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ORIGINAL ARTICLE Table of Contents  
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Correlations of tumor depth and width with lymphovascular invasion in non-muscle invasive bladder cancer


1 Department of Urology, Hasan Sadikin Academic Medical Center, Universitas Padjajaran, Bandung, Indonesia
2 Department of Anatomy Pathology, Hasan Sadikin Academic Medical Center, Universitas Padjajaran Bandung, Indonesia

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Date of Submission28-Jul-2021
Date of Decision07-Oct-2021
Date of Acceptance01-Nov-2021
Date of Web Publication29-Mar-2022
 

  Abstract 


Purpose: Around 75% of all bladder cancers are classified into nonmuscle invasive bladder cancer (NMIBC). The NMIBC's high recurrence and progressivity rate are most commonly found in tumors invading the lamina propria (LP), classified as staged pT1 when it extended to the LP with a heterogeneous recurrence and progression. This study aimed to correlate the measurement of tumor depth and width to lymphovascular invasion (LVI) in NMIBC. Materials and Methods: A 5-year retrospective analytical study (2015–2019) was conducted in a tertiary hospital in Indonesia. We reassessed and analyzed the tumor depth and width of 64 patients with pT1 bladder cancer based on histopathological reports and analyzed the correlation of tumors and LVI. The depth was reassessed by measuring the transitional urothelium with the LP as an initial marking point, up to the tumor's edge in the LP, and tumor's width by measuring the largest width of one tumor focus in the LP, along with the presence of LVI by histopathological exams. Data were analyzed using the Mann − Whitney test. Results: The participants were 64 patients with pT1 bladder cancer. The mean tumor pT1 invasion depth was 2.03 ± 0.918 mm. The non-LVI group's mean tumor invasion depth was 1.72 ± 0.721 mm, whereas the LVI group was 2.21 ± 0.980 mm. The tumor invasion depth was a significant factor for LVI, whereas the tumor maximum diameter was not. Conclusion: The tumor invasion's depth was significantly associated with the LVI. The pT1 tumor invasion depth measurement might serve as a predictive variable of tumor recurrence and progressivity.

Keywords: Bladder cancer, lymphovascular invasion, nonmuscle invasive bladder cancer, tumor depth


How to cite this URL:
Tampubolon KA, Pramod SV, Safriadi F, Fitriana MN, Hernowo BS. Correlations of tumor depth and width with lymphovascular invasion in non-muscle invasive bladder cancer. Urol Sci [Epub ahead of print] [cited 2022 Jun 27]. Available from: https://www.e-urol-sci.com/preprintarticle.asp?id=341249





  Introduction Top


With an annual incidence rate of 430,000 cases, carcinoma of the bladder is known as the eleventh most diagnosed cancer worldwide but ranks the eighth among male populations.[1] Bladder carcinoma ranks number 13th in the mortality rate among other cancers.[1] The standardized incidence rate age (per 100,000 person/years) is 9.0 for men and 2.2 for women worldwide.[1] The age-standardized incidence rate is 19.1 for men and 4.0 for women in the European Union, with Belgium leading the highest age-standardized incidence rate (31 in men and 6.2 in women), and the least in Finland (18.1 in men and 4.3 in women).[1]

According to the 2018 GLOBOCAN data, the incidence of bladder cancer in Indonesia ranks the 14th worldwide with 6716 new cases (1.9%), though the precise incidence rate is hard to determine, especially the nonmuscle invasive bladder cancer (NMIBC) type.[2] Based on previous data from Hasan Sadikin Academic Medical Center, a total of 464 patients were diagnosed with bladder cancer, of which 36 (7.76%) cases were NMIBC.[3]

Around 75% of all bladder cancer are classified as NMIBC upon diagnosis (defined as a T1, Ta, or Tis stage tumor), while the rest are classified as muscle invasive bladder cancer (MIBC).[4] Stage pT1 bladder cancer is when the invading tumor has extended to the lamina propria (LP) with a heterogeneous recurrence and progression. Up to 50%–78% of the pT1 tumors will involve some progression, resulting in a 5-year mortality rate of 10%–34% pT1 patients.[4],[5]

