ABSTRACT

Conclusion:

It has been found out that in the surgery of metastatic brain tumors, FL dyeing decreases the blood loss, shortens the surgical time, and aids in the differentiation of tumor glial tissue.

Results:

The study comprised of 48 patients in total. The median age of patients was 61.5 years (minimum: 20, maximum: 80), the average age was 59.1±11.8 years. There was no difference between the group with FL dyeing and the one without dyeing in terms of gender, age, tumor size, GTR rates and surgical time. Blood loss and duration of hospital stay in the FL used group was significantly less. In the group with FL dyeing (staining) (92.5%), this method contributed to the surgery by giving yellow highlights.

Materials and Methods:

Twenty one patients, who were operated under surgical white light, and 27 patients who were operated via sodium fluorescein (FL) dyeing (staining) due to metastatic brain tumors were evaluated retrospectively. The gross total resection (GTR) rates, surgical time, amount of blood loss, and the duration of hospital stay for both groups were compared. The contribution of FL dyeing (staining) to surgery was evaluated for the group with FL dyeing (staining).

Aim:

We investigated the reflection of tumor dyeing (staining), an auxiliary technique for the resection of metastases, which are the most prevalent group among brain tumors, via microsurgery.

INTRODUCTION

Cerebral metastases are the most common lesions among all brain tumors and are more common than primary glial masses¹. Cerebral metastases can be seen in 20-40% of patients with known cancer, while approximately 70% of these patients are symptomatic². As a result of the success in the treatment of the primary disease in recent years, prolonged life expectancy, accessibility to imaging methods, and advances in the techniques of these methods have led to an increase in the incidence of brain metastases³. While life expectancy is expressed in months in many patients with brain metastases, it is known that surgery, whole-brain radiotherapy and chemotherapy treatment algorithm, respectively, are the treatment modalities that increase total survival the most in the recent period^4,5. The aim of surgery, which is the first step of the treatment in these patients, is total resection⁶. The higher the amount of resection, the less the possibility of local recurrence⁷. Recently, many methods such as navigation systems, brain mapping, fluorescein (FL) staining, intraoperative ultrasound and magnetic resonance (MR) have been used to increase the surgical safety and the amount of resection in brain tumors^8,9. Sodium FL, a FL salt, is a water-soluble organic dye that has been used safely in eye angios for a long time and accumulates in areas where the blood-brain barrier is disrupted¹⁰. Brain tumors cause contrast enhancement by disrupting the blood-brain barrier where they are located. FL has been used for many years in standard surgical microscopes that give off white light or with the naked eye at high doses of 15-20 mg/kg in order to distinguish tumor glial tissue in contrast-enhancing areas¹¹.

Side effects, up to anaphylaxis, have been avoided by using low doses of 3-4 mg/kg, thanks to filters that give a yellow highlight to FL at a wavelength of 560 nm, which have recently been installed on surgical microscopes¹². There are studies showing that the use of FL in brain metastases increases the amount of resection^13,14. We will also present the results, surgical differences and our experience in patients with brain metastases in which we used and did not use FL staining with a 560 nm filter microscope in surgery.

