Journal Article
. 2013 Oct;38(1).
doi: 10.1097/PAS.0000000000000086.

A quantitative histomorphometric classifier (QuHbIC) identifies aggressive versus indolent p16-positive oropharyngeal squamous cell carcinoma

James S Lewis 1 Sahirzeeshan Ali  Jingqin Luo  Wade L Thorstad  Anant Madabhushi  
Affiliations
  • PMID: 24145650
  •     36 References
  •     28 citations

Abstract

Human papillomavirus-related (p16-positive) oropharyngeal squamous cell carcinoma patients develop recurrent disease, mostly distant metastasis, in approximately 10% of cases, and the remaining patients, despite cure, can have major morbidity from treatment. Identifying patients with aggressive versus indolent tumors is critical. Hematoxylin and eosin-stained slides of a microarray cohort of p16-positive oropharyngeal squamous cell carcinoma cases were digitally scanned. A novel cluster cell graph was constructed using the nuclei as vertices to characterize and measure spatial distribution and cell clustering. A series of topological features defined on each node of the subgraph were analyzed, and a random forest decision tree classifier was developed. The classifier (QuHbIC) was validated over 25 runs of 3-fold cross-validation using case subsets for independent training and testing. Nineteen (11.9%) of the 160 patients on the array developed recurrence. QuHbIC correctly predicted outcomes in 140 patients (87.5% accuracy). There were 23 positive patients, of whom 11 developed recurrence (47.8% positive predictive value), and 137 negative patients, of whom only 8 developed recurrence (94.2% negative predictive value). The best other predictive features were stage T4 (18 patients; 83.1% accuracy) and N3 nodal disease (10 patients; 88.6% accuracy). QuHbIC-positive patients had poorer overall, disease-free, and disease-specific survival (P<0.001 for each). In multivariate analysis, QuHbIC-positive patients still showed significantly poorer disease-free and disease-specific survival, independent of all other variables. In summary, using just tiny hematoxylin and eosin punches, a computer-aided histomorphometric classifier (QuHbIC) can strongly predict recurrence risk. With prospective validation, this testing may be useful to stratify patients into different treatment groups.

Cyclin d1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma.
Ziwei Yu, Paul M Weinberger, +8 authors, Amanda Psyrri.
Clin Cancer Res, 2005 Feb 15; 11(3). PMID: 15709184
The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.
Jonathan I Epstein, William C Allsbrook, +2 authors, ISUP Grading Committee.
Am J Surg Pathol, 2005 Aug 13; 29(9). PMID: 16096414
Highly Cited. Review.
Learning the topological properties of brain tumors.
Cigdem Demir, S Humayun Gultekin, Bülent Yener.
IEEE/ACM Trans Comput Biol Bioinform, 2006 Oct 19; 2(3). PMID: 17044189
A structured review and theme analysis of papers published on 'quality of life' in head and neck cancer: 2000-2005.
S N Rogers, S A Ahad, A P Murphy.
Oral Oncol, 2007 Jun 30; 43(9). PMID: 17600755
Review.
Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers?
Erich M Sturgis, Paul M Cinciripini.
Cancer, 2007 Aug 29; 110(7). PMID: 17724670
Highly Cited. Review.
Multifeature prostate cancer diagnosis and Gleason grading of histological images.
Ali Tabesh, Mikhail Teverovskiy, +4 authors, Olivier Saidi.
IEEE Trans Med Imaging, 2007 Oct 24; 26(10). PMID: 17948727
Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer.
S F Preuss, A Weinell, +10 authors, J P Klussmann.
Br J Cancer, 2008 Jan 24; 98(3). PMID: 18212752    Free PMC article.
EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer.
Bhavna Kumar, Kitrina G Cordell, +16 authors, Thomas E Carey.
J Clin Oncol, 2008 May 14; 26(19). PMID: 18474878    Free PMC article.
Highly Cited.
P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis.
Harriët C Hafkamp, Jeroen J Mooren, +9 authors, Ernst-Jan M Speel.
Mod Pathol, 2009 Mar 24; 22(5). PMID: 19305381
Transoral laser microsurgery (TLM) +/- adjuvant therapy for advanced stage oropharyngeal cancer: outcomes and prognostic factors.