The incidence and mortality rates of bladder cancer vary greatly across different countries due to the differences in risk factors, early detection and diagnostic applications, and the availability of treatments.[5] However, the variations are partly caused by the different research methodologies and collected data quality.[5]

The pathophysiology underlying the aggressive nature of T1 bladder cancer remains unexplained in the present time, but several hypotheses of the mechanisms were suggested by recent studies.[6] The accurate diagnosis and staging of the T1 stage bladder tumor remain difficult to be determined through histopathological examinations due to the possibilities of failure in sampling the invasive segment of the muscular architecture, lack of tissues sampled, or tissue damages due to cauterization.[5],[6] Furthermore, the biological mechanism where recurrence and or the development of aggressive cancer is triggered upon imperfect resection remained.[7]

The NMBIC's high recurrence and progressivity rate are most commonly found in tumors invading the LP.[8] The invasion depth is known to correlate with the tumor's increasing progressivity. A deeper LP invasion will increase cancer's risk of invading the muscular tunic. Furthermore, the width of the tumor invasion is also correlated with an increased recurrence and progressivity of the NMBIC.[8] Lymphovascular invasion (LVI) is also a determining factor in the progressivity of bladder cancer.[8] Our research aimed to study the correlation of the tumor invasion toward the involvement of blood vessels.

Numerous efforts in the past have been made to identify the subsets of T1 carcinoma present with high recurrence and progression risks.[8],[9] At present, parameters have been used to predict the prognosis of pT1 patients, i.e., the early stages, tumor grade, the quantity of tumors, and the presence of carcinoma in situ, but these parameters are unable to accurately predict the patients' prognosis, especially in patients with pT1 tumors.[9]

Some studies have attempted to classify a sub-staging of pT1, generally by assessing the image of the muscular mucosa.[8] Unfortunately, the muscular mucosa was not always found in histopathological examinations due to corrupted tissue preparation or from misinformation from the pathologists.[9] Until the present day, no sub-staging of pT1 tumor is recommended.[7],[8]

This study aimed to learn the characteristics and description of the histopathological results of pT1 bladder cancer based on the tumor depth and width along with their correlation with LVI. Our study is the first study conducted in Indonesia regarding this subject.


  Materials and Methods Top


A 5-year retrospective analytical study (2015–2019) was conducted at Hasan Sadikin Academic Medical Center, a tertiary hospital in Indonesia. We reassessed and analyzed the tumor depth and width of 64 patients with pT1 bladder cancer based on histopathological examination and analyzed the correlation of tumors and LVI. The specimen/preparation is assessed for their depth and width, along with the presence of LVI. Every preparation was assessed by one of the many experienced professional pathologists.

The inclusion criteria of this study were all patients diagnosed with pT1 bladder cancer based on eligible histopathological results of the preparations from 2015 to 2019. The exclusion criteria were all patients with a history of previous bladder cancer and patients with a history of TURB/bladder operation. This study was approved by our Institutional Review Board of Hasan Sadikin Academic Medical Center (no. LB02.01/X.6.5/64/2021) and informed consent was obtained from the subjects.

The recorded demographic characteristics of the patients were age, gender, tumor count, depth of tumor invasion, tumor diameter, and LVI. The invasion depth of the tumor was measured in millimeters (mm) by measuring from the transitional urothelium with the LP as an initial marking point, up to the edge of the tumor in the LP [Figure 1]. The tumor diameter was measured in millimeters (mm) by measuring the largest tumor width of one tumor focus in the LP [Figure 1]. LVI was determined by the presence of tumor invasion in blood vessels by histopathological examinations [Figure 2]. The description of tumor depth, diameter, and their correlation with the invasion of blood vessels was obtained by these data.
Figure 1: (a) Tumor's invasion depth (1.64 mm); Tumor's invasion width (1.27 mm) in lamina propria of bladder. (b) Tumor's invasion depth (2.37 mm); Tumor's invasion width (2.75mm) in lamina propria of the bladder. LP: Lamina propria