GİRİŞ

Serebral metastazlar tüm beyin tümörleri içerisinde en sık görülen lezyonlardır ve primer glial kitlelere göre daha fazla görülürler¹. Bilinen kanseri olan hastaların %20-40’ında serebral metastaz görülebilirken bu hastaların yaklaşık %70’i semptomatiktir². Son yıllarda primer hastalığın tedavisindeki başarılar sonucunda uzayan yaşam süreleri, görüntüleme yöntemlerine erişebilirlik ve bu yöntemlerin tekniklerindeki gelişmeler beyin metastazı görülme sıklığının artmasına neden olmuştur³. Beyin metastazı olan birçok hastada beklenen yaşam süreleri aylarla ifade edilirken son dönemde sırasıyla cerrahi, tüm beyin radyoterapi ve kemoterapi tedavi algoritmasının toplam sağkalımı en fazla artıran tedavi şekli olduğu bilinmektedir^4,5. Bu hastalarda tedavinin ilk ayağı olan cerrahide amaç total rezeksiyondur⁶. Rezeksiyon miktarı ne kadar fazla olursa lokal nüks görülme ihtimali o kadar azalır⁷. Son dönemde beyin tümörlerinde cerrahi güvenliği ve rezeksiyon miktarını artırmak amaçlı navigasyon sistemleri, beyin haritalaması, fluorescein (FL) boyama, intraoperatif ultrason ve manyetik rezonans (MR) gibi birçok yöntem kullanılmaktadır^8,9. FL tuzu olan sodyum FL uzun zamandır göz anjiyolarında güvenle kullanılmış, suda çözünebilen organik bir boyadır ve kan beyin bariyerinin bozulduğu alanlarda birikir¹⁰. Beyin tümörleri bulundukları yerlerde kan beyin bariyerini bozarak kontrast tutulumuna neden olurlar. FL, kontrast tutan sahalarda tümör glial doku ayrımını yapmak için uzun yıllar 15-20 mg/kg gibi yüksek dozlarda çıplak gözle ya da beyaz ışık veren standart cerrahi mikroskoplarda kullanılmıştır¹¹. Yakın zamanda cerrahi mikroskoplara takılan 560 nm dalga boyunda FL’ye sarı röfle kazandıran filtreler sayesinde 3-4 mg/kg gibi düşük dozlarda kullanılarak anafilaksiye varan yan etkilerinden kaçınılmıştır¹². Beyin metastazlarında FL kullanımının rezeksiyon miktarını artırdığına yönelik çalışmalar mevcuttur^13,14. Biz de cerrahisinde 560 nm filtreli mikroskop ile FL boyama kullandığımız ve kullanmadığımız beyin metastazlı hastalardaki sonuçları, cerrahi farkları ve tecrübemizi sunacağız.

MATERIALS AND METHODS

In our clinic, 21 patients (group 1) who were operated under white light by two surgeons in 2015-2016 due to metastatic brain tumors and 27 patients (group 2) who were operated between 2017-2019 by performing FL staining were evaluated retrospectively.

Patients with significant contrast enhancement on MR images, aged between 34-75 years, diagnosed with metastatic brain tumor and who underwent surgery were included in the study. Cases that did not have contrast enhancement on MR images and for whom administering contrast agent was contraindicated were excluded from the study.

All patients were operated under general anesthesia. Group 1 patients were operated under white light with a standard surgical microscope. In group 2 patients, 3 mg/kg FL was given as a 10% bolus through the central catheter before the skin incision following the induction of anesthesia. Leica M530 OHX (Wetzlar and Mannheim, Germany) microscope with FL560 fluorescein module was used in the surgery of the patients. The yellow highlights around the tumor tissue under FL560, which could not be clearly differentiated under white light, were excised. Contrast-enhanced control brain MRIs taken at the first month after surgery were evaluated with open source software (Sectra UniView, https://medical.sectra.com/product/sectra-uniview) and residual tumor volumes were calculated. Patients with no contrast enhancement in postoperative MR images were evaluated as gross total resection (GTR), while those with contrast enhancement were considered as subtotal resection. Length of hospital stay, duration of surgery and amount of blood loss were recorded from patient files. NA-FL’s aid to surgery was evaluated by examining the surgery notes and surgery videos.

Statistical Analysis

Data were analyzed by entering Statistical Package for the Social Sciences (SPSS) 24.0 (SPSS Inc., Chicago, IL, USA) statistical computer program. Chi-square test for categorical variables (Fisher’s Exact test if not applicable) was used to compare the groups using NA-FL and those not using it. In comparison of continuous variables, independent sample t-test was used for those with normal distributions and Mann-Whitney U test for those without normal distribution. The cases where the p value was below 0.05 and the type 1 error level was below 5% were interpreted as statistically significant.

