Primary liver cancer is the sixth most common cancer worldwide with more than 800,000 people diagnosed. Additionally, it is one of the most common causes of cancer deaths globally, accounting for more than 700,000 deaths each year. Most primary liver cancers are hepatocellular carcinoma (HCC) that includes 75-85 percent of cases.
The key to a successful treatment is early detection of the disease, as the prognosis strongly correlates with delayed diagnosis. For people who are diagnosed with liver cancer at an early stage, the 5-year survival rate is 34 percent. For stages of cancer that are regional and distant, the 5-year survival rate is 12 percent and 3 percent, respectively.
To address this issue, scientists at the Orel State University in Russia have developed a new optical biopsy system compatible with a needle biopsy system which shows promise in reliably distinguishing between cancerous and healthy tissue in the liver. The study was reported in the journal Biomedical Optics Express (2022; https://doi.org/10.1364/BOE.447687).
The optical biopsy system makes use of two light-based techniques-diffuse reflectance spectroscopy and fluorescence lifetime measurements-to evaluate markers of cellular metabolism that differ between healthy and cancerous cells. According to the researchers, diffuse reflectance spectroscopy uncovers tissue properties centered on how they reflect light, while fluorescence lifetime analysis exposes tissues to a wavelength of light that stimulates fluorescence, and then quantifies how long that fluorescence takes to fade. The timing of the fluorescence decay varies on the presence of molecules that influence metabolism.
In the present study, the team describes the technical details of in vivo and in situ measurements of HCC by the developed optical biopsy system. To perform their technique and with a focus on using the new instrument to guide future liver biopsies in the clinic, the researchers selected modern compact components for the device. The 1 mm diameter probe is compatible with a standard 17.5G biopsy needle and has separate optical channels for diffuse reflectance spectroscopy and fluorescence lifetime measurements.
To assess the sensitivity of the assembled system, the fluorescence lifetime measurements observed by the setup were verified in fresh solutions of the co-factors, NAD(P)H and FAD++, which were identified to be important participants and potential biomarkers to distinguish normal and tumor tissues. The findings revealed that the oncogenic processes in surrounding liver tissues significantly modify the metabolic state in the liver cells, which manifests itself in the altered set of observed fluorescence lifetime parameters.
Once these satisfactory results were obtained, the technology was analyzed in a murine model for the characterization of inoculated HCC and adjacent liver tissue, as well as in a preliminary clinical study in patients with suspected and subsequently confirmed HCC. Analysis of the obtained results demonstrated high sensitivity and specificity of the proposed optical biopsy technique in measuring the characteristic changes in registered fluorescent parameters to reliably distinguish the HCC tissue, liver tissue in the control, and the metabolically changed liver tissues around the developed HCC tumor.
Additionally, the technique was utilized during the routing procedure of the percutaneous needle biopsy in humans with suspected HCC. The comparative data from murine and human HCC tissues indicates that the in vivo mouse model is illustrative of the registered fluorescence lifetime parameters, while statistically significant variations between their absolute values can still be detected, the authors concluded.
Oncology Times reached out to lead author, Evgenii Zherebtsov, PhD, for additional insights into their study. He is a research fellow of the University of Oulu in Finland.
Oncology Times: What was the rationale for pursuing an optical biopsy method for HCC?
Zherebtsov: "Hepatocellular carcinoma is one of the most common types of primary malignant tumors in liver. The surgical resection of the tumor with a sufficient margin of healthy tissue at an early stage significantly increases the hope of a complete cure. But in most cases, the discovery of the tumor status should be confirmed by standard biopsy procedure. The typical localization of liver cancer is quite convenient for the percutaneous needle biopsy technique, and one is broadly used for tissue sampling. Nevertheless, the samples which are taken by the biopsy instrument still can be non-informative due to the uncertainties in the exact distribution of the tumor cells in respect to the tip of the biopsy stylet.
"In this work, we have developed a diagnostic system with a needle-like optical probe, which is compatible with biopsy needle standards. The system utilizes very short laser pulses of ultraviolet spectral range, which excite the fluorescence in the nearest proximity to the tip of the biopsy instrument. From the same tiny sampling volume, the optical channel collects fluorescence photons and the system analyzes how the fluorescence decays after each excitation pulse. The shape of the decay caries import information on the mitochondrial metabolism in the cells. Also, by the optical tool, we can estimate the blood oxygen saturation in the same probe localization. The idea behind the technology is to use the combination of the parameters we are registering by the system to (in a matter of seconds) detect cancer cells and confirm that the biopsy instrument is in the right position."
Oncology Times: What is one of the most compelling aspects of this study?
Zherebtsov: "One of the most compelling results of the study is that in real-time we can distinguish the tumor [and] liver, and metabolically change liver tissues, which are allocated on the tumor border and provide the doctor with feedback on the position of biopsy instrument before taking the tissue sample."
Oncology Times: As primary liver cancer includes HCC and cholangiocellular cancer, along with other rare types, can this imaging approach potentially differentiate between other cancer types? Are there medical applications it can be useful for?
Zherebtsov: "At the moment, we have published the results on the HCC, but we are collecting data on other types of tumors which are usual in liver, including metastasis of various origins. The results are promising, but the studies should be finalized to be certain about the recognition of different cancer types.
"The technology can be of high interest for the personalized cancer treatment, when the precisely taken samples of tumor will be used for the development of the individualized treatment therapy or applied in the tests of the sensitivity to the known. Precise navigation of the instrument for taking relevant tissue samples may become a critical factor for the successful broad use of personalized cancer therapy."
Oncology Times: What limitations of the current study remain to be addressed before implementing this novel methodology into the clinic?
Zherebtsov: "At the moment, we are certain about HCC, but unfortunately, it is not a single type of tumor that localizes in the liver. So, for the technology to be broadly introduced into the clinic, fluorescence signatures from various potential malignant tissues should be received and analyzed (including metastasis). We are working on this now."
Dibash Kumar Das is a contributing writer.