Making the invisible visible with fluorescence

Interview with Peter Solleder, Executive Director New Applications at KARL STORZ

Bladder tumors have different growth characteristics. In most cases, they are limited to the inner wall of the bladder and thus well resectable. Unlike carcinoma in situ, which becomes muscle invasive after a certain amount of time.


Photo: Peter Solleder

Peter Solleder; © KARL STORZ

To be able to completely remove the tumor during resection, photodynamic diagnostics (PDD) can make sense. In this interview with, Peter Solleder, Executive Director New Applications at KARL STORZ, explains the advantages of this process in combination with a transurethral resection of the bladder tumor (TURBT) and provides an overview of the current research status.

Mr. Solleder, what is meant by photodynamic diagnostics?

Peter Solleder: Photodynamic diagnostics (PDD) is the combined use of light and fluorescent dyes in medical imaging. On the one hand, tumors can be made visible with the help of applicable substances and light to enable better detection while making a more successful therapy possible on the other.

Today, these substances are routinely used to diagnose bladder cancer. To do this, they are instilled into the urinary bladder where they subsequently accumulate in the cancerous tissue. After the bladder has been emptied and flushed with a saline solution, it is irradiated with light in the 400-430 nanometer short wavelength range. The fluorophores subsequently send back light in the red spectral range. That means the malignant tissue lights up red.

For which types of tumors is this method particularly beneficial?

Solleder: PDD in addition to an endoscopic treatment with transurethral resection of the bladder tumor (TURBT) has a significant advantage, especially for tumors that are not visible under white light and could thus be overlooked. This is especially important in the case of the so-called carcinoma in situ since this type of tumor can break into the muscle layer of the bladder. Carcinoma in situ is a very flat lesion that is difficult to spot under white light. Once the bladder muscles are affected, the urinary bladder is normally being removed and the patient receives a neobladder or an artificial bladder, which significantly restricts the quality of life.

Photo: Image with red luminous bladder, next cystoscope

The advantage of rigid PDD: tumor borders are better visualized and marked. Thus a more efficient TURBT is guaranteed; © KARL STORZ

Aside from diagnostics, this method can also be used for therapy purposes. What does the treatment entail?

At KARL STORZ, we differentiate between "flexible" and "rigid" PDD. Flexible video cystoscopes by KARL STORZ are being used in "flexible PDD". The flexible system is perfectly suited for diagnostics in outpatient settings and is also often used in follow-up care. Using the flexible endoscope, the physician checks if there are any new tumors that require another treatment or if the patient is tumor-free.

In the case of "rigid" PDD, rigid cystoscopes in conjunction with so-called working elements are used to enable tumor removal during surgery. The patient is anesthetized, which means unlike with "flexible" PDD, these surgeries are performed at a hospital facility. KARL STORZ provides coordinated instruments for this process.

In both cases, the fluorescent dye is instilled into the urinary bladder through a catheter and remains there for at least one hour. During this time, it is being absorbed by the urothelial cells and accumulates in the tumor cells. During the treatment, the urologist inserts a rigid endoscope with a resectoscope (working element) into the urinary bladder. Tumors visible in white light are being removed with an electrical loop. To make sure that all tumors have been completely resected and no tumors have been overlooked, the urinary bladder is subsequently being irradiated with blue light. Healthy tissue glows blue while malignant tissue glows red. The urologist is then able to remove any remaining cancer cells.

Keyword tumor borders. How efficient can they be removed with PDD?

The so-called cancer recurrence rate provides a clear indication that tumor tissue was better detected and therefore tumor borders more effectively removed with PDD.

In a clinical trial, only 4.5 percent of patients, where PDD was being used, had residual tumors after the treatment was completed compared to 25 percent of patients who were exclusively examined with white light.

In another study, patients were monitored over eight years and the time until a cancer recurrence analyzed. After two years, 73 percent of patients in the "white light group" were tumor-free compared to 88 percent in the "fluorescent group". After eight years, the difference was even more significant: 45 percent of patients exclusively treated with white light were tumor-free compared to 71 percent of fluorescence patients.

I think this is clear evidence that fluorescence supports the diagnosis, which results in a complete resection of tumors. Other studies also show that resection rates are significantly higher when using fluorescent light, which subsequently reduces recurrence rates.
Photo: fluorescent liquid in a glass jar

The method traces back to George Gabriel Stokes, who has identified about 200 years ago that when the mineral fluorite is irradiated with ultraviolet light, it radiates blue light; ©ürgen Bautsch

PDD is mainly used in urology…

Solleder: That’s correct. There are two approved fluorescent dyes in Europe. These are 5-aminolevulinic acid (5-ALA) and a 5-ALA hexyl ester. The latter is approved for diagnosing and treating bladder cancer. 5-ALA is used to diagnose brain tumors, the very aggressive glioblastoma multiforme. These are essentially the only substances that are officially approved for these two indications.

What are the current trends in PDD?

Many research groups are working on new fluorescent dyes that bind even more specifically to tumor cells. Substances that also work with longwave light would be ideal in this case. Particularly while using infrared light, you would then be able to look deeper into the tissue by several millimeters and detect deeper lying tumors during surgery.

Something that is also met with great interest in the medical community is a fluorescent dye by the name of indocyanine green (ICG), which can –among other things- be used to identify perfusion defects, biliary tracts or lymph nodes. You can test anastomoses, for example, to see whether blood circulation has been restored after both ends of the colon have been reconnected after colorectal cancer surgery.

The primary goal of PDD is and will continue to be the early detection of cancer cells to remove them as promptly and completely as possible. KARL STORZ is one of the pioneers in this field and has offered products for fluorescence-based diagnostics since 1995.
Photo: Melanie Günther; Copyright: B. Frommann

© B. Frommann

The interview was conducted by Melanie Günther and translated by Elena O'Meara.