Immunohistochemistry and Next-generation Sequencing Are Complementary Tests in Identifying PTEN Abnormality in Endometrial Carcinoma Biopsies

International Journal of Gynecological Pathology, vol. 41, pp. 12–19

Abstract

PTEN plays a central role in the pathogenesis of endometrial carcinoma. Previous studies reported a high interobserver reproducibility for the interpretation of PTEN immunohistochemistry (IHC). However, PTEN IHC and its interpretation remain challenging during laboratory practice. The purpose of this study was to reevaluate PTEN IHC pattern in direct comparison to next-generation sequencing in identifying PTEN abnormality. IHC and tagged-amplicon next-generation sequencing PTEN sequencing was performed on 182 endometrial carcinoma biopsy/curetting samples from five centers (Barts, Calgary, Cambridge, Leiden, and Vancouver). Sensitivity, specificity and accuracy of PTEN IHC to predict loss of function PTEN mutations were calculated. Abnormalities of PTEN in association with histotype and molecular subtype were assessed. A total of 5 PTEN IHC patterns were recorded: absent, subclonal loss, equivocal, reduced (relative to internal control) and retained. The absence of PTEN IHC has a sensitivity of 75.4% (95% confidence interval: 62.7-85.5%), a specificity of 84.6% (95% confidence interval: 76.2%-90.9%), and accuracy of 81.2% (95% confidence interval: 74.4%-86.9%) in predicting loss of function PTEN mutation. PTEN abnormality by complementary interpretation of both assays was present in 91.9% of endometrial endometrioid carcinoma, grade 1, and significantly higher in endometrial endometrioid carcinomas of all grades compared with endometrial serous carcinoma (80.0% vs. 19.4%, P<0.0001). PTEN abnormalities are common across all molecular subtypes of endometrioid carcinomas. Our data support the use of ancillary PTEN IHC for diagnostic purposes in endometrial neoplasms. However, for clinical trial design complementary testing of both IHC and sequencing of PTEN should be considered to assess the PTEN status in endometrial carcinomas.

Authors 9

1. Linyuan Wang Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

2. Anna Piskorz Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

3. Tjalling Bosse Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

4. Mercedes Jimenez‐Liñan Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

5. Brian Rous Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

6. C. Blake Gilks Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

7. James D. Brenton Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

8. Naveena Singh Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

9. Martin Köbel corresponding Aachen Department of Pathology, University of Leiden, Leiden

   Leiden University · University of Calgary · Barts Health NHS Trust · University of Cambridge · Cancer Research UK · Vancouver General Hospital · Addenbrooke's Hospital

   Affiliation as printed

   Cancer Research UK Cambridge Institute, University of Cambridge (A.P., J.D.B.)

   Department of Pathology Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada

   Department of Pathology, Addenbrooke's Hospital (M.J.-L., B.R.), Cambridge

   Department of Pathology, Barts Health NHS Trust, London (N.S.), UK

   Department of Pathology, University of Calgary, Calgary, Alberta (L.W., M.K.)

   Department of Pathology, University of Leiden, Leiden, The Netherlands (T.B.)

   to Martin Köbel, MD, Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada T2N 2S9. E-mail: [email protected]