The Value of Preoperative Alpha-L-Fucosidase Levels in Evaluation of Malignancy and Differential Diagnosis of Urothelial Neoplasms

Chen, Dongshan; Xing, Naidong; Cui, Zhanwu; Zhang, Cong; Zhang, Zhao; Li, Dawei; Yan, Lei

doi:https://doi.org/10.1155/2020/6723616

Journal of Oncology

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Abstract Introduction Materials and Methods Results Discussion Data Availability Ethical Approval Conflicts of Interest Authors’ Contributions Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2020 | Article ID 6723616 | https://doi.org/10.1155/2020/6723616

The Value of Preoperative Alpha-L-Fucosidase Levels in Evaluation of Malignancy and Differential Diagnosis of Urothelial Neoplasms

Dongshan Chen,¹Naidong Xing,¹Zhanwu Cui,²Cong Zhang,¹Zhao Zhang,¹Dawei Li,¹and Lei Yan¹

Academic Editor: Nihal Ahmad

Received19 Apr 2020

Revised30 Jun 2020

Accepted02 Jul 2020

Published25 Jul 2020

Abstract

Purpose. To evaluate the role of Alpha-L-fucosidase (AFU) in diagnosis and differential diagnosis of pure urothelial carcinoma (UC), urothelial carcinoma with squamous differentiation (UCSD), and squamous cell carcinoma (SqCC). Methods. A retrospective study was performed for 599 patients who were histologically confirmed with urothelial tumor. Preoperative AFU levels were compared across the distinct subgroups with different clinicopathological parameters. ROC curve analysis and logistic regression analysis were performed to further evaluate the clinical application value of serum AFU levels in diagnosis and differential diagnosis of urothelial tumors. Results. There were no statistically significant differences in the AFU levels between different groups with different malignant degrees (UC versus papilloma and papillary urothelial neoplasm of low malignant potential [PUNLMP], high-grade UC versus low-grade UC, invasive versus noninvasive malignant uroepithelial tumor) and different pathological types (UC, UCSD, and SqCC) (all ). ROC curve analysis and logistic regression analysis showed that there was no statistically significant association between AFU levels and the tumor characteristics (all ). Conclusions. Preoperative AFU levels cannot serve as a reliable predictor for malignant degree and differential diagnosis, including pure UC, UCSD, and SqCC of urothelial tumors.

1. Introduction

Malignant uroepithelial tumor (MUT) is a common malignant tumor in the genitourinary system and can be categorized as urothelial and nonurothelial carcinomas (nUC). Although the majority of malignancy are urothelial in histology, variants or divergent differentiations, such UCSD, exist [1, 2], which poses a great diagnostic and treatment challenge. In addition, nonurothelial carcinomas are relatively rare, and the most common subtypes of those include SqCC, adenocarcinoma and neuroendocrine tumors [3]. However, previous research has shown that nUC confer a worse prognosis and are more resistant to conventional treatment [4]. The differential diagnosis of pure UC (UC without divergent differentiations), UCSD, and SqCC relies not only on histopathological features, but also on sufficient precedent pathology and medical history taking [5]. Therefore, there is an urgent need to find a sensitive biological marker to identify SqCC, UC, and UCSD and evaluate the malignant degree of them.

Fucosylated glycan, such as blood type A, B, and H antigens and various Lewis antigens, is of crucial importance in a variety of physiological and pathological processes, including tissue development, infection, inflammation, and tumor metastasis [6]. The variation of fucosylated glycan both in quantity and in structure had been observed in a number of cancers [7]. Alpha-L-fucosidase (AFU), a liposomal enzyme involving the degradation of various fucosylated glycans, has been generally accepted as tumor markers which are correlated with early diagnosis and prognosis of hepatic carcinoma and colorectal cancer [8, 9]. Additionally, alpha-L-fucosidase-1 was reported to be a useful marker to distinguish mucoepidermoid carcinoma from oral squamous cell carcinoma [10]. However, the clinical application value of AFU in the MUT is unclear up to date. In this study, we mainly investigated the association between serum AFU levels and clinicopathological characteristics of MUT patients and explored the diagnostic significance of circulating AFU levels in patients with SqCC, UC, and UCSD.