RESULTS

A total of 48 patients were included in the study. The median age of the patients was 61.5 years (minimum: 20, maximum: 80), and the mean age was 59.1±11.8 years. In group 1, 21 patients (female=9 and male=12) were operated without using NA-FL, and in group 2, 27 patients (female=11 and male=16) were operated using NA-FL. There was no difference between the groups in terms of gender (p=0.883). When the mean tumor volumes detected in the contrast-enhanced brain MR images of the patients before the operation were examined, it was seen that it was 13.7±11.4 cm³ in group 1 and 13.3±13.3 cm³ in group 2, and both groups were similar in this respect (p=0.540). Considering the blood loss during surgery, there was an average of 434.3 cc of bleeding in group 1, and this average was 320.4 cc in group 2. This amount of bleeding in group 2 was significantly less than group 1 (p=0.001). While the duration of surgery was 275.7±62.8 minutes in group 1, it was 272.0±60.7 minutes in group 2 and both groups were similar in terms of surgery time (p=0.837). When the control MR images taken after the operation were examined, the GTR rate in group 2 was 92.6%, while it was 71.4% in group 1 (p=0.059) (Figure 1). While the mean hospital stay was 9.6±5.2 in group 2, it was 13.5±7.3 in group 1 and was significantly longer than group 2 (p=0.013). Demographic data and results of both groups are summarized in Table 1, primary focus types are summarized in Table 2 and Table 3. In group 2, it did not appear to be beneficial in two patients with FL, malignant melanoma, and cystic AC adenocarcinoma. In 25 patients (92.5%), FL contributed to the surgery by giving a light yellow highlight (Figure 2). No complications were observed in any of the patients who used FL.

DISCUSSION

The life expectancy of a patient with a metastatic brain tumor is usually quite short, regardless of which organ the primary tumor originates from. Active physical activity, presence of a solitary metastatic mass, no signs of systemic metastasis, and young age (<60-65 years) are generally associated with a good prognosis^15,16. In addition to these, total resection and mini-mental testing of the patient, namely memory and cognitive functions. are also associated with good prognosis^13,17. In brain tumor surgery, the surgeon should ensure that these prognostic factors do not change. The target of the surgery should be total resection, but the patient’s motor, memory and cognitive functions should not be affected. For this purpose, in recent years, auxiliary techniques such as intraoperative ultrasound, intraoperative MR, navigation, and brain mapping have been used⁸. In recent years, tumor staining techniques using substances such as 5-ALA, FL and indocyanine green have been a light of hope in distinguishing glial tissue from tumors. High-dose (15-20 mg/kg) FL in brain tumor surgery has been used for many years to increase the amount of resection. More secure and clearer images are obtained at doses of 3-4 mg/kg thanks to special filters that give a yellow highlight with FL at 560 nm, which are recently attached to surgical microscopes^18,19. Thus, GTR rates have increased in both primary glial and metastatic masses with contrast enhancement^18,20. Schebesch et al.¹⁴ in their series of 30 patients in which they used low-dose FL with a yellow 560 filter, reported that FL gave bright highlight in 27 patients and was beneficial in surgery, with a GTR rate of 83.3%. They found that FL was not helpful in two patients with AC adenocarcinoma and one patient with malignant melanoma.

Again, Hamamcıoğlu et al.²⁰ in their series of 23 primary glial tumors and 7 metastatic masses, reported that FL was beneficial in all of their patients, except for one low-grade glial mass.Okuda et al.²¹ reported the GTR rate as 86.1% and the local recurrence rate as 19.4% in 36 patients with metastatic brain tumors for whom FL was used.Although there was no statistical significance between the two groups in our series, when we looked at the GTR ratios, it was 71.4% in white light and 92.6% in those using FL (Table 1). We think that GTR ratios should be compared in larger series. The increase in GTR with FL in metastatic brain tumors can be explained by the resection of the yellow highlights on the walls by switching to the filter, especially after cleaning the inside of the lodge with debulking. FL was not found to be beneficial in two cases with a cystic AC adenocarcinoma and a malignant melanoma metastasis.

