Journal Article
. 2021 Mar; 131(8):.
doi: 10.1172/JCI145488.

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma

Can F Koyuncu 1 Cheng Lu 1 Kaustav Bera 1 Zelin Zhang 2 Jun Xu 2 Paula Toro 1 German Corredor 1 Deborah Chute 3 Pingfu Fu 4 Wade L Thorstad 5 Farhoud Faraji 6 Justin A Bishop 7 Mitra Mehrad 8 Patricia D Castro 9 Andrew G Sikora 9 Lester Dr Thompson 10 R D Chernock 5 Krystle A Lang Kuhs 8 Jingqin Luo 5 Vlad Sandulache 9 David J Adelstein 3 Shlomo Koyfman 3 James S Lewis 8 Anant Madabhushi 1 
Affiliations
  • PMID: 33651718
  •     34 References
  •     2 citations

Abstract

BACKGROUNDPatients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability.METHODSWe present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI.RESULTSThe MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately.CONCLUSIONMuNI holds promise as a low-cost, tissue-nondestructive, H&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.FUNDINGNational Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostate Cancer Idea Development Award; DOD Lung Cancer Investigator-Initiated Translational Research Award; DOD Peer-Reviewed Cancer Research Program; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award (CTSA) program, Case Western Reserve University; NCI Cancer Center Support Grant, NIH; Career Development Award from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant, NIH; and Computational Genomic Epidemiology of Cancer Program, Case Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government.

Keywords: Head and neck cancer; Oncology.

