Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma

Can F. Koyuncu; Reetoja Nag; Cheng Lu; Germán Corredor; Vidya S. Viswanathan; Vlad C. Sandulache; Pingfu Fu; Kailin Yang; Quintin Pan; Zelin Zhang; Jun Xu; Deborah J. Chute; Wade L. Thorstad; Farhoud Faraji; Justin A. Bishop; Mitra Mehrad; Patricia D. Castro; Andrew G. Sikora; Lester D.R. Thompson; Rebecca D. Chernock; Krystle A. Lang Kuhs; Jay K. Wasman; Jingqin R. Luo; David J. Adelstein; Shlomo A. Koyfman; James S. Lewis; Anant Madabhushi

doi:10.1002/cncr.34446

Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma

Can F. Koyuncu, Reetoja Nag, Cheng Lu, Germán Corredor, Vidya S. Viswanathan, Vlad C. Sandulache, Pingfu Fu, Kailin Yang, Quintin Pan, Zelin Zhang, Jun Xu, Deborah J. Chute, Wade L. Thorstad, Farhoud Faraji, Justin A. Bishop, Mitra Mehrad, Patricia D. Castro, Andrew G. Sikora, Lester D.R. Thompson, Rebecca D. ChernockKrystle A. Lang Kuhs, Jay K. Wasman, Jingqin R. Luo, David J. Adelstein, Shlomo A. Koyfman, James S. Lewis, Anant Madabhushi

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Background: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. Methods: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin–eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, T_TR, is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, T_B for Blacks and T_W for Whites, for risk stratification. Results: MuNI was statistically significantly different between Black (mean, 3.88e–4; median, 3.67e–04) and White patients (mean, 3.36e–04; median, 2.99e–04), with p =.0078. Using T_TR, MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p =.002; 95% confidence interval [CI], 1.21–2.43) and in White patients with HR of 1.72 (p =.005; 95% CI, 1.18–2.51). Population-specific cutoff, T_W, yielded improved HR of 1.77 (p =.003; 95% CI, 1.21–2.58) for White patients, whereas T_B did not improve risk-stratification in Black patients with HR of 0.6 (p =.3; HR, 0.6; 95% CI, 0.2–1.80). Conclusions: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.

Original language	English
Pages (from-to)	3831-3842
Number of pages	12
Journal	Cancer
Volume	128
Issue number	21
DOIs	https://doi.org/10.1002/cncr.34446
State	Published - Nov 1 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