Jason T Rich, Simon Milov, +3 authors, Bruce H Haughey.
Laryngoscope, 2009 Jul 03; 119(9). PMID: 19572271    Free PMC article.
Integrated diagnostics: a conceptual framework with examples.
Anant Madabhushi, Scott Doyle, +5 authors, Michael Feldman.
Clin Chem Lab Med, 2010 May 25; 48(7). PMID: 20491597
Review.
High-throughput detection of prostate cancer in histological sections using probabilistic pairwise Markov models.
James P Monaco, John E Tomaszewski, +7 authors, Anant Madabhushi.
Med Image Anal, 2010 May 25; 14(4). PMID: 20493759    Free PMC article.
Use of cyclin D1 in conjunction with human papillomavirus status to predict outcome in oropharyngeal cancer.
Angela M Hong, Timothy A Dobbins, +15 authors, Barbara R Rose.
Int J Cancer, 2010 May 27; 128(7). PMID: 20503270
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.
Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer.
Angela Hong, Timothy Dobbins, +8 authors, Barbara Rose.
Eur J Cancer, 2010 Jun 12; 46(11). PMID: 20537890
HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome.
Rebecca D Chernock, Samir K El-Mofty, +2 authors, James S Lewis.
Head Neck Pathol, 2010 Jul 03; 3(3). PMID: 20596971    Free PMC article.
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.
Update of prognostic and predictive biomarkers in oropharyngeal squamous cell carcinoma: a review.
Carolin M Grimminger, Peter V Danenberg.
Eur Arch Otorhinolaryngol, 2010 Sep 10; 268(1). PMID: 20827554
Review.
Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study.
Bruce H Haughey, Michael L Hinni, +6 authors, Murli Krishna.
Head Neck, 2011 Feb 02; 33(12). PMID: 21284056
An epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention.
Torbjörn Ramqvist, Tina Dalianis.
Anticancer Res, 2011 May 28; 31(5). PMID: 21617204
Review.
The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms?
Erich M Sturgis, K Kian Ang.
J Natl Compr Canc Netw, 2011 Jun 04; 9(6). PMID: 21636538
Review.
High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma.
Odey C Ukpo, John J Flanagan, +3 authors, James S Lewis.
Am J Surg Pathol, 2011 Aug 13; 35(9). PMID: 21836494
Highly Cited.
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.
Systematic analysis of breast cancer morphology uncovers stromal features associated with survival.
Andrew H Beck, Ankur R Sangoi, +6 authors, Daphne Koller.
Sci Transl Med, 2011 Nov 11; 3(108). PMID: 22072638
Highly Cited.
HPV positive squamous cell carcinoma of the oropharynx. Are we observing an unusual pattern of metastases?
Susan Müller, Fadlo R Khuri, +3 authors, Nabil F Saba.
Head Neck Pathol, 2012 Apr 25; 6(3). PMID: 22528827    Free PMC article.
Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer.
Maura L Gillison, Qiang Zhang, +7 authors, K Kian Ang.
J Clin Oncol, 2012 May 09; 30(17). PMID: 22565003    Free PMC article.
Highly Cited.
Partial p16 staining in oropharyngeal squamous cell carcinoma: extent and pattern correlate with human papillomavirus RNA status.
James S Lewis, Rebecca D Chernock, +5 authors, Samir K El-Mofty.
Mod Pathol, 2012 May 19; 25(9). PMID: 22596101
An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: a staging system in need of repair.
Kristina R Dahlstrom, Gabriel Calzada, +6 authors, Erich M Sturgis.
Cancer, 2012 Jun 28; 119(1). PMID: 22736261    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.
p16 Immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma.
James S Lewis.
Head Neck Pathol, 2012 Jul 13; 6 Suppl 1. PMID: 22782226    Free PMC article.
Review.
Equivocal p16 immunostaining in squamous cell carcinoma of the head and neck: staining patterns are suggestive of HPV status.
Zhongchuan Will Chen, Ilan Weinreb, Suzanne Kamel-Reid, Bayardo Perez-Ordoñez.
