Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas

Purpose The College of American Pathologists produced an evidence-based guideline on testing, application, interpretation, and reporting of human papillomavirus (HPV) and surrogate marker tests in head and neck carcinomas that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. Methods The College of American Pathologists HPV Testing in Head and Neck Carcinomas guideline was reviewed by ASCO content experts for clinical accuracy and by methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations. Results The ASCO Expert Panel determined that the recommendations from the HPV Testing in Head and Neck Carcinomas guideline, published in 2018, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline and added minor qualifying statements. Recommendations It is recommended that HPV tumor status should be determined for newly diagnosed oropharyngeal squamous cell carcinomas. HPV tumor status testing may be performed by surrogate marker p16 immunohistochemistry either on the primary tumor or from cervical nodal metastases only if an oropharyngeal primary tumor is present. The threshold for positivity is at least 70% nuclear and cytoplasmic expression with at least moderate to strong intensity. Additional confirmatory testing may be done at the discretion of the pathologist and/or treating clinician. Pathologists should not routinely determine HPV tumor status in nonsquamous carcinomas of the oropharynx or non–oropharyngeal squamous cell carcinomas of the head and neck. When there is uncertainty of histologic type or whether a poorly differentiated oropharyngeal tumor is nonsquamous, HPV tumor status testing may be warranted and at the discretion of the pathologist and/or treating clinician. Additional information is available at: www.asco.org/head-neck-cancer-guidelines .

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Expression of Erythropoietin and Erythropoietin Receptor in Squamous Cell Carcinomas of the Head and Neck: Levels of Erythropoietin Expression Correlate with Tumor Hypoxia.

Blood ◽

10.1182/blood.v104.11.2908.2908 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2908-2908

Author(s):

Murat O. Arcasoy ◽

Khalid Amin ◽

Shu-Chuan Chou ◽

Zishan A. Haroon ◽

Mahesh Varia ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Head And Neck Cancer ◽

Cell Carcinoma ◽

Head And Neck ◽

Tumor Cells ◽

Neck Cancer ◽

Squamous Cell ◽

Tumor Hypoxia ◽

Squamous Cell Carcinomas ◽

Glycoprotein Hormone

Abstract Erythropoietin (EPO), an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor EPOR. The recombinant form of human EPO is widely used in clinical practice for the prevention or treatment of anemia associated with cancer and chemo-radiation therapy. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, EPO treatment was associated with poorer loco-regional progression-free survival. The purpose of this study was to determine whether EPOR and its ligand EPO are expressed in primary squamous cell carcinomas of the head and neck. We also investigated the hypothesis that EPO expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness and poor prognosis. Twenty-one patients with squamous cell carcinoma of the head and neck were enrolled in a tumor hypoxia study under a research protocol approved by the Institutional Review Board at the University of North Carolina Hospitals. All patients provided signed informed consent. The patients received an intravenous infusion of the hypoxia marker pimonidazole hydrochloride (Hypoxyprobe-1™) prior to multiple tumor biopsies. Two or more biopsies were available from all except one primary tumor. The tissue specimen from one patient with laryngeal carcinoma was excluded because of availability of only a single, small and fragmented biopsy. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for expression of EPOR and EPO as well as pimonidazole binding. We found EPOR expression in tumor cells in 97% of the biopsies. The pattern of EPOR immunoreactivity was predominantly cytoplasmic but was found to be localized to the membrane in some sections. Co-expression of EPO was observed in 90% of biopsies. Qualitative and semi-quantitative analyes for EPO staining and tumor hypoxia on a section-by-section basis revealed that EPO and pimonidazole adduct staining did not always co-localize within tumors but there was a significant positive correlation between levels of micro-regional EPO expression and pimonidazole binding (r = 0.736, P < 0.001, n=20 by two-tailed Spearman’s rank correlation analysis). These data demonstrate the co-expression of EPOR and its ligand EPO in squamous carcinoma cells suggesting that EPO may play a novel role as a potential autocrine or paracrine growth factor in head and neck cancer. Furthermore, EPO expression in tumor cells may be modulated, at least in part, by tumor hypoxia. The expression of EPOR needs to be taken into consideration in the design of future clinical trials investigating the role of recombinant human EPO in head and neck cancer.