2. Materials and Methods

2.1. Patient Data

A retrospective study was performed for 599 patients who were histologically confirmed with urothelial tumor and underwent operation at the Department of Urology, Qilu Hospital of Shandong University, between July 2014 and March 2018. Among 599 patients, 588 patients were diagnosed with urothelial tumor, and 11 patients were diagnosed with SqCC. The exclusion criteria for all patients in this study were as follows:(1)Coexisting any other malignancy(2)History of malignant tumor, including MUT and other malignancies(3)Patients receiving any adjuvant treatments, such as radiotherapy or chemotherapy before surgery(4)Patients with inadequate clinical information

2.2. Data Collection

The clinical information including patient age at the time of diagnosis, sex, smoking history, routine blood examination results (white blood cell count, platelet count, plasma fibrinogen level, etc.), and corresponding tumor characteristics were obtained from the electronic patient records at our institution. Tumor grade was assessed according to the 1998 WHO/ISUP classification. However, the postoperative pathology results collected in clinical practice could not provide sufficient information for clinicopathologic stage.

2.3. AFU Measurement

Prior to any clinical interventions, venous blood of patients was collected in the early morning after 12 hours of fast and was stored in test tubes with separating gel and coagulant. Subsequently, the serum AFU activity was detected by The Roche Cobas 8000 automatic analyzer. The tests were carried out complying with the standard operating procedure.

2.4. Statistical Analysis

The Statistical Package for Social Science version 22.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analyses and data was presented as mean ± standard deviation (SD). The normal distribution was assessed by the Kolmogorov–Smirnov test. Normal distribution data was compared by the student tests, otherwise by the Mann–Whitney U test or Kruskal–Wallis H-test for two or more than two groups, respectively. values <0.05 in two-tailed tests were considered statistically significant.

3. Results

3.1. Clinical Characteristics of Study Population

There were a total of 599 patients with newly diagnosed uroepithelial tumor enrolled in this study, which included 579 pure urothelial tumor. In addition, 455 were men and 144 were women, with a median age at diagnosis of 65 years ranging from 17 to 94. The mean preoperative AFU level of all patients was 14.94 ± 4.53 U/L. We found that preoperative AFU levels were significantly correlated with sex, smoking history, painless macroscopic hematuria, white blood cell (WBC), and lactate dehydrogenase (LDH) (all ). In the cohort of UC, the mean preoperative AFU level of patients with pure UC (14.99 ± 4.50) was higher than that in patients with PUNLMP (14.93 ± 4.67 U/L) and papilloma (14.56 ± 5.22 U/L), but with no statistical significance (, Figure 1). Besides, there was no obvious statistical significance in AFU levels between early-stage and advanced-stage disease (high-grade versus low-grade pure UC: 14.64 ± 4.10 versus 15.67 ± 5.12 U/L, ; invasive MUT versus noninvasive MUT: 14.79 ± 4.27 versus 15.38 ± 4.36 U/L, , Figure 1). The other clinical characteristics of enrolled patients are presented in Table 1.

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(b)

(c)

(d)

Linear correlation analyses were performed to further evaluate correlations between AFU levels and clinical parameters in urothelial tumor. The result showed that there was a weak linear correlation between age, WBC, platelet (PLT) and AFU levels (r = −0.126, ; r = 0.148, ; r = 0.082, , respectively) (Figures 2(a)–2(c)). However, alkaline phosphatase (AKP), LDH, and plasma fibrinogen (PFL) did not show any correlation with AFU levels (all , Figures 2(d)–2(f)).