In retrospect, the patient with AC adenocarcinoma showed very weak thin-edged contrast enhancement around the cyst in preoperative MR images. FL involvement is proportional to impaired blood-brain barrier and intense contrast enhancement²². Especially in cystic masses, there is a thin wall enhancement, FL efficiency should be evaluated in larger series in these patients. FL involvement was not observed in the patient with malignant melanoma metastasis, but the black, gray tumor could easily be separated from the brain tissue. There is no study in the literature regarding the amount of bleeding, surgical durations, and hospital stays in surgeries performed with FL yet. In our series, blood loss in the FL group was significantly less than in the other group (p=0.001) (Table 1). We think that the reason for this is that the surgeon acts more controlled and decisively because he distinguishes between tumor and neural tissue while inside or outside the tumor. Again, in the FL group, by minimizing neural tissue damage, patients were discharged from the hospital more rapidly in the postoperative period (p=0.013) (Table 1). The low amount of bleeding in the patients causes the preservation of brain perfusion during surgery. Both the preservation of brain perfusion and the preservation of their motor and cognitive abilities without damaging the glial tissue caused the patients to return to their normal lives more quickly.

Study Limitations

While it would be appropriate to say that the use of FL is an effective method in the surgery of AC Ca metastases, which are the most common in our series of metastatic brain tumors, more cases should be evaluated for this inference in rare metastatic masses and cystic metastases.

TARTIŞMA

Metastatik beyin tümörü olan bir hastanın primer tümörü hangi organdan olursa olsun beklenen yaşam süreleri genellikle oldukça kısadır. Hastanın aktif fiziksel aktiviteye sahip olması, soliter metastatik kitle varlığı, sistemik metastaz bulgularının olmaması ve genç yaş (<60-65 yaş) genellikle iyi prognozla beraberdir^15,16 . Bunlara ek olarak total rezeksiyon ve hastanın mini-mental testinin yani hafıza ve bilişsel fonksiyonlarının iyi olması da iyi prognozla ilişkilidir^13,17. Beyin tümörü cerrahisinde cerrah bu prognostik faktörlerin değişmemesini sağlamalıdır. Yapılacak cerrahide hedef total rezeksiyon olmalı, ancak hastanın motor, bellek ve bilişsel fonksiyonları etkilenmemelidir. Bu amaç doğrultusunda son yıllarda intraoperatif ultrason, intraoperatif MR, navigasyon, beyin haritalandırması gibi yardımcı teknikler kullanılmaya başlanmıştır⁸. Son yıllarda 5-ALA, FL ve indocyanine green gibi maddelerin kullanılmasıyla yapılan tümör boyama teknikleri ise glial doku tümör ayrımını yapmakta umut ışığı olmuştur. Beyin tümörleri cerrahisinde yüksek doz (15-20 mg/kg) FL uzun yıllardır rezeksiyon miktarını artırmak amacıyla kullanılmaktadır. Son dönemde cerrahi mikroskoplara takılan 560 nm’de FL ile sarı röfle verdiren özel filtreler sayesinde 3-4 mg/kg dozlarda daha güvenli ve daha net görüntüler elde edilmektedir^18,19. Bu sayede kontrast tutan hem primer glial hemde metastatik kitlelerde GTR oranları artmıştır^18,20.

Schebesch ve ark.¹⁴ sarı 560 filtresi ile düşük doz FL kullandıkları 30 hastalı serilerinde, FL’nin 27 hastada parlak röfle verdiğini ve cerrahide yarar sağladığını, %83,3’lük GTR oranları olduğunu bildirmişlerdir. Schebesch ve ark.¹⁴ AC adenokarsinomlu iki hasta ve bir malign melanom hastasında FL’nin yararlı olmadığını görmüşlerdir.

