BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations (original) (raw)
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Benha Medical Journal
Background: Malignant mesothelioma (MM) is an aggressive tumor which arises from the lining of serous cavities. Distinguishing between begnin and malignant mesothelial proliferation on effusions is a challenge. This study aims to evaluate the diagnostic utility of BAP1 in distinguishing MM from reactive mesothelial proliferation. Material and methods: This is a retrospective study on 61 cases; pleural biopsies (n=36) and pleural cell blocks (n=25). Included were synchronous cytology/ biopsy pair samples. All cases were stained with BAP-1antibody using avidin-biotin complex. BAP1 immunohistochemistry was evaluated using cut off value; negative staining indicate malignancy. Statistical analysis was done using SPSS (version 20), P value (P value <0.05 was considered statistically significant). ROC curve to predict cut off value. Results: In MM cases 61.1% showed BAP1 negative nuclear expression. In reactive mesothelial proliferation cases; 20% showed BAP1 negative expression. In atypical mesothelial proliferation cases, 80% showed BAP1 negative nuclear expression. synchronous cytology/ biopsy pairs (13 cases) showed BAP1 matching results. There was a highly statistically significant correlation between BAP1 expression and the study groups (P-value <0.001). There was statistically significant correlation between BAP-1 expression and histological types of mesothelioma (P-value <0.05) and stage (P-value <0.05). In cell blocks; sensitivity was 80% and specificity was 80% for atypical mesothelial proliferation. In tissue biopsy; sensitivity was 61.1% and Specificity was 80% for mesothelioma. Conclusion: In effusions, negative BAP1 strongly support the diagnosis of malignant mesothelioma, so BAP1 may be included in immunohistochemical panels for malignant mesothelioma cytodiagnosis.
Diagnostic Cytopathology, 2018
Background: Malignant mesothelioma (MM) is a diagnostically challenging entity in cytology specimens due to the lack of architectural context and a cytomorphologic overlap between malignant and reactive mesothelial cells (RMCs). A diagnostic marker with excellent specificity is not currently available in clinical practice. The newly appreciated BRCA1-associated protein 1 (BAP1) antibody may help distinguish MM from RMC based on its immunohistochemical (IHC) staining pattern but its role in cytopathology is controversial. Methods: Immunohistochemistry with BAP1 antibody was performed on cell blocks from 39 cytology specimens including 13 cases of RMC and 26 cases of effusion and fine-needle aspiration specimens (FNAC) with tissue-specimen-proven MM. Cases were dichotomised into positive and negative cohorts. Positivity was defined as >50% loss of nuclear BAP1 IHC staining. Results: Of the 26 MM cases, a slight majority (14/26, 54%) showed loss of BAP1 nuclear IHC staining, while all 13 RMC controls showed strong nuclear BAP1 IHC staining. MM was more likely to show loss of BAP1 than RMC (P < .001); and peritoneal MM was more likely to demonstrate loss of BAP1 than pleural MM (P = .04). There was perfect specificity at 1.0 and positive predictive value of 1.0 for loss of nuclear BAP1 IHC staining. However, only modest sensitivity at 0.52 and negative predictive value of 0.50 was seen. Conclusion: These data confirm that absence of BAP1 nuclear staining identifies malignant mesothelial cells. On the other hand, positive BAP1 nuclear staining can occur in both benign and malignant pleural effusions.
BAP1 Immunohistochemistry and p16 FISH to Separate Benign From Malignant Mesothelial Proliferations
The American Journal of Surgical Pathology, 2015
A variety of immunohistochemical (IHC) stains have been proposed to mark either benign or malignant mesothelial proliferations. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions of 9p21, is a good marker of mesotheliomas but lacks sensitivity. Recent reports indicate that some mesotheliomas are associated with loss of BRCA-associated protein 1 (BAP1) expression. Here we investigate BAP1 and p16 as potential markers of malignancy and compare test characteristics with previously proposed markers using a wellcharacterized tissue microarray. BAP1 protein expression was interrogated by IHC. The p16 locus was examined by fluorescence in situ hybridization (FISH) directed toward chromosome 9p21. Loss of BAP1 was identified in 7/26 mesotheliomas and 0/49 benign proliferations. Loss of p16 was identified in 14/ 27 mesotheliomas and 0/40 benign proliferations, yielding 100% specificity and positive predictive value for each marker. Together, BAP1 IHC and p16 FISH were 58% sensitive for detecting malignancy. Various combinations of p53, EMA, IMP3, and GLUT1 showed reasonably high specificity (96% to 98%) but poor to extremely poor sensitivity. Combined BAP1 IHC/ p16 FISH testing is a highly specific method of diagnosing malignant mesotheliomas when the question is whether a mesothelial proliferation is benign or malignant and is particularly useful when tissue invasion by mesothelial cells cannot be demonstrated. However, combined BAP1/p16 FISH testing is not highly sensitive, and negative results do not rule out a mesothelioma. The test characteristics of previously proposed markers EMA, p53, GLUT1, IMP3 suggest that, even in combination, these markers are not useful tools in this clinical setting.