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(b)

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(e)

(f)

3.2. Associations between AFU Levels and Pathological Characteristics of MUT Patients

To further evaluate the diagnostic value of AFU in MUT, the levels of serum AFU were studied and compared in pure UC, UCSD, and SqCC. Among 535 MUT patients, 11 were SqCC and 524 were UC, including 9 with UCSD. We found that the gradation from high to low according to the levels of serum AFU was pure UC (14.99 ± 4.50), UCSD (14.78 ± 6.44), and SqCC (13.15 ± 3.03), with no statistical significance (, Table 2 and Figure 1(d)).

3.3. Diagnostic Value of Preoperative AFU Levels in Urothelial Tumor

The receiver operating characteristic (ROC) curves analysis for preoperative AFU levels was used to evaluate its value of qualitative diagnosis in urothelial tumor. The areas under the ROC curve (AUC) were 0.52 (95% CI 0.44–0.59, UC versus papilloma and PUNLMP), 0.55 (95% CI 0.50–0.60, high-grade UC versus low-grade UC), 0.54 (95% CI 0.48–0.60, invasive versus noninvasive MUT), 0.55 (95% CI 0.32–0.79, pure UC versus UCSD), and 0.63 (95% CI 0.48–0.78, pure UC versus SqCC), respectively. The corresponding optimal threshold values were 13.59 U/L, 13.27 U/L, 14.76 U/L, 11.50 U/L, and 15.67 U/L. However, all of values were greater than 0.05, indicating that there was no clinical value of AFU levels in differential diagnosis and evaluation of malignancy extent of MUT. The sensitivity, specificity, cut-off value, and exact value were shown in Figure 3.

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(b)

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Subsequently, logistic regression model of univariate and multivariate analysis was used to further evaluate the clinical impact of preoperative AFU levels on the prediction of histopathology. The univariate analysis showed that AFU levels were not significantly correlated with the differential diagnosis of urothelial tumor (UC and papilloma and PUNLMP, pure UC vs. UCSD, pure UC vs. SqCC; all ; Table 3). Additionally, hematuria shows significant predictability on pathology results (UC versus Papilloma and PUNLMP: HR = 2.640, ; pure UC versus SqCC: HR = 3.591, ; Table 3). By multivariable analysis, AFU levels were not independent predictors of pathologic diagnosis (all , Table 4). However, hematuria was an independent risk factor for UC and UCSD (UC versus Papilloma and PUNLMP: HR = 2.154, ; pure UC versus UCSD: HR = 4.761, ; Table 4).

4. Discussion

Although most of the neoplasms located in the urinary tract are mainly histologically urothelial carcinomas, the variation of morphological characteristics exists within tumors [11]. The most common variation type is squamous differentiation, which is characterized by the presence of keratin pearls, intercellular bridges, or both [12, 13]. Previous studies have shown that squamous differentiation is more resistant to radiotherapy, chemotherapy, and immunotherapy and possesses the characteristics of high risk of recurrence and poor prognosis as an independent prognostic factor of UC [2, 14, 15]. In addition, SqCC, as the most common variant in nonurothelial carcinomas, is usually discovered and diagnosed at its advanced stage, while a considerable number of patients have lymph node metastasis in neoplasms resection [5, 16]. Currently, there are limited clinical approaches for the early diagnosis and treatment of MUT. Therefore, there is a pressing need to find a specific, high sensitivity marker to improve differential diagnosis rate of pure UC, UCSD, and SqCC and predict the degree of malignancy, development trend, and prognosis.