Head Neck Pathol, 2012 Jul 18; 6(4). PMID: 22801997    Free PMC article.
Multi-field-of-view strategy for image-based outcome prediction of multi-parametric estrogen receptor-positive breast cancer histopathology: Comparison to Oncotype DX.
Ajay Basavanhally, Michael Feldman, +4 authors, Anant Madabhushi.
J Pathol Inform, 2011 Jan 01; 2. PMID: 22811953    Free PMC article.
Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer.
Shao Hui Huang, Bayardo Perez-Ordonez, +18 authors, Brian O'Sullivan.
Oral Oncol, 2012 Aug 25; 49(1). PMID: 22917550
Patients perceive tonsil cancer as a strike at psycho-socially "vital organs".
Gitte Lee Mortensen, Peter Bertram Paaske.
Dan Med J, 2012 Sep 07; 59(9). PMID: 22951199
Cyclin D1-a prognostic marker in oropharyngeal squamous cell carcinoma that is tightly associated with high-risk human papillomavirus status.
Juliette B Scantlebury, Jingqin Luo, +2 authors, James S Lewis.
Hum Pathol, 2013 Apr 10; 44(8). PMID: 23566410    Free PMC article.
Digital pathology image analysis: opportunities and challenges.
Anant Madabhushi.
Imaging Med, 2009 Jan 01; 1(1). PMID: 30147749    Free PMC article.
Emerging Tools for Computer-Aided Diagnosis and Prognostication.
Scott Ritter, Kenneth B Margulies.
J Clin Trials, 2014 Aug 22; 4(2). PMID: 25143872    Free PMC article.
Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology.
Andreas Heindl, Sidra Nawaz, Yinyin Yuan.
Lab Invest, 2015 Jan 20; 95(4). PMID: 25599534
Review.
Stacked Sparse Autoencoder (SSAE) for Nuclei Detection on Breast Cancer Histopathology Images.
Jun Xu, Lei Xiang, +4 authors, Anant Madabhushi.
IEEE Trans Med Imaging, 2015 Jul 25; 35(1). PMID: 26208307    Free PMC article.
Highly Cited.
Emerging Themes in Image Informatics and Molecular Analysis for Digital Pathology.
Rohit Bhargava, Anant Madabhushi.
Annu Rev Biomed Eng, 2016 Jul 16; 18. PMID: 27420575    Free PMC article.
Review.
Image analysis and machine learning in digital pathology: Challenges and opportunities.
Anant Madabhushi, George Lee.
Med Image Anal, 2016 Jul 18; 33. PMID: 27423409    Free PMC article.
Highly Cited. Review.
Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases.
Andrew Janowczyk, Anant Madabhushi.
J Pathol Inform, 2016 Aug 27; 7. PMID: 27563488    Free PMC article.
Highly Cited.
Automated Tubule Nuclei Quantification and Correlation with Oncotype DX risk categories in ER+ Breast Cancer Whole Slide Images.
David Romo-Bucheli, Andrew Janowczyk, +2 authors, Anant Madabhushi.
Sci Rep, 2016 Sep 08; 6. PMID: 27599752    Free PMC article.
Multi-Pass Adaptive Voting for Nuclei Detection in Histopathological Images.
Cheng Lu, Hongming Xu, +3 authors, Anant Madabhushi.
Sci Rep, 2016 Oct 04; 6. PMID: 27694950    Free PMC article.
Evaluating stability of histomorphometric features across scanner and staining variations: prostate cancer diagnosis from whole slide images.
Patrick Leo, George Lee, +3 authors, Anant Madabhushi.
J Med Imaging (Bellingham), 2016 Nov 03; 3(4). PMID: 27803941    Free PMC article.
A deep learning based strategy for identifying and associating mitotic activity with gene expression derived risk categories in estrogen receptor positive breast cancers.
David Romo-Bucheli, Andrew Janowczyk, +2 authors, Anant Madabhushi.
Cytometry A, 2017 Feb 14; 91(6). PMID: 28192639    Free PMC article.
Accurate and reproducible invasive breast cancer detection in whole-slide images: A Deep Learning approach for quantifying tumor extent.