Funding

Rebecca D. Chernock reports funding from Caris Life Sciences and Merck. Deborah J. Chute reports book royalties. Germán Corredor reports a grant from the US Department of Defense. Farhoud Faraji reports funding from the National Institute on Deafness and Other Communication Disorders and Stand Up To Cancer. James S. Lewis Jr reports a grant from National Institutes of Health and payment as an expert witness from Shook, Hardy, and Bacon. Jingqin R. Luo reports a grant from National Institutes of Health. Anant Madabhushi reports grants from AstraZeneca, Boehringer Ingelheim, and Bristol‐Myers Squibb; consulting fees from Aiforia, Caris, and SimBioSys; participation as a fiduciary officer with Picture Health; and stock options with Elucid Bioimaging. Andrew G. Sikora reports consulting fees from F. Hoffmann‐La Roche. Lester D.R. Thompson reports funding from Elsevier. Jun Xu reports a grant from the National Natural Science Foundation of China. Kailin Yang reports grants from the Conquer Cancer Foundation, the National Cancer Institute, and RSNA Research and Education Foundation; and travel funding from Case Comprehensive Cancer Center and Case Western Reserve University. The other authors made no disclosures. Research reported in this publication was supported by the National Cancer Institute under award numbers R01CA268207‐01A1, R01CA249992‐01A1, R01CA202752‐01A1, R01CA208236‐01A1, R01CA216579‐01A1, R01CA220581‐01A1, R01CA257612‐01A1, 1U01CA239055‐01, 1U01CA248226‐01, 1U54CA254566‐01, National Heart, Lung and Blood Institute 1R01HL15127701A1, R01HL15807101A1, National Institute of Biomedical Imaging and Bioengineering 1R43EB028736‐01, National Center for Research Resources under award number 1 C06 RR12463‐01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Servicethe Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program (W81XWH‐19‐1‐0668), the Prostate Cancer Research Program (W81XWH‐20‐1‐0851), the Lung Cancer Research Program (W81XWH‐18‐1‐0440, W81XWH‐20‐1‐0595), the Peer Reviewed Cancer Research Program (W81XWH‐18‐1‐0404, W81XWH‐21‐1‐0345, W81XWH‐21‐1‐0160, and W81XWH‐22‐1‐0236), the Kidney Precision Medicine Project (KPMP) Glue Grant and sponsored research agreements from Bristol Myers‐Squibb, Boehringer‐Ingelheim, Eli‐Lilly and Astrazeneca. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government. This study was reviewed and approved by the institutional review boards of Washington University in St. Louis, Missouri, USA; Johns Hopkins University in Baltimore, Maryland, USA; the Cleveland Clinic in Cleveland, Ohio, USA; Case Western Reserve University in Cleveland, Ohio, USA; Cleveland University Hospital Seidman Cancer Center in Cleveland, Ohio, USA; the Southern California Permanente Medical Group in Los Angeles, California, USA; Vanderbilt University Medical Center in Nashville, Tennessee, USA; and the Michael E. DeBakey VA Medical Center in Houston, Texas, USA. This study was supported by the National Cancer Institute (R01CA249992-01A1, R01CA202752-01A1, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, R01CA257612-01A1, 1U01CA239055-01, 1U01CA248226-01, and 1U54CA254566-01), National Heart, Lung and Blood Institute (1R01HL15127701A1 and R01HL15807101A1), National Institute of Biomedical Imaging and Bioengineering (1R43EB028736-01), National Center for Research Resources (1 C06 RR12463-01), a VA Merit Review Award (IBX004121A) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program (W81XWH-19-1-0668), the Prostate Cancer Research Program (W81XWH-15-1-0558 and W81XWH-20-1-0851), the Lung Cancer Research Program (W81XWH-18-1-0440 and W81XWH-20-1-0595), the Peer Reviewed Cancer Research Program (W81XWH-18-1-0404 and W81XWH-21-1-0345), the Kidney Precision Medicine Project (KPMP) Glue Grant, and sponsored research agreements from Bristol Myers-Squibb, Boehringer-Ingelheim, and AstraZeneca. Vlad C. Sandulache is supported by Career Development Award (IK2 CX001953) from the US Department of Veterans Affairs Clinical Sciences R&D Service. Farhoud Faraji is supported by Stand Up to Cancer (308268-00001) Precision Therapy for Fanconi Anemia and HPV-related Head & Neck Cancer and National Institutes of Health (T32DC000028). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the US Department of Veterans Affairs, the Department of Defense, or the US Government. This study was reviewed and approved by the institutional review boards of Washington University in St. Louis, Missouri, USA; Johns Hopkins University in Baltimore, Maryland, USA; the Cleveland Clinic in Cleveland, Ohio, USA; Case Western Reserve University in Cleveland, Ohio, USA; Cleveland University Hospital Seidman Cancer Center in Cleveland, Ohio, USA; the Southern California Permanente Medical Group in Los Angeles, California, USA; Vanderbilt University Medical Center in Nashville, Tennessee, USA; and the Michael E. DeBakey VA Medical Center in Houston, Texas, USA. This study was supported by the National Cancer Institute (R01CA249992‐01A1, R01CA202752‐01A1, R01CA208236‐01A1, R01CA216579‐01A1, R01CA220581‐01A1, R01CA257612‐01A1, 1U01CA239055‐01, 1U01CA248226‐01, and 1U54CA254566‐01), National Heart, Lung and Blood Institute (1R01HL15127701A1 and R01HL15807101A1), National Institute of Biomedical Imaging and Bioengineering (1R43EB028736‐01), National Center for Research Resources (1 C06 RR12463‐01), a VA Merit Review Award (IBX004121A) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program (W81XWH‐19‐1‐0668), the Prostate Cancer Research Program (W81XWH‐15‐1‐0558 and W81XWH‐20‐1‐0851), the Lung Cancer Research Program (W81XWH‐18‐1‐0440 and W81XWH‐20‐1‐0595), the Peer Reviewed Cancer Research Program (W81XWH‐18‐1‐0404 and W81XWH‐21‐1‐0345), the Kidney Precision Medicine Project (KPMP) Glue Grant, and sponsored research agreements from Bristol Myers‐Squibb, Boehringer‐Ingelheim, and AstraZeneca. Vlad C. Sandulache is supported by Career Development Award (IK2 CX001953) from the US Department of Veterans Affairs Clinical Sciences R&D Service. Farhoud Faraji is supported by Stand Up to Cancer (308268‐00001) Precision Therapy for Fanconi Anemia and HPV‐related Head & Neck Cancer and National Institutes of Health (T32DC000028). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the US Department of Veterans Affairs, the Department of Defense, or the US Government.