As we know, AFU extensively exists in human cells and is continuously released into blood to circulate as a product of cell metabolism [17]. Human AFU is a hydrolase with particular biological and medical interest, whose main role is to hydrolyze the glycans participated in diverse interactions between cells and extracellular matrix [18, 19]. Glycosylation is an important physiological and pathological process, and abnormality of content and function of fucosylated glycan are common features of malignant neoplastic transformation, including tumor invasion and metastases, and other human diseases [20, 21]. The decreased or increased activities of serum AFU are commonly used as a diagnostic biomarker for fucosidosis and hepatocellular carcinoma, respectively [22, 23]. And constantly elevated AFU level in patients with liver cirrhosis contributes to early detection of hepatocellular carcinoma [24]. Besides, many studies on the relationships between the serum form of AFU and other diseases had been reported. The alterations of AFU activity and properties also possess a high clinical value in the diagnosis of colorectal cancer [25], ovarian cancer [26], chronic inflammation, and autoimmune disorders [27]. Moreover, a comprehensive research project that contains 188,077 patients with 64 clinically defined diseases and 9,519 healthy controls showed that serum AFU activities were higher in patients with preeclampsia, liver cancer, hepatitis, psoriasis, and multiple myeloma, while serum AFU activities were the lowest in patients with uremia, azotemia, myeloproliferative disorder, and Alzheimer’s disease among the 64 diseases studied [28]. Although serum AFU is potentially valuable indicators for many cancers and many different types of diseases, investigation about its serum levels in a cohort of patients with urinary tract neoplasms is still lacking.

In the present study, we analyzed preoperative AFU levels and clinicopathological features of 599 patients with urothelial tumor. There were no statistically significant differences in the AFU levels between different groups with different malignant degrees (UC versus papilloma versus PUNLMP, ; high-grade versus low-grade UC, ; invasive versus noninvasive MUT, ). In addition, we did not find a statistically significant difference in AFU levels among distinct pathologic type (pure UC versus UCSD versus SqCC, ). Interestingly, we found that AFU levels were closely related to sex, smoking history, painless macroscopic hematuria, WBC, and LDH (all ). Next, linear correlation analyses were performed and showed that only age, WBC, and PLT were related slightly to AFU levels (r = −0.126, ; r = 0.148, ; r = 0.082, , respectively). However, the correlation coefficients were low; they had no medical significance. To further evaluate the practical application value of AFU levels in diagnosis and differential diagnosis of urothelial tumor, ROC curves were performed for preoperative AFU levels regarding the prediction of pure UC, high-grade UC, invasive MUT, UCSD, and SqCC. AUC were 0.52 (UC versus papilloma and PUNLMP), 0.55 (high-grade UC versus low-grade UC), 0.54 (invasive versus noninvasive MUT), 0.55 (pure UC versus UCSD), and 0.63 (pure UC versus SqCC (all )), respectively, which indicated that AFU levels could not serve as a valuable indicator to reflect the extent of malignancy and pathological type of urothelial tumor. Furthermore, univariate and multivariate analysis further strengthened the evidence that serum AFU level was not an independent predictor of pure UC, UCSD, and SqCC. Interestingly, multivariate logistic regression analysis showed that painless macroscopic hematuria was an independent risk factor for UC and UCSD (UC versus Papilloma and PUNLMP: HR = 2.154, ; pure UC versus UCSD: HR = 4.761, ).

However, there are several limitations in the present study. Firstly, because the number of patients with UCSD and SqCC was relatively small and this is a retrospective, observational study, unknown sources of bias may exist. Secondly, all clinicopathological information was collected from a single institution; the universal conclusions of the study may be subject to certain restrictions.

In conclusion, there was no direct correlation between the levels of serum AFU and the tumor characteristics (tumor number, tumor size, and pathological characteristics (all )) in statistics. Thus, preoperative AFU levels cannot serve as a reliable predictor for malignant degree and differential diagnosis, including pure UC, UCSD, and SqCC, of urothelial tumor.

Data Availability

The data used to support the findings of this study are included within the supplementary information files.

Ethical Approval

Ethical approval was waived by the Local Ethics Committee in view of the retrospective nature of the study.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

Dongshan Chen and Naidong Xing contributed equally to this work. All those who had contributed to the work are listed as coauthors.

Acknowledgments

This work was supported by the Focused Research and Development Program of Shandong Province (Grant no. 2019GSF108255) and the Department of Science Technology of Jinan City (Grant no. 201805030).