Tumor-infiltrating lymphocytes favor the response to chemoradiotherapy of head and neck cancer.
Panagiotis Balermpas, Franz Rödel, +2 authors, Emmanouil Fokas.
Oncoimmunology, 2014 Apr 09; 3(1). PMID: 24711959    Free PMC article.
Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.
Peter Ström, Kimmo Kartasalo, +29 authors, Martin Eklund.
Lancet Oncol, 2020 Jan 14; 21(2). PMID: 31926806
An oral cavity squamous cell carcinoma quantitative histomorphometric-based image classifier of nuclear morphology can risk stratify patients for disease-specific survival.
Cheng Lu, James S Lewis, +3 authors, Anant Madabhushi.
Mod Pathol, 2017 Aug 05; 30(12). PMID: 28776575    Free PMC article.
Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study.
Brian O'Sullivan, Shao Hui Huang, +20 authors, Wei Xu.
Lancet Oncol, 2016 Mar 05; 17(4). PMID: 26936027
Highly Cited.
Deep Adversarial Training for Multi-Organ Nuclei Segmentation in Histopathology Images.
Faisal Mahmood, Daniel Borders, +4 authors, Nicholas J Durr.
IEEE Trans Med Imaging, 2019 Jul 10; 39(11). PMID: 31283474    Free PMC article.
Eliminating Postoperative Radiation to the Pathologically Node-Negative Neck: Long-Term Results of a Prospective Phase II Study.
Jessika A Contreras, Christopher Spencer, +15 authors, Wade Thorstad.
J Clin Oncol, 2019 Jun 28; 37(28). PMID: 31246526
A review of the 8th edition of the AJCC staging system for oropharyngeal cancer according to HPV status.
Piotr Machczyński, Ewa Majchrzak, +2 authors, Wojciech Golusiński.
Eur Arch Otorhinolaryngol, 2020 Apr 29; 277(9). PMID: 32342197    Free PMC article.
Review.
Automated deep-learning system for Gleason grading of prostate cancer using biopsies: a diagnostic study.
Wouter Bulten, Hans Pinckaers, +6 authors, Geert Litjens.
Lancet Oncol, 2020 Jan 14; 21(2). PMID: 31926805
Nuclear Shape and Architecture in Benign Fields Predict Biochemical Recurrence in Prostate Cancer Patients Following Radical Prostatectomy: Preliminary Findings.
George Lee, Robert W Veltri, +3 authors, Anant Madabhushi.
Eur Urol Focus, 2017 Jul 30; 3(4-5). PMID: 28753763    Free PMC article.
Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma.
Douglas J Hartman, Fahad Ahmad, +2 authors, Liron Pantanowitz.
Oral Oncol, 2018 Nov 10; 86. PMID: 30409313    Free PMC article.
A Dataset and a Technique for Generalized Nuclear Segmentation for Computational Pathology.
Neeraj Kumar, Ruchika Verma, +3 authors, Amit Sethi.
IEEE Trans Med Imaging, 2017 Mar 14; 36(7). PMID: 28287963
HistoQC: An Open-Source Quality Control Tool for Digital Pathology Slides.
Andrew Janowczyk, Ren Zuo, +2 authors, Anant Madabhushi.
JCO Clin Cancer Inform, 2019 Apr 17; 3. PMID: 30990737    Free PMC article.
Prognostic Impact of AJCC/UICC 8th Edition New Staging Rules in Oropharyngeal Squamous Cell Carcinoma.
Nora Würdemann, Steffen Wagner, +5 authors, Claus Wittekindt.
Front Oncol, 2017 Jul 18; 7. PMID: 28713770    Free PMC article.
Segmentation of Nuclei in Histopathology Images by Deep Regression of the Distance Map.
Peter Naylor, Marick Lae, Fabien Reyal, Thomas Walter.
IEEE Trans Med Imaging, 2019 Feb 05; 38(2). PMID: 30716022
Histopathological image analysis: a review.
Metin N Gurcan, Laura E Boucheron, +3 authors, B Yener.
IEEE Rev Biomed Eng, 2009 Jan 01; 2. PMID: 20671804    Free PMC article.
Highly Cited. Review.
Intra-observer and inter-observer variability in two grading systems for oral epithelial dysplasia: A multi-centre study in India.
Kannan Ranganathan, Loganathan Kavitha, +8 authors, Saman Warnakulasuriya.
J Oral Pathol Med, 2020 Jun 10; 49(9). PMID: 32516857
Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer: ASCO Provisional Clinical Opinion.
David J Adelstein, Nofisat Ismaila, +11 authors, John A Ridge.
J Clin Oncol, 2019 Apr 26; 37(18). PMID: 31021656
Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma.
Maura L Gillison, Anil K Chaturvedi, William F Anderson, Carole Fakhry.
J Clin Oncol, 2015 Sep 10; 33(29). PMID: 26351338    Free PMC article.
Highly Cited. Review.
Deep learning for prediction of colorectal cancer outcome: a discovery and validation study.
Ole-Johan Skrede, Sepp De Raedt, +17 authors, Håvard E Danielsen.
Lancet, 2020 Feb 03; 395(10221). PMID: 32007170