Cytopathology
Objective: The aim of this study was to investigate the utility of BRCA1-associated protein-1 (BAP1), glucose transporter (GLUT)-1 and desmin expression by immunohistochemistry in the discrimination between reactive and malignant mesothelial proliferations. Methods: A total of 88 biopsies and 30 effusions from mesothelioma cases were studied. Control groups were composed of 35 tissues and 30 cell blocks. The 88 mesothelioma cases were from 43 males and 45 females (mean age 56 years). Tumours were mostly localised to pleura (66/88, 75%) and of epithelioid histology (75/88, 85%). Cytology samples were from 17 males and 13 females (mean age 58 years), and 16 pleural and 14 peritoneal effusions. Twenty cytology cases had corresponding tissue biopsies. Results: BAP1 loss was detected in 61/88 (69%) tissues and in 20/30 (67%) cytology samples from mesothelioma with a specificity of 100% for both sampling methods. BAP1 loss was observed more frequently in pleural and biphasic tumours. GLUT-1 immunoreactivity was identified in 54/81 (67%) and 23/25 (92%) malignant tissues and effusions, and in 6/33 (18%) and 6/30 (20%) benign tissues and effusions, respectively. Desmin loss was observed in 74/80 (92%) malignant biopsy samples, 16/21 (76%) malignant effusions and 10/34 (29%) of benign tissues, but in none of the reactive effusions. Concordance rate of results between biopsy and cytology was as follows: BAP1 20/20 (100%); GLUT-1 13/18 (72%); and desmin 10/14 (71%). Conclusions: BAP1, GLUT-1 and desmin are useful markers in the discrimination between reactive and malignant mesothelial proliferations. BAP1 loss seems to be diagnostic for mesotheliomas both in biopsy and cytology samples.
Comparative study of BAP1 and CD147 expression in the diagnosis of malignant mesothelioma
2020
Introduction: Malignant mesothelioma (MM) is a lethal tumor of serosal surfaces. Its differentiation from reactive mesothelial hyperplasia is mandatory, and may be problematic in many situations. Thus, the application of a targeted panel of specific markers permits proper diagnosis in the majority of cases.Aim of the work: This study aimed to determine the potential use of BAP1 and CD147 antibodies to differentiate between MM and reactive mesothelial hyperplasia.Materials and methods: The current work was carried out on 120 cases (56 reactive mesothelial hyperplasia and 64 malignant mesothelioma cases), retrieved as 70 cell blocks and 50 tissue samples. Immunohistochemical staining, using calretinin (to confirm the mesothelial lineage), BAP1 and CD147 antibodies, was performed for each case. Results: Lost nuclear BAP1 expression was detected in 45.3% of the mesotheliomas versus 19.6% of reactive mesothelial hyperplasia cases. Positive membranous CD147 expression was found in 84.4% o...