Supplementary Materials

The given supplementary material was the data used to support the findings of this study. (Supplementary Materials)

References

Y. Klaile, K. Schlack, M. Boegemann, J. Steinestel, A. J. Schrader, and L.-M. Krabbe, “Variant histology in bladder cancer: how it should change the management in non-muscle invasive and muscle invasive disease?” Translational Andrology and Urology, vol. 5, no. 5, pp. 692–701, 2016.
View at: Publisher Site | Google Scholar
Y. Liu, M. M. Bui, and B. Xu, “Urothelial carcinoma with squamous differentiation is associated with high tumor stage and pelvic lymph-node metastasis,” Cancer Control, vol. 24, no. 1, pp. 78–82, 2017.
View at: Publisher Site | Google Scholar
P. Dahm and J. E. Gschwend, “Malignant non-urothelial neoplasms of the urinary bladder: a review,” European Urology, vol. 44, no. 6, pp. 672–681, 2003.
View at: Publisher Site | Google Scholar
J. B. Aragon-Ching and L. C. Pagliaro, “New developments and challenges in rare genitourinary tumors: non-urothelial bladder cancers and squamous cell cancers of the penis,” American Society of Clinical Oncology Educational Book, vol. 37, pp. 330–336, 2017.
View at: Google Scholar
S. Park, V. E. Reuter, and D. E. Hansel, “Non-urothelial carcinomas of the bladder,” Histopathology, vol. 74, no. 1, pp. 97–111, 2019.
View at: Publisher Site | Google Scholar
J. Li, H.-C. Hsu, J. D. Mountz, and J. G. Allen, “Unmasking fucosylation: from cell adhesion to immune system regulation and diseases,” Cell Chemical Biology, vol. 25, no. 5, pp. 499–512, 2018.
View at: Publisher Site | Google Scholar
Y. Lan, C. Hao, X. Zeng et al., “Serum glycoprotein-derived N- and O-linked glycans as cancer biomarkers,” American Journal of Cancer Research, vol. 6, no. 11, pp. 2390–2415, 2016.
View at: Google Scholar
W. L. Hutchinson, P. J. Johnson, M.-Q. Du, and R. Williams, “Serum and tissue α-l-fucosidase activity in the pre-clinical and clinical stages of hepatocellular carcinoma,” Clinical Science, vol. 81, no. 2, pp. 177–182, 1991.
View at: Publisher Site | Google Scholar
M. Delacadena, J. Fernandez, A. Decarlos, V. Martinezzorzano, E. Gilmartin, and F. Rodriguezberrocal, “Low levels of alpha-L-fucosidase activity in colorectal cancer are due to decreased amounts of the enzymatic protein and are related with Dukes’ stage,” International Journal of Oncology, vol. 9, pp. 747–754, 1996.
View at: Publisher Site | Google Scholar
S. Ishida, K. Kayamori, K. Sakamoto et al., “Alpha-L-fucosidase-1 is a diagnostic marker that distinguishes mucoepidermoid carcinoma from squamous cell carcinoma,” Pathology International, vol. 69, pp. 76–85, 2019.
View at: Publisher Site | Google Scholar
P. E. Clark, “Urothelial carcinoma with squamous differentiation: response to chemotherapy and radiation,” Urologic Oncology: Seminars and Original Investigations, vol. 33, no. 10, pp. 434–436, 2015.
View at: Publisher Site | Google Scholar
P. C. Black, G. A. Brown, and C. P. N. Dinney, “The impact of variant histology on the outcome of bladder cancer treated with curative intent,” Urologic Oncology: Seminars and Original Investigations, vol. 27, no. 1, pp. 3–7, 2009.
View at: Publisher Site | Google Scholar
A. Lopezbeltran and L. Cheng, “Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications,” Human Pathology, vol. 37, no. 11, pp. 1371–1388, 2006.
View at: Publisher Site | Google Scholar
G. Li, J. Yu, H. Song et al., “Squamous differentiation in patients with superficial bladder urothelial carcinoma is associated with high risk of recurrence and poor survival,” BMC Cancer, vol. 17, no. 1, p. 530, 2017.