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Figure 2: Lymphovascular involvement in Lamina Propria

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Statistical comparison between the groups was conducted using the Mann − Whitney test. Statistical analysis was performed using the IBM SPSS Statistics software (IBM Corp., NY, USA) version 25. P < 0.05 was considered statistically significant.


  Results Top


The characteristics of the participants were described [Table 1] detailing the age, gender, single/multiple tumors, tumor depth and diameter, and the LVI. The study included 64 patients diagnosed with pT1 bladder cancer as participants. The mean age of participants was 51.22 ± 4.296. 78.1% of participants were male and 21.9% were female. Multiple tumors were discovered in 85.9% of cases. All of the participants are in high grade pathological grade.
Table 1: Study subjects' characteristics

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The mean tumor invasion depth was 2.03 ± 0.918 mm. The mean tumor diameter was 2.36 ± 1.092 mm with 10 (15.6%) <1 mm deep, 13 (20.3%) between 1–2 mm deep, and 41 (64.1%) >2 mm deep. LVI was found in 62.5% of all cases [Table 2].
Table 2: Comparison of the lymphovascular invasion group's characteristics

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[Table 3] describes a comparison of the tumor invasion depth among the no blood vessel invasion and the present blood vessel invasion groups. The mean invasion depth of the no blood vessel invasion group was 1.72 ± 0.721 mm. The mean invasion depth of the present blood vessel invasion group was 2.21 ± 0.980 mm. A significant relationship between the tumor invasion depth toward LVI was found (P < 0.05).
Table 3: The comparison of invasion depth of the lymphovascular group

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[Table 4] presents the comparison of tumor invasion diameter in the no blood vessel invasion group and the present blood vessel invasion groups. The mean invasion diameter of the no blood vessel invasion group was 2.13 ± 1.027 mm. The mean invasion diameter of the present blood vessel invasion group was 2.49 ± 1.120 mm. No significant relationship between the tumor invasion diameter toward the LVI was found (P = 0.208), and no significant relationship was found in the diameter size category, in the <1 mm nor the >2 mm (P = 0.846).
Table 4: The comparison of maximum tumor diameter of the lymphovascular group

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  Discussion Top


pT1 stage bladder cancer is classified as noninvasive bladder cancer, but tumor invasion to the LP of the bladder comes with a high rate of recurrence and progressivity.[7],[8],[10] It is estimated that around 15%–70% of newly diagnosed patients with pT1 bladder cancer will suffer from a recurrence in 1 year after the diagnosis was made.[2] 50% of newly diagnosed pT1 bladder cancer patients will suffer from progressivity in 5 years.[10] This high rate of recurrence and progressivity calls for a holistic approach in monitoring and the delivery of treatment.[11] Some potential factors to determine the risk of pT1 recurrence and progressivity have been explored, but currently, none pass as a standard for assessment.[12] This research explored the relationship between pT1 tumor invasion depth and diameter toward LVI.

Metastasis is a complex process.[13] Malignant cells of the primary tumor must first exit the primary tumor to invade surrounding tissues, and later, the lymphatic or vascular circulation.[13] Regarding this, attempts were made to identify the prognosis and LVI of malignancies. Previous studies have shown a 28% LVI rate in T1 bladder cancer cases.[14] However, our study has uncovered a strikingly higher proportion of 62.5% histologically confirmed LVI cases, which to our knowledge is the highest value reported to date. In our series, the high prevalence of LVI in T1 bladder cancer cases may be due to the nature of our cancer center being a tertiary referral center, the highest referral level in the National Health-care System designed to treat more complex cases, which were unable to be solved in lower referral levels. Thus, the proportion of aggressive bladder tumors could differ greatly from normally observed. Another more likely reason for this higher prevalence is the immense detail of LVI evaluations, as we implemented a protocol for our surgeons and pathologists to routinely evaluate the LVI. Furthermore, multiple serial sections were added in patients suspected of having aggressive tumors.

