The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma

Our plain-English summary of The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma, by A. Chou, C.W. Toon, A. Clarkson, et al (Histopathology, 2018).

The study

• Authors: A. Chou, C.W. Toon, A. Clarkson, A. Sheen, L. Sioson, A.J. Gill
• Journal: Histopathology
• Published: 2018;72(3):509-515
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aims: Mesothelioma is a relatively uncommon but highly malignant neoplasm. Most patients die of disease within 1 year of diagnosis, but some have prolonged survival. Prospective identification of these longer-term survivors may help to guide treatment. We therefore sought to investigate the role of p16 immunohistochemistry (IHC) both alone and in combination with other markers as a potential predictor of prolonged survival in mesothelioma.

Methods And Results: P16 IHC was performed on unselected pleural mesotheliomas biopsied from 1991 to 2014; 153 of 208 (74%) cases were p16-negative, which correlated significantly with poor overall survival in both univariate (median survival 7.6 versus 13.6 months; P = 0.001) and multivariate analysis [hazard ratio (HR): 1.632; 95% confidence interval (CI): 1.103-2.415; P = 0.014]. Other independent factors associated with prolonged survival included loss of expression of BAP1 and epithelioid morphology. We therefore stratified patients further based on these three independent prognostic variables and demonstrated an unusually prolonged survival in mesotheliomas which were epithelioid, BAP1 IHC negative and p16 IHC positive (12% of cases, median survival 31.7 months, P < 0.0001).

Conclusions: In conclusion, p16 IHC is an independent prognostic biomarker in pleural mesothelioma. When used in combination with BAP1 IHC and morphological subtyping, patients with exceptionally prolonged survival can potentially be identified.

© 2017 John Wiley & Sons Ltd.

In plain English

This study, from Royal North Shore Hospital in Sydney, Australia, examined tumour biopsies from 208 people diagnosed with pleural mesothelioma between 1991 and 2014. The authors stained the samples for a protein called p16. They combined that result with earlier staining for a protein called BAP1 and with the tumour's cell type (epithelioid, sarcomatoid or biphasic). Asbestos exposure was not studied. Tumours in 153 of 208 patients (74%) lacked p16. Those patients had a median survival of 7.6 months, against 13.6 months when p16 was present. After taking age, cell type and BAP1 into account, lacking p16 was still linked to shorter survival (hazard ratio 1.632, 95% confidence interval 1.103 to 2.415, p = 0.014). Patients whose tumours were epithelioid, lacked BAP1 and had p16 (24 of 208, 12%) had a median survival of 31.7 months. All other patients combined had a median survival of 7.7 months. The authors concluded that p16 staining is a promising predictor of survival and might help in routine care if confirmed in other patient groups. They noted that detailed staging and treatment data were not available.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective cohort study of archived tumour biopsies, using tissue staining (immunohistochemistry) and survival analysis
• Who was studied: 208 patients with malignant pleural mesothelioma diagnosed between January 1991 and August 2014 at the Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia. Of 229 cases, 21 were excluded because the tissue sections lacked tumour cells. Median age at diagnosis was 72 and 82% were male. 109 (52%) tumours were epithelioid, 60 (30%) sarcomatoid and 39 (19%) biphasic.
• Exposure: Not studied. The article examined tumour features (p16 staining, BAP1 staining and histological subtype), not asbestos or other exposures.
• Main results:
  • Of 208 tumours, 19 (9%) showed strong diffuse p16 staining (scored 2+), 36 (17%) showed patchy staining (1+) and 153 (74%) showed no staining (0). Scores 1+ and 2+ were grouped as p16-positive.
  • Patients with p16-negative tumours had a median survival of 7.6 months, compared with 13.6 months for patients with p16-positive tumours (P = 0.001).
  • In the multivariate (Cox regression) analysis, p16-negative tumours were associated with worse survival: hazard ratio 1.632, 95% CI 1.103 to 2.415, p = 0.014. This is the figure given in Table 2 and the abstract; the results text prints 1.623.
  • In the same multivariate analysis, BAP1-positive tumours were associated with worse survival: hazard ratio 1.555, 95% CI 1.113 to 2.172, P = 0.01.
  • In the same multivariate analysis, sarcomatoid or biphasic subtypes were associated with worse survival: hazard ratio 2.21, 95% CI 1.583 to 3.085, P less than 0.0001.
  • In the same multivariate analysis, age over 72 years had a hazard ratio of 1.358, 95% CI 0.977 to 1.889, P = 0.069.
  • The group with epithelioid, BAP1-negative and p16-positive tumours made up 12% of the cohort (24 of 208).
  • In the epithelioid, BAP1-negative, p16-positive group, 1-year survival was 57% and median survival was 31.7 months.
  • The epithelioid, BAP1-negative, p16-positive group had a median survival of 31.7 months, compared with 7.7 months for all other groups combined (p less than 0.0001).
  • The other seven groups had 1-year survival between 0% and 27% and median survival between 3.2 and 15.4 months, according to the text.
  • Median overall survival for the whole cohort of 208 patients was 9 months.
  • Women had better survival than men (21.7 versus 14.4 months), but the difference was not statistically significant (p = 0.16).
• The authors' conclusion: The authors concluded that p16 staining is a promising predictor of all-cause survival in malignant pleural mesothelioma. They also concluded that, combined with BAP1 staining and tumour subtyping, it helps identify a subgroup (epithelioid, BAP1-negative, p16-positive) with long median survival.
• Limitations the authors state:
  • Detailed staging and treatment data were not available. All specimens were pleural biopsies, as the institution does not perform radical surgery.
  • The authors did not perform p16 FISH (a genetic test), so they could not compare it with the staining results.
  • The authors stated that the findings need to be confirmed in other cohorts before p16 staining is used in routine care.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Epithelioid, BAP1, Pleural Mesothelioma, Mesothelioma, Neoplasm, Immunohistochemistry, Overall Survival, Median Survival.

Related studies

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• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma — R. Pillappa, J.J. Maleszewski, et al. (2018)
• BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma — H.E. Lee, J.R. Molina, et al. (2018)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)

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