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© 2001 American Society for Clinical Oncology Increased Temperature of Malignant Urinary Bladder Tumors In Vivo: The Application of a New Method Based on a Catheter TechniqueFrom the Hippokration Hospital, Athens University Medical School, Athens, Greece. Address reprint to Christodoulos Stefanadis, MD, 9 Tepeleniou St, Paleo Psychiko, Athens 154 52, Greece; email: cstefan{at}cc.uoa.gr
PURPOSE: The aim of this study was to investigate the existence of any thermal difference between malignant tumors and inflammatory benign lesions of the human urinary bladder and to determine whether it correlates with tumor angiogenesis quantification.
PATIENTS AND METHODS: A new method, developed in our institute, is introduced to detect temperature in human urinary bladder, in vivo. This method is based on a thermography catheter. We calculated the differences of the temperature of the solid tumor and of a normal area (
RESULTS: We found significant differences of CONCLUSION: These findings suggest that the calculated difference of temperature between normal tissue and neoplastic area could be a useful criterion in the diagnosis of malignancy in tumors of the human urinary bladder.
THERE IS A large body of evidence suggesting that increased blood flow,1 angiogenesis,2,3 and inflammation process are often associated with malignant transformation of urinary bladder tumors, although their exact relationship remains unclear. Angiogenesis is the formation of new capillaries from the existing vascular bed. In normal conditions, this tightly regulated process occurs only during embryonic development, the female reproductive cycle, and wound repair. In contrast, in pathologic conditions such as malignant growth, atherosclerosis,4,5 and diabetic retinopathy, angiogenesis becomes persistent because of an imbalance in the interplay between the positive and negative regulatory signals controlling the process.6,7 Furthermore, sequential interaction of neoplastic cells with this submucosa hypervascularization is now believed to be one of the most significant steps in metastasis.8-10 Also, several investigators have evaluated angiogenesis as an independent predictor of survival in patients with invasive bladder carcinoma.2,3,11 Regional hyperthermia of a malignant tumor seems to reflect this procedure, and several investigators have featured ultrasound12 or other methods13-15 that prove the increased blood flow inside a malignant tumor. Attempts have been made to reveal occult bladder cancer in vivo by using the fluorescence of acridine orange, hematoporphyrin, and tetracycline.16,17 Unfortunately, the poor quality of the results obtained was the main reason to abandon these techniques. Other investigators used ultraviolet cystoscopy18 to reveal precancerous and cancerous flat bladder lesions. This procedure was based on the examination of bladder mucosa and the tracing of the hypervascularization present in the submucosa after the intravenous injection of fluorescein. Although, the results obtained with this technique were not satisfactory, flow cytometry seems to represent a useful noninvasive method of approaching the real extent of bladder cancer. In this direction, various protocols of ultraviolet and white light cystoscopy are under investigation.19 However, the direct measure of local temperature of tumors within the urinary tract for diagnostic reasons has not ever been attempted in vivo. The aim of this study was to investigate the existence of any thermal distinction between malignant tumors and inflammatory benign lesions of the human urinary bladder and to determine whether it correlates with tumor angiogenesis quantification.
Patients A randomized case control study was designed to evaluate the diagnostic ability of the temperature-measurement technique. We applied this procedure in 20, randomly selected, consecutive patients with hematuria. The procedure took place during transurethral resection of a urinary bladder tumor. Excisions/biopsies were routinely obtained from each patient. All the patients had been informed about the purpose of the study, the methodology used, and the procedure. Also, they had signed an informed consent, according to bioethical principles in medical research and the Declaration of Helsinki (revised 1983). The procedure was brief and uncomplicated for all the patients.
Thermography Catheter
The technical characteristics of the polyamide thermistor include the following: (1) temperature accuracy, 0.05°C; (2) time constant, 300 milliseconds; (3) spatial revolution, 0.5 mm; and (4) linear correlation of resistance versus temperature over the range of 33°C to 43°C.