Funders	Funder number
Breast Cancer Research Program	W81XWH‐19‐1‐0668
Caris Life Sciences and Merck
Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University
Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University
Cleveland University Hospital Seidman Cancer Center in Cleveland
Johns Hopkins University in Baltimore
Kentucky Lung Cancer Research Program	W81XWH‐21‐1‐0160, W81XWH‐18‐1‐0404, W81XWH‐20‐1‐0595, W81XWH‐22‐1‐0236, W81XWH‐18‐1‐0440, W81XWH‐21‐1‐0345
Michael E. DeBakey VA Medical Center
National Institute on Deafness and Other Communication Disorders and Stand Up To Cancer
Office of the Assistant Secretary of Defense for Health Affairs
US Department of Veterans Affairs Biomedical Laboratory Research and Development Service
US Department of Veterans Affairs Clinical Sciences R&D Service
United States Department of Veterans Affairs Biomedical Laboratory Research and Development Servicethe Office of the Assistant Secretary of Defense for Health Affairs
National Institutes of Health (NIH)	T32DC000028
National Institutes of Health (NIH)
U.S. Department of Defense
National Heart, Lung, and Blood Institute (NHLBI)	1R01HL15127701A1, R01HL15807101A1
National Heart, Lung, and Blood Institute (NHLBI)
National Childhood Cancer Registry – National Cancer Institute	1U01CA239055‐01, R01CA208236‐01A1, R01CA216579‐01A1, R01CA268207‐01A1, 1U54CA254566‐01, R01CA202752‐01A1, R01CA257612‐01A1, R01CA220581‐01A1, R01CA249992‐01A1, U01CA248226
National Childhood Cancer Registry – National Cancer Institute
National Institute of Biomedical Imaging and Bioengineering	1R43EB028736‐01
National Institute of Biomedical Imaging and Bioengineering
National Center for Research Resources	IBX004121A, 1 C06 RR12463‐01
National Center for Research Resources
U.S. Department of Veterans Affairs
Conquer Cancer Foundation
Boehringer-Ingelheim
Bristol-Myers Squibb
AstraZeneca	IK2 CX001953
AstraZeneca
RSNA Research and Education Foundation
Case Western Reserve University
Case Comprehensive Cancer Center, Case Western Reserve University
Stand Up To Cancer-Prostate Cancer Dream Team Translational Research	308268‐00001
Stand Up To Cancer-Prostate Cancer Dream Team Translational Research
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
DOD Prostate Cancer Research Program	W81XWH‐15‐1‐0558, W81XWH‐20‐1‐0851
DOD Prostate Cancer Research Program
Government of South Australia
National Natural Science Foundation of P.R. China

Keywords

Black
HPV
MuNI
OPSCC
White
image analysis

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/cncr.34446

Cite this

Koyuncu, C. F., Nag, R., Lu, C., Corredor, G., Viswanathan, V. S., Sandulache, V. C., Fu, P., Yang, K., Pan, Q., Zhang, Z., Xu, J., Chute, D. J., Thorstad, W. L., Faraji, F., Bishop, J. A., Mehrad, M., Castro, P. D., Sikora, A. G., Thompson, L. D. R., ... Madabhushi, A. (2022). Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer, 128(21), 3831-3842. https://doi.org/10.1002/cncr.34446

@article{081abcf1a162480aabf7a045fb6f9dde,

title = "Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma",

abstract = "Background: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. Methods: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin–eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR, is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification. Results: MuNI was statistically significantly different between Black (mean, 3.88e–4; median, 3.67e–04) and White patients (mean, 3.36e–04; median, 2.99e–04), with p =.0078. Using TTR, MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p =.002; 95% confidence interval [CI], 1.21–2.43) and in White patients with HR of 1.72 (p =.005; 95% CI, 1.18–2.51). Population-specific cutoff, TW, yielded improved HR of 1.77 (p =.003; 95% CI, 1.21–2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p =.3; HR, 0.6; 95% CI, 0.2–1.80). Conclusions: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.",