Human papillomavirus and rising oropharyngeal cancer incidence in the United States.
Anil K Chaturvedi, Eric A Engels, +15 authors, Maura L Gillison.
J Clin Oncol, 2011 Oct 05; 29(32). PMID: 21969503    Free PMC article.
Highly Cited.
Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology.
Kaustav Bera, Kurt A Schalper, +2 authors, Anant Madabhushi.
Nat Rev Clin Oncol, 2019 Aug 11; 16(11). PMID: 31399699    Free PMC article.
Highly Cited. Review.
Human papillomavirus and survival of patients with oropharyngeal cancer.
K Kian Ang, Jonathan Harris, +12 authors, Maura L Gillison.
N Engl J Med, 2010 Jun 10; 363(1). PMID: 20530316    Free PMC article.
Highly Cited.
Phase II Evaluation of Aggressive Dose De-Escalation for Adjuvant Chemoradiotherapy in Human Papillomavirus-Associated Oropharynx Squamous Cell Carcinoma.
Daniel J Ma, Katharine A Price, +18 authors, Robert L Foote.
J Clin Oncol, 2019 Jun 05; 37(22). PMID: 31163012    Free PMC article.
Validation and assessment of discordance of the 8th edition AJCC (American Joint Committee on Cancer) clinical and pathologic staging systems in patients with p16+ oropharyngeal cancer treated with surgery and adjuvant radiation at a single institution.
Piyush Gupta, Jocelyn C Migliacci, +7 authors, Ian Ganly.
Oral Oncol, 2018 Aug 14; 83. PMID: 30098770    Free PMC article.
Tumor cell anaplasia and multinucleation are predictors of disease recurrence in oropharyngeal squamous cell carcinoma, including among just the human papillomavirus-related cancers.
James S Lewis, Juliette B Scantlebury, Jingqin Luo, Wade L Thorstad.
Am J Surg Pathol, 2012 Jun 30; 36(7). PMID: 22743286    Free PMC article.
Selective invocation of shape priors for deformable segmentation and morphologic classification of prostate cancer tissue microarrays.
Sahirzeeshan Ali, Robert Veltri, +2 authors, Anant Madabhushi.
Comput Med Imaging Graph, 2014 Dec 04; 41. PMID: 25466771    Free PMC article.
Confirmation of the eighth edition of the AJCC/UICC TNM staging system for HPV-mediated oropharyngeal cancer in Japan.
Takatsugu Mizumachi, Akihiro Homma, +3 authors, Satoshi Fukuda.
Int J Clin Oncol, 2017 Mar 09; 22(4). PMID: 28271391
A quantitative histomorphometric classifier (QuHbIC) identifies aggressive versus indolent p16-positive oropharyngeal squamous cell carcinoma.
James S Lewis, Sahirzeeshan Ali, +2 authors, Anant Madabhushi.
Am J Surg Pathol, 2013 Oct 23; 38(1). PMID: 24145650    Free PMC article.
The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas.
Eleni Benson, Ryan Li, David Eisele, Carole Fakhry.
Oral Oncol, 2013 Oct 19; 50(6). PMID: 24134947    Free PMC article.
Review.
Risk Factors for Overall Survival Outcome in Surgically Treated Human Papillomavirus-Negative and Positive Patients with Oropharyngeal Cancer.
Nora Wuerdemann, Claus Wittekindt, +5 authors, Steffen Wagner.
Oncol Res Treat, 2017 May 31; 40(6). PMID: 28558385
Biomarker driven treatment of head and neck squamous cell cancer.
Nnamdi Eze, Ying-Chun Lo, Barbara Burtness.
Cancers Head Neck, 2017 Aug 29; 2. PMID: 31093353    Free PMC article.
Review.
Validation of the 8th edition UICC/AJCC TNM staging system for HPV associated oropharyngeal cancer patients managed with contemporary chemo-radiotherapy.
Kirsten van Gysen, Mark Stevens, +10 authors, Thomas Eade.
BMC Cancer, 2019 Jul 11; 19(1). PMID: 31288767    Free PMC article.
Detection of human papillomavirus in cervical lymph nodes: a highly effective strategy for localizing site of tumor origin.
Shahnaz Begum, Maura L Gillison, +2 authors, William H Westra.
Clin Cancer Res, 2003 Dec 26; 9(17). PMID: 14695150
Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers.
Gaurav Verma, Kanchan Vishnoi, +11 authors, Alok Chandra Bharti.
Cancer Med, 2017 Feb 06; 6(3). PMID: 28155253    Free PMC article.
Artificial intelligence for automating the measurement of histologic image biomarkers.
Toby C Cornish.
J Clin Invest, 2021 Apr 16; 131(8). PMID: 33855974    Free PMC article.
Radiomic Features Associated With HPV Status on Pretreatment Computed Tomography in Oropharyngeal Squamous Cell Carcinoma Inform Clinical Prognosis.
Bolin Song, Kailin Yang, +11 authors, Anant Madabhushi.
Front Oncol, 2021 Sep 25; 11. PMID: 34557418    Free PMC article.