Data Acquisition and Processing
Procedure
Histopathology
Statistical Analysis
We studied 20 subjects, 16 males and four females, with a mean age of 72.5 years (95% CI, 68.5 to 76.4). Eight of the patients (40%) had benign tumor, and 12 of the patients (60%) had malignant tumor, according the biopsy histology. Four of the malignant tumors (33%) were grade 1, five (42%) were grade 2, and three (25%) were grade 3. In all the patients, the biopsy examination of the two locations, in an area 3 to 5 cm outside the circumference of the tumor where the temperature of the urinary bladder wall was measured, revealed normal urinary bladder epithelium. Significant differences were found for the mean values of angiogenesis level. Specifically, patients with benign tumors had a mean value of angiogenesis level of 40.25 (95% CI, 37.8 to 42.7), and patients with malignant tumors had a mean value of 53.3 (95% CI, 43.8 to 63.8). The difference between the mean values of angiogenesis, by malignancy, was statistically significant (P = .0261). A borderline significant result was found between angiogenesis level and increasing grade of tumors (P = .07).
In each location, tumor and proximal normal tissue, two temperatures were calculated. The temperature of the normal urinary tissue was extracted by the mean value of the two measurements, although no statistical difference was found between them (P = .780). Also, the temperature of the location of the urinary bladder tumor was calculated by the mean value of the two measurements, although again no statistical significant difference was found (P = .730). Because the main factor of interest was the differences of the temperatures between a normal tissue and a malignant or benign tumor (
Afterward, we applied univariate analysis to assess whether age and sex of patients, grade of tumors, degree of angiogenesis, and penetration of chorio and muscle layer correlated with the differences of temperature (  T) in the presence of malignant tumors or not. Based on Mann-Whitney criterion we found that there is not any relation between T and penetration of chorio or muscle layer (P = .71 and P = .54, respectively). Furthermore, according to Spearman’s correlation coefficient, we found moderated positive correlation between degree of angiogenesis and T ( = 0.50, P = .02), which indicates that higher levels of angiogenesis correspond to greater differences between the two locations.
Also,
Based on the results from the univariate analysis, a logistic model was fitted to assess the diagnostic ability of T in the presence of levels of angiogenesis and grade of tumors. The results from the model indicate that values of T greater than 1°C can estimate with high accuracy a malignant tumor. Specifically, a 1-degreee of T triples the odds of a patient having a malignant tumor (OR = 2.91; 95% CI, 1.97 to 7.78; P < .001), adjusted for the degree of angiogenesis (P = .0236) and grade of tumor (P < .001).
Furthermore, according to our stepwise analysis and log-rank test, the age and sex of the patients were not found to be significant factors in our study (P = .59 and P = .77, respectively). No significant interaction was found between main effect, ie, Finally, we applied cutoff point analysis based on the fitted logistic model and found that differences greater than 0.7°C can discriminate a malignant tumor with high precision. The sensitivity for this threshold point was 83%, and the specificity was 75% ( Table 3).
As we conclude from Table 3, both the positive (83%) and negative (75%) predictive values of the diagnostic method that we applied were high. This result enforces the diagnostic ability of the intended procedure. The area under the receiver operating characteristic curve was found equal to 0.92 and compared with the Wilcoxon test was found highly significant (P < .001). This outcome strengthens the main purpose of the study, which was the examination of the role of T for the diagnosis of a malignant tumor ( Fig 3).
