Medical Genetics, University of British Columbia, Vancouver, Canada; [2] Department of Pathology and [3] Michael Smith Ge nome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada; [5] Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada

(1.) Sheffield BS, Hwang HC, Lee AF, et al. BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations. Am J Surg Pathol. 2015; 39(7):977-982.

(2.) Churg A, Sheffield BS, Galateau-Salle F. New markers for separating benign from malignant mesothelial proliferations: are we there yet? Arch Pathol Lab Med. 2016; 140(4):318-321.

(3.) Miyanaga A, Masuda M, Tsuta K, et al. Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. I Thorac Oncol. 2015; 10(5):844-851.

(4.) Guo G, Chmielecki J, Goparaju C, et al. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res. 2015; 75(2):264-269.

(5.) Singhi AD, Krasinskas AM, Chourdy HA, et al. The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. Mod Pathol. 2016; 29(1):14-24.

(6.) Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015; 163(4):811-828.

(7.) Sheffield BS, Tinker AV, Shen Y, et al. Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing. PLoS One. 2015; 10(3):e0119689.

The authors have no relevant financial interest in the products or companies described in this article. This project was supported by funding from the University of British Columbia's Department of Pathology Residency Program.

doi: 10.5858/arpa.2015-0508-LE
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Title Annotation:Letters to the Editor
Author:Sheffield, Brandon S.; Lorette, Julie; Shen, Yaoqing; Marra, Marco A.; Churg, Andrew
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:May 1, 2016
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