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Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2016.05.005 ◽

2016 ◽

Vol 103 ◽

pp. 86-98 ◽

Cited By ~ 10

Author(s):

Kelly K. Curtis ◽

William W. Wong ◽

Helen J. Ross

Keyword(s):

Head And Neck ◽

Squamous Cell ◽

Tumor Hypoxia ◽

Squamous Cell Carcinomas ◽

Future Directions

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Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0286-cp ◽

2017 ◽

Vol 142 (5) ◽

pp. 559-597 ◽

Cited By ~ 169

Author(s):

James S. Lewis ◽

Beth Beadle ◽

Justin A. Bishop ◽

Rebecca D. Chernock ◽

Carol Colasacco ◽

...

Keyword(s):

Systematic Review ◽

Squamous Cell Carcinoma ◽

Human Papillomavirus ◽

Head And Neck ◽

Squamous Cell ◽

Expert Panel ◽

Surrogate Marker ◽

Squamous Cell Carcinomas ◽

Head And Neck Carcinomas ◽

High Risk Hpv

Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.

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HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker?

British Journal of Cancer ◽

10.1038/bjc.2013.55 ◽

2013 ◽

Vol 108 (5) ◽

pp. 1157-1162 ◽

Cited By ~ 54

Author(s):

F Bussu ◽

M Sali ◽

R Gallus ◽

V G Vellone ◽

G F Zannoni ◽

...

Keyword(s):

Head And Neck ◽

Squamous Cell ◽

Surrogate Marker ◽

Neck Region ◽

Hpv Infection ◽

Squamous Cell Carcinomas ◽

Head And Neck Region ◽

P16 Immunohistochemistry

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Hypoxia and metallothionein expression in squamous cell carcinomas of the cervix or head and neck using pimonidazole as a marker of tumor hypoxia at the cellular level

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/s0360-3016(98)80315-5 ◽

1998 ◽

Vol 42 (1) ◽

pp. 231

Author(s):

J.A. Raleigh ◽

S.-C. Chou ◽

L.H. Rinker ◽

M.C. Weissler ◽

W.C. Fowler ◽

...

Keyword(s):

Head And Neck ◽

Squamous Cell ◽

Tumor Hypoxia ◽

Cellular Level ◽

Squamous Cell Carcinomas

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Epithelial–Mesenchymal Transition Associated with Head and Neck Squamous Cell Carcinomas: A Review

Cancers ◽

10.3390/cancers13123027 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3027

Author(s):

Rogelio González-González ◽

Gamaliel Ortiz-Sarabia ◽

Nelly Molina-Frechero ◽

José Manuel Salas-Pacheco ◽

Sergio Manuel Salas-Pacheco ◽

...

Keyword(s):

Head And Neck ◽

Signaling Pathways ◽

Squamous Cell ◽

Viral Infections ◽

Epithelial Mesenchymal Transition ◽

Tumor Hypoxia ◽

Squamous Cell Carcinomas ◽

Major Type ◽

Mesenchymal Transition ◽

Malignant Conversion

Head and neck squamous cell carcinomas (HNSCCs) are aggressive, recurrent, and metastatic neoplasms with a high occurrence around the world and can lead to death when not treated appropriately. Several molecules and signaling pathways are involved in the malignant conversion process. Epithelial–mesenchymal transition (EMT) has been described in HNSCCs, a major type of aggressive carcinoma. EMT describes the development of epithelial cells into mesenchymal cells, which depends on several molecular interactions and signaling pathways that facilitate mesenchymal conversion. This is related to interactions with the microenvironment of the tumor, hypoxia, growth factors, matrix metalloproteinases, and the presence of viral infections. In this review, we focus on the main molecules related to EMT, their interactions with the tumor microenvironment, plasticity phenomena, epigenetic regulation, hypoxia, inflammation, their relationship with immune cells, and the inhibition of EMT in the context of HNSCCs.

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