J Nucl Med. 2013 May;54(5):664-7.

Enriching the interventional vision of cancer with fluorescence and optoacoustic imaging.

Garcia-Allende PB, Glatz J, Koch M, Ntziachristos V.

Institute for Biological and Medical Imaging, Technische Universität München and Helmholtz Zentrum München, Munich, Germany.



Among several techniques considered for surgical and endoscopic imaging, novel optical methods are evolving as a promising approach for interventional guidance. Pilot clinical applications of fluorescence molecular imaging have demonstrated the benefits of using targeted fluorescent agents in cancer surgery. This premise can be extended broadly to interventional guidance through an increasing number of targeted agents and detection techniques. Beyond epi-illumination fluorescence imaging, optoacoustic (photoacoustic) methods are emerging to offer high-resolution cross-sectional optical imaging through several millimeters to centimeters of depth. We present an overview of key recent developments in optical interventional imaging and outline the potential for a paradigm shift in surgical and endoscopic visualization.

KEYWORDS: endoscopy, fluorescence molecular imaging, fluorescent agents, optoacoustic imaging, photoacoustic imaging, surgery

PMID: 23559587




Medical imaging is an invaluable tool for cancer tumor detection, staging and treatment evaluation. Non-invasive radiological imaging has grown and diversified significantly over the past 40 years, through the development of tomographic methods such as X-ray Computed Tomography, Magnetic Resonance Imaging, Ultrasound or Positron Emission Tomography. However, translating these technologies to the operation room is challenging because of their cost, size and the exposure of the patient and care-givers to ionizing radiation. In light of this, clinical decision making still relies on the visual appearance or palpation of various lesions and tissue areas in many interventional procedures such as surgery and diagnostic or surgical endoscopy. This complicates the cancer spread identification and the accurate delineation of the tumor margins, leading to incomplete resections of tumors that compromise the patient prognosis. Similarly, a major challenge that physicians face during surveillance and endoscopic resection is the low contrast between small cancerous lesions and benign lesions or surrounding tissue and the lack of information on lesion depth that complicates detection or decision-making about the appropriate excision procedure. Lesion identification in these cases is primarily based on macroscopic color features or on a tissue fraction that is randomly sampled, which, even in the cases of rigorous adherence to biopsy protocols, results in substantial lesion miss-rates, that can be as high as 55 % in patients with an inherited predisposition to colon cancer.

Optical imaging is a natural modality for guiding surgical and endoscopy procedures since it relates directly to the practitioner’s color vision and offers highly attractive advantages over existing radiological techniques, including high flexibility in contrast mechanisms and ease of adaptation to intra-operative practice. Among the distinct available optical techniques, wide-field molecular imaging using near-infrared fluorescence agents with targeting specificity to cancer moieties holds the most significant promise for enhancing endoscopic and surgical vision. As a macroscopic method, it is particularly suitable for the screening of large surfaces for the detection of small foci of tumor or small lesions that would otherwise remain imperceptible. Secondly, operation in the near-infrared allows sub-surface visualization, overcoming limitations of the human vision or photographic color imaging.  And last but not least, the use of targeted agents enables “contrast engineering” so that specific tissue biomarkers can be visualized, enhancing the specificity of detection and improving target contrast over background. This is a substantial improvement over non-specific fluorochromes such as indocyanine green (ICG) and other nonspecific fluorescent dyes, which offer high background signals and may lead to false positives and contrast reduction. Using targeting agents, fluorescence molecular imaging can be seen as a red-flag detection strategy that allows the quick identification of suspicious entities over large fields of view as required in surgical oncology to assure clean resection margins and in surveillance endoscopy to minimize lesion miss-rates.

Despite the challenges of the clinical translation of fluorescent agents engineered to be disease-specific (Scheuer W et al, 2012), the significant potential of fluorescence molecular imaging has recently driven the first human use of tumor-specific fluorescent agents for real-time surgical visualization of tumor tissue in patients undergoing laparatomy for ovarian cancer (van Dam G et al, 2011). Folate conjugated to fluorescein isothiocyanate (folate-FITC), an agent that allows targeting of folate receptor-α (FRα), was injected intravenously into patients that were earlier diagnosed with ovarian cancer and scheduled for surgery. Figure 1 displays representative results from this study. Only a fraction of malignant lesions is visible on the color image. Conversely, fluorescence contrast seen as pseudo-green color superimposed on the color image greatly improved the ability to assess the disease extent. All lesions collected under fluorescence guidance were histologically confirmed as cancer, whereby five times as many lesions were identified compared to the lesions identified by the naked human eye (van Dam G et al, 2011).

fig1                     Fig 1: Composition of representative images from (van Dam G et al, 2011) that showcases enhanced cancer visualization in surgery through fluorescence molecular imaging. From left to right: Color and fluorescence imaging system placed above a patient prepared for surgery, color image from an ovarian cancer patient and color image with superimposed fluorescence (green).


In addition to strategies developed for engineering contrast in tissues, progress in imaging technology plays a significant role in the clinical acceptance of optical molecular imaging. It has been generally acknowledged that conventional epi-illumination fluorescence imaging (photography) comes with performance limitations since fluorescence signals may be modified by tissue optical properties, leading to inaccurate measurements (Valdes P et al, 2011). For the abovementioned clinical study an approved real-time multi-spectral imaging system was used. This new generation of fluorescence imaging can resolve optical and fluorescence video in real-time through a common objective and importantly, it utilizes multi-spectral information to correct for the heterogeneous tissue light-absorption. Hence it offers accurate fluorescence images that do not contain the artifacts and high-background typically seen on conventional epi-illumination fluorescence approaches. This system meets the required criteria for accurate, highly sensitive and reproducible real-time fluorescence acquisition that is independent of tissue discoloration, thereby minimizing the false positive and negative rates.

Despite the progress with obtaining a large field of view, real-time simultaneous color and fluorescence images and improved accuracy via spectral correction and background signal suppression, planar fluorescence imaging does not allow cross-sectional imaging and high-resolution interrogation beyond the tissue surface. Conversely, opto-acoustic (photo-acoustic) imaging is a modality that also with strong surgical and endoscopic potential (Razansky D et al, 2009). Optoacoustic imaging is an imaging technique which irradiates light of transient intensity onto tissue and detects ultrasonic waves generated in response to the absorption of this light by tissue absorbers. The detection of the ultrasonic waves at multiple positions and subsequent tomographic reconstruction result in optical images of ultrasonic resolution. The clinical application of optoacoustic imaging is expected to grow over the next years in order to enable high-resolution cross-sectional optical imaging through tissues. A shortcoming of opto-acoustic methods over fluorescence imaging is the typically smaller field of view, which is similar to the field of view in ultrasonography. Correspondingly the combination of fluorescence imaging for large-field-of-view guidance with optoacoustic for cross-sectional imaging may further improve the accuracy of tissue interrogation and decision making in interventional clinical settings. Thereby, novel optical and opto-acoustic imaging employing functional and molecular guidance will change surgical and endoscopic guidance from a visual interrogation practice to biomarker-based detection.

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