Neoangiogenesis is a well-known phenomenon of malignant transformation in solid tissues, resulting in submucosa hypervascularization during bladder epithelium carcinogenesis.24,25 However, submucosa hypervascularization is a nonspecific phenomenon that develops in other processes as well, such as inflammation or orthoplastic regeneration.4,6 Previous in vivo studies tried to demonstrate flat cancerous and precancerous bladder lesions based on fluorescein intravenous injection to reveal the submucosa neoangiogenesis.17,18 Unfortunately, the results obtained were disappointing, and other techniques based on more specific principles to get better visualization are being investigated. In this study, the quantification of microvascularity, by the field counting method, reveals that neoangiogenesis can be a marker of neoplastic lesion, although angiogenic activity exists on an important level also in benign lesions.6 These remarks correspond to other investigators’ results that revealed no significant difference in the microvascular density between preneoplastic and low malignancy neoplastic lesions.24 Also, other investigations8 support that the number of micro-vessels counted per field in endothelial cells of an invasive breast carcinoma may be an independent predictor of metastatic disease and the aggressive attitude of the tumor. This increased vascularity in tumor cells with invasive carcinoma attracted many investigators who tried to visualize this thermal heterogeneity by ultrasound or four magnetic resonance methods.26,27 In our institute, consistent with the development of other cardiac and vascular catheters,20,21,28,29 we developed a catheter-based technique for the temperature measurement of solid bladder tumors in vivo. The thermal difference, between the tumor area and the proximal normal urinary bladder wall, was found to be larger in malignant tumors than in benign or hyperplastic lesions, and the increase of temperature difference by one degree triples the odds (OR = 2.91) of a patient having a malignant tumor. Methods for quantification of blood vessels in other studies of neoangiogenesis have usually involved some element of subjectivity, mainly in the selection of the most vascular area for counting. Therefore, in this study, the highest vascularity within the tumor was counted, according to Weidner et al8 who stressed the importance of the selection of these vascular hotspots for predicting outcome. According to the above, we found positive correlation between the degree of angiogenesis and the temperature difference, which indicates that higher levels of angiogenesis correspond to greater temperature differences between the two locations (tumor and normal urinary bladder wall). Also, this temperature difference seems to increase as the grade of tumors increases too. This positive relation between stage and vessel count is not surprising when it is considered that stage could be regarded as a composite variable, dependent on tumor size and the degree of spread, both of which rely on angiogenesis.3 On the other hand, no relation was found between temperature difference and penetration by the malignant tumor of the chorio- and the muscle-cell layers. These results probably reflect the observations of other investigators who support that angiogenesis is necessary but not sufficient for continued tumor growth. On the contrary, others believe that while the absence of angiogenesis will severely limit tumor growth, the existence of angiogenic activity permits expansion of the tumor.9 The insertion of water into the urinary bladder is common during transurethral tumor resections. This urinary tract washout may influence the results of any thermography technique used. For this reason, we tried to eliminate the amount of water washout of the urinary tract and to maintain a constant water temperature. Also, we waited for 2 minutes to obtain temperature measurements so that the temperature of the water inserted into the urinary tract was stabilized. Although several factors, such as inflammation procedures and angiogenesis, are involved in the natural history of urinary bladder carcinoma, increased thermal temperature seems to discriminate malignant urinary bladder tumors, whereas temperature between benign solid tumors and normal location is increased, although without any statistical significant difference. Also, microvascular density as a marker of angiogenesis can be useful in identifying malignant from benign lesions, especially when the malignant lesion is more aggressive. In this study, we observed that the calculated difference of temperature between normal tissue and tumor in the presence of a high level of micro-vessel density, along with the estimation of grade level of tumor malignancy, could be a high magnitude diagnostic tool in the diagnosis of malignancy in tumors of the human urinary bladder. This in vivo technique may prove useful in identifying precancerous lesions as well as in assessing the prognosis of malignant bladder tumors, by detecting thermal heterogeneity in a suspicious area prone to neoplastic transformation, before a neoplastic lesion becomes visible on conventional cystoscopy.
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Gasparini G, Harris AL: Clinical importance of the determination of tumor angiogenesis in breast carcinoma: Much more than a new prognostic tool. J Clin Oncol 13: 765-782, 1995 16. Koss LG, Melamed MR, Ricci A, et al: Carcinogenesis in human urinary bladder: Observation after exposure to para-aminodiphenyl. N Engl J Med 272: 767-770, 1965 17. Fukui I, Yokokawa M, Mitani G: In vivo staining test with methylene blue for bladder cancer. J Urol 130: 252-255, 1983[Medline] 18. Devonec M, Lenz P, Bouvier R, et al: Clinically occult bladder cancer diagnosis: Trial using ultraviolet cystoscopy. Cancer 55: 468-471, 1985[Medline] 19. Devonec M, Darzynkeiwicz Z, Kostyrka-Claps ML, et al: Flow cytometry of low stage bladder tumors: Correlation with cytologic and cystoscopic diagnosis. Cancer 49: 109-118, 1982[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test to be accurate. A logistic regression model with a stepwise analysis was fitted to assess the effect of the cofactors in the possibility of diagnosing a malignant tumor and to calculate the corresponding odds ratio (OR). Deviance and Pearson’s residuals were used to evaluate the model’s goodness-of-fit. Finally, a cutoff point analysis was performed to determine significant changes of the temperatures (