keywords = "Black, HPV, MuNI, OPSCC, White, image analysis",

author = "Koyuncu, {Can F.} and Reetoja Nag and Cheng Lu and Germ{\'a}n Corredor and Viswanathan, {Vidya S.} and Sandulache, {Vlad C.} and Pingfu Fu and Kailin Yang and Quintin Pan and Zelin Zhang and Jun Xu and Chute, {Deborah J.} and Thorstad, {Wade L.} and Farhoud Faraji and Bishop, {Justin A.} and Mitra Mehrad and Castro, {Patricia D.} and Sikora, {Andrew G.} and Thompson, {Lester D.R.} and Chernock, {Rebecca D.} and {Lang Kuhs}, {Krystle A.} and Wasman, {Jay K.} and Luo, {Jingqin R.} and Adelstein, {David J.} and Koyfman, {Shlomo A.} and Lewis, {James S.} and Anant Madabhushi",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.",

year = "2022",

month = nov,

day = "1",

doi = "10.1002/cncr.34446",

language = "English",

volume = "128",

pages = "3831--3842",

number = "21",

}

Koyuncu, CF, Nag, R, Lu, C, Corredor, G, Viswanathan, VS, Sandulache, VC, Fu, P, Yang, K, Pan, Q, Zhang, Z, Xu, J, Chute, DJ, Thorstad, WL, Faraji, F, Bishop, JA, Mehrad, M, Castro, PD, Sikora, AG, Thompson, LDR, Chernock, RD, Lang Kuhs, KA, Wasman, JK, Luo, JR, Adelstein, DJ, Koyfman, SA, Lewis, JS & Madabhushi, A 2022, 'Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma', Cancer, vol. 128, no. 21, pp. 3831-3842. https://doi.org/10.1002/cncr.34446

TY - JOUR

T1 - Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma

AU - Koyuncu, Can F.

AU - Nag, Reetoja

AU - Lu, Cheng

AU - Corredor, Germán

AU - Viswanathan, Vidya S.

AU - Sandulache, Vlad C.

AU - Fu, Pingfu

AU - Yang, Kailin

AU - Pan, Quintin

AU - Zhang, Zelin

AU - Xu, Jun

AU - Chute, Deborah J.

AU - Thorstad, Wade L.

AU - Faraji, Farhoud

AU - Bishop, Justin A.

AU - Mehrad, Mitra

AU - Castro, Patricia D.

AU - Sikora, Andrew G.

AU - Thompson, Lester D.R.

AU - Chernock, Rebecca D.

AU - Lang Kuhs, Krystle A.

AU - Wasman, Jay K.

AU - Luo, Jingqin R.

AU - Adelstein, David J.

AU - Koyfman, Shlomo A.

AU - Lewis, James S.

AU - Madabhushi, Anant

PY - 2022/11/1

Y1 - 2022/11/1

N2 - Background: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. Methods: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin–eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR, is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification. Results: MuNI was statistically significantly different between Black (mean, 3.88e–4; median, 3.67e–04) and White patients (mean, 3.36e–04; median, 2.99e–04), with p =.0078. Using TTR, MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p =.002; 95% confidence interval [CI], 1.21–2.43) and in White patients with HR of 1.72 (p =.005; 95% CI, 1.18–2.51). Population-specific cutoff, TW, yielded improved HR of 1.77 (p =.003; 95% CI, 1.21–2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p =.3; HR, 0.6; 95% CI, 0.2–1.80). Conclusions: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.

AB - Background: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. Methods: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin–eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR, is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification. Results: MuNI was statistically significantly different between Black (mean, 3.88e–4; median, 3.67e–04) and White patients (mean, 3.36e–04; median, 2.99e–04), with p =.0078. Using TTR, MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p =.002; 95% confidence interval [CI], 1.21–2.43) and in White patients with HR of 1.72 (p =.005; 95% CI, 1.18–2.51). Population-specific cutoff, TW, yielded improved HR of 1.77 (p =.003; 95% CI, 1.21–2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p =.3; HR, 0.6; 95% CI, 0.2–1.80). Conclusions: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.

KW - Black

KW - HPV

KW - MuNI

KW - OPSCC

KW - White

KW - image analysis

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U2 - 10.1002/cncr.34446

DO - 10.1002/cncr.34446

M3 - Article

C2 - 36066461

AN - SCOPUS:85138273581

SN - 0008-543X

VL - 128

SP - 3831

EP - 3842

JO - Cancer

JF - Cancer

IS - 21

ER -

Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma

Abstract

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UN SDGs

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