Pathology - Research and Practice, 2020
Fifty-three cases of sarcomatoid pleural mesothelioma were evaluated for CDKN2A (p16) homozygous deletion and correlated with BRCA-associated protein-1 (BAP1) expression by immunohistochemistry. The patients are 45 men and 8 women between the ages of 37 and 79 years (average age: 58 years), who presented with symptoms of chest pain, cough, and weight loss. Diagnostic imaging showed the presence of diffuse pleural thickening with encasement of the lung parenchyma in all the cases. All patients were surgically treated with extrapleural pneumonectomy. Loss of BAP1 reactivity was seen in 49 tumors and p16 homozygous deletion was seen in 41 tumors, while in 16 patients either BAP1 or p16 were noncontributory to the diagnosis of mesothelioma. However, we were able to detect a better survival rate in those patients in whom BAP1 was lost and p16 showed homozygous deletion. Our findings showed that even though the use of BAP1 and p16 are important tools in the diagnosis of mesothelioma, a proportion of cases still remains negative with approximately 30 % of the cases in which the concordance of BAP1 loss and p16 homozygous deletion will not be present. We consider that the final diagnosis of mesothelioma is best accomplished by a global interpretation of clinical, radiographic, and pathological features including immunohistochemistry and molecular studies.
Journal of Thoracic Oncology, 2017
Background: BRCA1-associated protein 1 (BAP1) gene is located at chromosome region 3p21.1, a genomic region that is deleted in several human malignancies, including approximately 30-60% of mesotheliomas(1). In this study, we retrospectively investigated BAP1 status in 41 unrelated patients with mesothelioma who had a history of environmental fibrous mineral exposure (erionite or asbestos). We have also reviewed histological type and clinical characteristics of the analyzed patients. Methods: A total of 41 malignant mesothelioma cases were reviewed histopathologically. Representative areas were selected and 4-mm-diameter tissue microarrays were composed from paraffin blocks. Immunohistochemistry (IHC) was performed on paraffin tissue sections prepared from microarrays with a monoclonal antibody against BAP1. Cases with loss of nuclear staining were considered as loss of BAP1 expression. Results: Satisfactory results were obtained in 37 patients (25 females, 12 males; mean age 56 yrs). Thirtyone cases were pleural, 5 cases were peritoneal and 1 case was paratesticular mesotheliomas. Histologically, 31 cases were epithelioid, and 6 cases were biphasic type. Overall all loss of BAP1 expression was 31/37 [83, 8% (87, 1% pleural, 80% peritoneal, 0 paratesticular)]. Histologically, all biphasic types and 25/31 (80, 6%) epithelioid types showed BAP1 expression loss. Conclusion: Loss of BAP1 expression seems to be a frequent event in Turkish malignant mesotheliomas. However, in our small cohort, no significant correlation was found between tumor type and localization. We need to demonstrate both somatic and germ-like mutations in familial cases especially from erionite villages.
New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet?
Archives of Pathology & Laboratory Medicine, 2016
The separation of benign from malignant mesothelial proliferations is crucial to patient care but is frequently morphologically difficult.Context.— To briefly review adjunctive tests claimed to be useful in this setting and to examine in detail 2 new tests: p16 fluorescence in situ hybridization (FISH) and BRCA1-associated protein 1 (BAP1) immunohistochemistry.Objective.— Literature review with emphasis on p16 FISH and BAP1 immunohistochemistry.Design.— Glucose transporter-1, p53, insulin-like growth factor 2 messenger RNA–binding protein 3 (IMP-3), desmin, and epithelial membrane antigen have all been claimed to mark either benign or malignant mesothelial processes, but in practice they at best provide statistical differences in large series of cases, without being useful in an individual case. Homozygous deletion of p16 by FISH or loss of BAP1 has only been reported in malignant mesotheliomas and not in benign mesothelial proliferations. BAP1 appears to be lost more frequently in ...
Disease Markers
Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor ...
The American journal of surgical pathology, 2016
The separation of sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis can be morphologically very difficult. Deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) testing appears to be a reliable marker of malignancy in mesothelial proliferations, and more recently it has been reported that, in this setting, loss of BAP1 by immunohistochemistry is only seen in malignant mesotheliomas. To determine how useful these tests are with sarcomatous and desmoplastic mesotheliomas, we examined 20 such tumors. Loss of BAP1 was seen in 3/20 (15%) and deletion of p16 by FISH was seen in 16/20 (80%) cases. Loss of one or the other marker was observed in 17/20 (85%). We also examined 13 sarcomatoid carcinomas, an important differential diagnosis of sarcomatoid mesotheliomas, and found that BAP1 was never lost, but p16 was deleted in 3/11 (27%). We conclude that: (1) BAP1 immunohistochemistry is relatively insensitive in the context of sarcomatous and desmopl...