Angel Cruz-Roa, Hannah Gilmore, +6 authors, Anant Madabhushi.
Sci Rep, 2017 Apr 19; 7. PMID: 28418027    Free PMC article.
Highly Cited.
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.
An Image Analysis Resource for Cancer Research: PIIP-Pathology Image Informatics Platform for Visualization, Analysis, and Management.
Anne L Martel, Dan Hosseinzadeh, +6 authors, Metin N Gurcan.
Cancer Res, 2017 Nov 03; 77(21). PMID: 29092947    Free PMC article.
Spatial interaction of tumor cells and regulatory T cells correlates with survival in non-small cell lung cancer.
Souptik Barua, Penny Fang, +4 authors, Steven H Lin.
Lung Cancer, 2018 Feb 08; 117. PMID: 29409671    Free PMC article.
Tissue Phenomics for prognostic biomarker discovery in low- and intermediate-risk prostate cancer.
Nathalie Harder, Maria Athelogou, +10 authors, Ralf Huss.
Sci Rep, 2018 Mar 15; 8(1). PMID: 29535336    Free PMC article.
A deep-learning classifier identifies patients with clinical heart failure using whole-slide images of H&E tissue.
Jeffrey J Nirschl, Andrew Janowczyk, +4 authors, Anant Madabhushi.
PLoS One, 2018 Apr 04; 13(4). PMID: 29614076    Free PMC article.
High-throughput adaptive sampling for whole-slide histopathology image analysis (HASHI) via convolutional neural networks: Application to invasive breast cancer detection.
Angel Cruz-Roa, Hannah Gilmore, +6 authors, Fabio González.
PLoS One, 2018 May 26; 13(5). PMID: 29795581    Free PMC article.
Quantitative nuclear histomorphometry predicts oncotype DX risk categories for early stage ER+ breast cancer.
Jon Whitney, German Corredor, +6 authors, Anant Madabhushi.
BMC Cancer, 2018 Jun 01; 18(1). PMID: 29848291    Free PMC article.
Innovative Technologies Changing Cancer Treatment.
Sara Charmsaz, Maria Prencipe, +2 authors, Denis M Collins.
Cancers (Basel), 2018 Jun 21; 10(6). PMID: 29921753    Free PMC article.
Big Data in Head and Neck Cancer.
Carlo Resteghini, Annalisa Trama, +8 authors, Lisa Licitra.
Curr Treat Options Oncol, 2018 Oct 27; 19(12). PMID: 30361937
Review.
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.
Glandular orientation and shape determined by computational pathology could identify aggressive tumor for early colon carcinoma: a triple-center study.
Meng-Yao Ji, Lei Yuan, +8 authors, Wei-Guo Dong.
J Transl Med, 2020 Mar 18; 18(1). PMID: 32178690    Free PMC article.
Innovations in risk-stratification and treatment of Veterans with oropharynx cancer; roadmap of the 2019 Field Based Meeting.
V C Sandulache, Y L Lei, +19 authors, A G Sikora.
Oral Oncol, 2019 Oct 28; 102. PMID: 31648864    Free PMC article.
Convolutional neural network initialized active contour model with adaptive ellipse fitting for nuclear segmentation on breast histopathological images.
Jun Xu, Lei Gong, +4 authors, Anant Madabhushi.
J Med Imaging (Bellingham), 2019 Mar 07; 6(1). PMID: 30840729    Free PMC article.
Innovative approaches for cancer treatment: current perspectives and new challenges.
Carlotta Pucci, Chiara Martinelli, Gianni Ciofani.
Ecancermedicalscience, 2019 Sep 21; 13. PMID: 31537986    Free PMC article.
Feature-driven local cell graph (FLocK): New computational pathology-based descriptors for prognosis of lung cancer and HPV status of oropharyngeal cancers.
Cheng Lu, Can Koyuncu, +8 authors, Anant Madabhushi.
Med Image Anal, 2020 Dec 23; 68. PMID: 33352373    Free PMC article.
Deep Learning in Head and Neck Tumor Multiomics Diagnosis and Analysis: Review of the Literature.
Xi Wang, Bin-Bin Li.
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Review.
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