Patterns and Levels of Hypoxia in Head and Neck Squamous Cell Carcinomas and Their Relationship to Patient Outcome

Abstract

Purpose-EF5, a 2-nitroimidazole hypoxia marker, was used to study the presence, levels and prognostic significance of hypoxia in primary head and neck squamous cell tumors.Methods and Materials-22 patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx or larynx with at least 2 years of clinical follow-up were included in this study. Quantitative analysis of EF5 immunofluorescence was carried out and these data were compared to patient outcome.Results-EF5 immunostaining demonstrated substantial inter-tumoral hypoxic heterogeneity. The majority of cells in all tumors were well oxygenated. Three patterns of EF5 binding in cells were identified using criteria of the cellular region that was stained (peripheral or central) and the relationship of binding to necrosis. We tested the association between EF5 binding levels with eventfree and overall survival, irrespective of the pattern of cellular binding or treatment regime. Patients with tumors containing EF5 binding regions corresponding to severe hypoxia (≤0.1% oxygen) had a shorter event-free survival time than patients with pO 2 values >0.1% (p=0.032). Nodal status was also predictive for outcome.Conclusions-These data illustrate the potential utility of EF5 binding based on quantitative immunohistochemistry of tissue pO 2 and provide support for development of noninvasive hypoxia PET studies with 18 F-EF5.

Invited editorial for the paper by Silvoniemi et al. “Repeatability of tumor hypoxia imaging using [18F]EF5 PET/CT in head and neck cancer.” in this issue of EJNMMI

“…Thus, it may be relatively easy to make image-guided boosts to such voxels in tumors that are mostly aerobic. Former studies, using EF5 at higher concentrations for immunohistochemical estimates of tumor pO 2 levels, found many examples of essentially non-hypoxic human tumors [2,3], in agreement with the current data. But for situations involving sparse occurrence of hypoxia, the IHC method did not have the key advantage of non-invasive imaging, namely access to the entire volume of tumor tissue.…”

“…One would never expect improvements in all three critical imaging parameters, since typically any improvement in one would be expected to negatively impact the others. The repeatability of the images, with detailed summaries in the tables and figures, indicates that prior suggestions of cycling hypoxia (see below) are not supportable at the resolution of voxels of size about (3.5 mm) 3 . Interestingly, an area of (3 mm) 2 is about the minimum possible size for modulation of radiation therapy, so this work sets the stage for realistic dose modulation (image-guided radiation therapy -IGRT, or dose painting) in tumors.…”

Usefulness of Pseudocontinuous Arterial Spin-Labeling for the Assessment of Patients with Head and Neck Squamous Cell Carcinoma by Measuring Tumor Blood Flow in the Pretreatment and Early Treatment Period

“…We suspected that this was because there will be intratumoral heterogeneity in treatment responses, such as that shown by a hypoxic lesion around the necrotic tissue or a deep area of the tumor with lower perfusion. 19,33 Such lesions would continue to show little change of either TBF or TV, whereas other tumor lesions would show a volume reduction with marked TBF change. Predicting the treatment result of local control or failure can provide useful information for decision-making regarding additional chemotherapy and the planning of earlier salvage surgery after the current chemoradiotherapy.…”

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

“…Quantification of oxygen levels in EF5-stained tissues is accomplished by normalizing the EF5 binding against the maximal tracer uptake under hypoxic conditions (''cube reference binding'') and referencing a calibrated pO 2 scale that generates estimated pO 2 values ranging from 75 mmHg (normoxic) to 0.75 mmHg (severe hypoxia) (86,88,91).…”