Laser system identifies brain tumor tissue in real time

Rapid multi-photon approach said to generate images of similar quality to conventional pathology slides; table-top system in development.

Photonics researchers in The Netherlands have developed an ultrafast laser system that produces path-lab quality images distinguishing brain tumor tissue from surrounding healthy tissue in real time.

Marloes Groot and colleagues from Vrije Universiteit Amsterdam reported in the open-access journal Biomedical Optics Express this week that the label-free approach could provide brain surgeons with high-quality pathological information during operations to remove tumors.


Tissue from patients diagnosed with glioma. The green/red images are taken with the new method, while the pink uses conventional hematoxylin and eosin staining. The images visualize various morphologies relevant for diagnosis, such as nucleus-cytoplasm ratio (top row), pleomorphism (tumor cells in the center images), and increased vascularization and tumor cells in the focus of a high grade glioma, images on the right. Image: VU Amsterdam.

They add that the technique could eventually be used both ex vivo, to identify tumor presence in excised brain tissue, and in vivo to tell surgeons the precise extent of malignancies such as diffuse glial tumors that are particularly difficult to eliminate. Groot also told that a smaller table-top system suitable for use in an operating room could be ready for clinical trials in less than a year.

Pathological advantage
The work represents the first time that second- and third-harmonic generation (SHG/THG) techniques have shown the ability to recognize the presence of diffuse infiltrative glioma in fresh, unstained human brain tissue.

“Images and a first diagnosis can be provided in seconds, with the ‘inspection mode’, by moving the sample under the scanning microscope, or in about five minutes if an area has to be inspected with sub-cellular detail,” reports the LaserLab Amsterdamteam.

That provides an obvious advantage over conventional histopathology approaches, which take several hours and are unsuitable for use during surgery, where it is extremely difficult for neurosurgeons to determine the boundaries of diffuse gliomas and completely remove the malignant tissue without also damaging surrounding healthy tissue.

And, unlike other real-time optical techniques like Raman spectroscopy and optical coherence tomography (OCT) – both of which are the subject of clinical trials for in vivo screening – the images generated by the multi-photon approach are very similar to those from conventional pathology.

“Our images are really of a quality similar to the pathology images, and they visualize the same information – making it a directly comparable technique,” Groot said. “When I showed these images to the pathologists that we work with, they were amazed.”

She also explained that Raman spectra must be compared against a set of reference spectra, and that the differences between spectra of healthy and tumor tissue can be very subtle. “Combined with noise, it must always be a battle to get high reliability numbers,” she added.

Groot and the Amsterdam team used a 200 fs pulse, 1200 nm wavelength laser in combination with a two-photon laser-scanning microscope from LaVision Biotec to generate the images. The laser source was an optical parametric oscillator, pumped by one of Coherent’s Chameleon Ultra II Ti:sapphire sources.

At the moment, the system sits on a 2 meter by 1.5 meter optical table, but Groot indicates that scaling that down to a size more suited to clinical use will be relatively straightforward – partly because the current laser is over-specified for the application.

“Much smaller laser systems are available, making a 1 x 1 meter table-top possible,” she told “We are now in the designing process, and a table-top can be ready for a clinical trial in less than a year.”

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