Fluorescence-guided Resection of Malignant Glioma – Only Red-fluorescing Areas Excised

May 29, 2009

When William Shakespeare has Prince Henry say the words "... and his pure brain, which some suppose the soul’s frail dwelling-house..." in his play "King John", he is expressing a mediaeval notion that we still find fascinating today, for instance when we see how brain disease can alter a person’s nature or when brain surgery is necessary. For resection of brain tumours in particular, neurosurgeons are faced with the same dilemma time and again: how to remove the tumour completely without ­destroying neurological functions. Nowadays, surgeons harness the possibilities of intraoperative fluorescence technology for exact and full excision of tumour tissue so that the patient’s quality of life can be saved or even enhanced.

Today, the issue of whether a brain tumour can be operated on is more a question of whether the operation makes medical sense, as every tumour localisation is possible with modern surgical techniques. One example is neuronavigation, a technique similar to GPS, which substantially improves not only the planning of the operation, but also intraoperative orientation. For malignant glioma, which are among the most common types of brain tumour, accounting for 30 per cent of all cases, and are 100 per cent fatal, exact localisation is not the only challenge, however.

No scope for resection errors

"Malignant glioma exhibit characteristic infiltrative proliferation and even under a powerful surgical microscope the tumour perimeters are hard to differentiate from healthy tissue. In brain surgery we can’t remove a bit of extra tissue to be on the safe side because that tissue is always functional," explains Dr. med. Carsten Schoof, Senior Consultant of the Neurosurgical Department of the Carl-Thiem hospital in Cottbus, Germany. "Since the beginning of 2008 we have been using a new fluorescence technique that shows up tumour cells extremely clearly and enables us to achieve much higher accuracy with tumour resection."

Under blue-violet light, the surgeon can clearly identify and safely remove the tumour cells labelled with 5-ALA during surgery. Under normal white light, the tumour perimeters and any remaining tumour residue are hard to spot after resection of  necrotic tissue and the solid tumour.

Well-tolerated 5-ALA labels tumour cells

Brain tumours like glioma are able to accumulate a substance called 5-aminolevulinic acid (5-ALA) and transform it into the strongly fluorescing protoporphyrin IX (PPIX). Three hours before the operation, patients drink a solution containing 20 mg of 5-ALA per kilogram bodyweight. The solution tastes rather sour, but is well tolerated and causes practically no side effects, because 5-ALA occurs naturally in the body as a precursor of the haem. The PPIX is made to fluoresce under blue-violet light, enabling the surgeon to clearly identify and safely remove the otherwise hard to spot tumour perimeters and any tumour residue remaining after resection of necrotic tissue and the solid tumour.

Fluorescence at a keystroke

To perform fluorescence-guide tumour resection, surgeons need a microscope that is equipped with a special light source and appropriate filters. Dr. Schoof uses a Leica surgical microscope configured with the Leica FL400 Fluorescence Module. He can switch between white light and fluorescence mode during the operation simply by pressing a key. "Fluorescence-guided surgery is easy to learn, not requiring any changes to the surgeon’s familiar routine. We have meanwhile operated on over 40 brain tumour patients with the fluorescence-­guided 5-ALA method and are highly satisfied with the ­surgical results," says Dr. Schoof. "Whereas I used to ask myself 'Where should I stop cutting?' I now know that I’ve done a good resection when I have removed everything that fluoresces red."

Right: Dr. med. Carsten Schoof, Senior Consultant of the Neurosurgical Department of the Carl-Thiem hospital in Cottbus, Germany has already operated on over 40 brain tumour patients with the 5-ALA fluorescence method.

Studies prove longer survival rates

Large-scale studies conducted between 2004 and 2006 have shown that the fluorescence-guided 5-ALA method yields better results than conventional resection. Patients treated with this method were relapse-free for comparatively longer and lived longer. The 5-ALA drug Gliolan has been officially approved since the beginning of 2008.

The Leica M525 OH4 with the integrated Leica FL400 5-ALA fluorescence module offers the lightest movement and highest quality optics of any surgical microscope. The two illumination systems, the observation filters and an optional blue mode optimised video camera interact automatically with a simple push on a button found on the pistol grip or foot pedal of the surgical microscope. This offers perfect bright blue illumination and easy and ergonomic change of the observation modes.

 

Leica FL400 Fluorescence Module

For precise and safe judgement of the situation under the microscope, the two most decisive factors are the experience of the surgeon and the high quality optics. In addition to the usual visible white light image, the Leica FL400 module provides the surgeon with information from optimised fluorescence procedures, not visible for the human eye.

This Photodynamic Imaging (PDI) is the combination of a tumour selective photosensitiser, excitation light of an appropriate wavelength and a well adjusted observation spectrum. Perfect filters and optimised optics allow good orientation in the resection area. The vital tumour shines with red sensitiser fluorescence in good contrast to normal ­tissue under blue light illumination.

To flip from white light to fluorescence mode and vice versa requires only a click of a button on the handle or foot pedal. The type of illumination, the observation filters for different fluorescence applications and an optional mode controlled video camera specifically aligned for fluorescence are controlled automatically via the Leica CAN bus. The resection can be performed not only in the white light mode but also in the blue light mode. The latter, however, requires sufficient brightness in order to resect the last residuals of the tumour which always appear red or pink in colour.

An appropriate microscope to facilitate working with fluorescence is needed but this represents a one-off investment, which at any rate is still more affordable than equipment required for an intra-operative MRI. To use blue light fluorescence on e.g. the Leica M525 OH4 the microscope can be easily upgraded with the Leica FL400 module.

Note: 5-ALA is not approved in the USA, Japan and some other countries. Please check the status of approval with your local Leica representative.

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