Yine Hamamcıoğlu ve ark.²⁰ 23 primer glial tümör, 7 metastatik kitleli serilerinde düşük dereceli bir adet glial kitle dışında tüm hastalarında FL’nin faydalı olduğunu bildirmişlerdir. Okuda ve ark.²¹ ise FL kullandıkları metastatik beyin tümörü olan 36 hastada GTR oranını %86,1, lokal rekürrens oranını %19,4 olarak vermişlerdir. Bizim serimizde de her ne kadar iki grup arasında istatistiksel anlamlılık olmasa da GTR oranlarına baktığımız zaman beyaz ışıkta %71,4 iken FL kullanılanlarda %92,6 olarak tespit edilmiştir (Tablo 1). Daha büyük serilerde GTR oranlarının karşılaştırılması gerektiğini düşünüyoruz. Metastatik beyin tümörlerinde GTR’nin FL ile bu kadar artması özellikle debulking ile loj içi temizlendikten sonra filtreye geçiş yapılarak duvarlarda sarı röfle veren alanların rezeksiyonu ile açıklanabilir. Bir kistik AC adenokarsinomu ve bir malign melanom metastazı olan iki olguda FL yararlı bulunmamıştır. Geriye dönük bakıldığında AC adenokarsinomu olan hastada preoperatif MR görüntülerinde kist etrafında çok zayıf ince kenarlı kontrast tutulumu olduğu izlenmiştir. FL tutulumu bozulmuş kan beyin bariyeri ve yoğun kontrast tutulumu ile orantılıdır²². Özellikle kistik kitlelerde cidarsal ince bir kontrast tutulumu olmaktadır, bu hastalarda FL etkinliği daha büyük serilerde değerlendirilmelidir. Malign melanom metastazı olan hastada ise FL tutulumu gözlenmemiştir, ancak siyah, gri renkte olan tümör kolaylıkla beyin dokusundan ayrılabilmiştir. Literatürde henüz FL ile uygulanan cerrahilerde kanama miktarı, cerrahi süreler, hastanede kalış süreleri ile ilgili bir yayın yoktur. Bizim serimizde FL kullanılan grupta kan kaybı diğer gruba göre belirgin azdır (p=0,001) (Tablo 1). Bunun nedeninin cerrahın tümör içinde ya da dışındayken tümör ya da nöral doku ayrımını yaptığı için daha kontrollü ve kararlı hareket etmesi olduğunu düşünüyoruz. Yine FL kullanılan grupta nöral doku hasarının en aza indirilmesi ile postoperatif dönemde hastalar daha hızlı bir şekilde hastaneden taburcu edilebilmiştir (p=0,013) (Tablo 1). Hastaların kanama miktarının az olması cerrahi sırasında beyin perfüzyonunun korunmasına neden olmaktadır. Hem beyin perfüzyonunun korunması hem de glial dokuya zarar vermeden motor ve bilişsel yetilerinin korunması hastaların daha hızlı bir şekilde normal hayatlarına dönmelerine neden olmuştur.

Çalışmanın Kısıtlılıkları

Metastatik beyin tümörleri serimizde en fazla görülen AC Ca metastazlarının cerrahisinde FL kullanımının etkin bir yöntem olduğunu söylemek yerinde olacak iken, nadir görülen metastatik kitlelerde ve kistik metastazlarda bu çıkarım için daha fazla olguda değerlendirme yapmak gerekmektedir.

CONCLUSION

FL, which has recently been used mainly in the surgery of high-grade glial masses, is also extremely useful in the surgery of contrast-enhancing metastatic brain tumors. It increases GTR rates, reduces blood loss and hospital stay, as a guide to the surgeon in separating the tumor glial tissue border.