View at: Publisher Site | Google Scholar
O. N. Gofrit, V. Yutkin, A. Shapiro et al., “The response of variant histology bladder cancer to intravesical immunotherapy compared to conventional cancer,” Frontiers in Oncology, vol. 6, p. 43, 2016.
View at: Publisher Site | Google Scholar
N. Lagwinski, A. Thomas, A. J. Stephenson et al., “Squamous cell carcinoma of the bladder: a clinicopathologic analysis of 45 cases,” The American Journal of Surgical Pathology, vol. 31, no. 12, pp. 1777–1787, 2007.
View at: Publisher Site | Google Scholar
Z. Junna, C. Gongde, X. Jinying, and Z. Xiu, “Serum AFU, 5′-NT and AFP as biomarkers for primary hepatocellular carcinoma diagnosis,” Open Medicine, vol. 12, no. 1, pp. 354–358, 2017.
View at: Publisher Site | Google Scholar
K. S. Lau and J. W. Dennis, “N-Glycans in cancer progression,” Glycobiology, vol. 18, no. 10, pp. 750–760, 2008.
View at: Publisher Site | Google Scholar
S. S. Pinho and C. A. Reis, “Glycosylation in cancer: mechanisms and clinical implications,” Nature Reviews Cancer, vol. 15, no. 9, pp. 540–555, 2015.
View at: Publisher Site | Google Scholar
S. Hakomori, “Glycosylation defining cancer malignancy: new wine in an old bottle,” Proceedings of the National Academy of Sciences, vol. 99, no. 16, pp. 10231–10233, 2002.
View at: Publisher Site | Google Scholar
I. Brockhausen, “Mucin-type O -glycans in human colon and breast cancer: glycodynamics and functions,” EMBO Reports, vol. 7, no. 6, pp. 599–604, 2006.
View at: Publisher Site | Google Scholar
M. Yang, H. Allen, and R. A. DiCioccio, “Pedigree analysis of α-l-fucosidase gene mutations in a fucosidosis family,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, vol. 1182, no. 3, pp. 245–249, 1993.
View at: Publisher Site | Google Scholar
C. Li, J. Qian, and J. S. Lin, “Purification and characterization of α-L-fucosidase from human primary hepatocarcinoma tissue,” World Journal of Gastroenterology, vol. 12, no. 23, pp. 3770–3775, 2006.
View at: Publisher Site | Google Scholar
M. G. Giardina, M. Matarazzo, R. Morante et al., “Serum α-L-fucosidase activity and early detection of hepatocellular carcinoma,” Cancer, vol. 83, no. 12, pp. 2468–2474, 1998.
View at: Publisher Site | Google Scholar
D. Ayude, M. Páez de la Cadena, V. S. Martínez-Zorzano, A. Fernández-Briera, and F. J. Rodríguez-Berrocal, “Preoperative serum alpha-L-fucosidase activity as a prognostic marker in colorectal cancer,” Oncology, vol. 64, no. 1, pp. 36–45, 2003.
View at: Publisher Site | Google Scholar
H. Abdel-Aleem, A. Ahmed, A. M. Sabra, M. Zakhari, M. Soliman, and H. Hamed, “Serum alphal-fucosidase enzyme activity in ovarian and other female genital tract tumors,” International Journal of Gynecology & Obstetrics, vol. 55, no. 3, pp. 273–279, 1996.
View at: Publisher Site | Google Scholar
I. Endreffy, G. Bjørklund, L. Szerafin, S. Chirumbolo, M. A. Urbina, and E. Endreffy, “Plasma alpha-L-fucosidase activity in chronic inflammation and autoimmune disorders in a pediatric cohort of hospitalized patients,” Immunologic Research, vol. 65, no. 5, pp. 1025–1030, 2017.
View at: Publisher Site | Google Scholar
M. Zhang, L. Wang, H. Zhang, J. Cong, and L. Zhang, “Serum α-l-fucosidase activities are significantly increased in patients with preeclampsia,” Progress in Molecular Biology and Translational Science, vol. 162, pp. 349–362, 2019.
View at: Publisher Site | Google Scholar

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Copyright © 2020 Dongshan Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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