Lopez and Angulo have conducted a multivariate analysis revealing that LVI in TURBT surgical specimens of T1 bladder cancer significantly correlates with the survival of patients and that high-grade neoplasms larger than 5 cm without papillary configuration were associated with vascular invasion.[15] However, their study differs from ours as they limit their measurements only macroscopically, without any microscopic assessment regarding tumor invasion.[15]

Brimo et al. have found that the invasion depth and tumor diameter can serve as markers in determining the prognosis of pT1 bladder tumors.[8] Their average invasion depth and tumor diameter were 1.1 mm and 2.2 mm, respectively.[8] They concluded that invasion depth of 2 mm and 3 mm were significantly correlated with the recurrence and progressivity of pT1 bladder cancer.[8] The average invasion depth and tumor diameter of our study were 2.03 mm and 2.36 mm, respectively. One determining factor is the variation of the LP thickness and anatomical location (in the bladder) of each individual. Cheng et al. have reported that the LP thickness is 1.4 mm.[10] This was turned down by both our study and a study by Brimo et al., where we found various LP thickness, which could exceed 4 mm.

Cheng et al. conducted a study to classify the sub staging of pT1 by conducting a measurement of the tumor invasion of the LP.[10] The result of their study was that a tumor invasion of at least 1.5 mm was correlated with a higher tumor grading and staging level.[10] Other studies by Brimo et al. have concluded that the invasion depth of >2 mm is correlated with the recurrence, and that >3 mm is correlated with progressivity.[8] However, up to the writing of this article, no sub staging classification of the pT1 tumor exists.

LVI remains an important component in histopathological examinations as a prognostic factor of bladder cancer.[2],[16] Several studies have discovered significant correlations between LVIs with tumor grade, stage, metastasis to lymph nodes, and the survival rates of bladder cancer.[17],[18] However, no study has assessed the correlation of LVI with the invasion depth and pT1 bladder tumor diameter. In this research, we discovered that the invasion depth was correlated with tumor invasion of the blood and lymph vessels. We discovered that a tumor depth of 2.21 mm was significantly correlated with LVI. We have also discovered that the risk of tumor invasion to the blood vessels would proportionally increase along with a higher depth of invasion. This is similar to the results of the study done by Cho et al., which stated that LVI can serve as an independent prognostic factor in bladder cancer.[13] However, they did not measure the depth of invasion as we did in our study.[13] Therefore, our study is the first to seek the relationship of both factors.

The study done by Cho et al. discovered that LVI is significantly related to the recurrence of newly diagnosed pT1 bladder cancer and could serve as a predictive factor for the progressivity and metastasis of bladder cancer.[13] They suggested that the LVI be applied as a standard assessment in pathology examinations.[13] This result is consistent with our research, where the invasion depth correlates significantly with LVI. A deeper tumor invasion of the LP will increase the risk of LVI proportionately.

Based on our findings, we recommend that the tumor depth and the involvement of the LVI be assessed in every future pT1 bladder cancer pathology report. We conducted no follow-up to monitor for the recurrence and progressivity of study subjects. This remained the limitation of our study.


  Conclusion Top


pT1 bladder cancer varies in tumor invasion depth. The depth of tumor invasion is significantly associated with the invasion of blood vessels LVI. We have discovered a mean pT1 tumor invasion of 2.21 mm. In future, the measurement of pT1 tumor invasion depth may serve as a predictive variable of tumor recurrence and progressivity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Brimo F, Wu C, Zeizafoun N, Tanguay S, Aprikian A, Mansure JJ, et al. Prognostic factors in T1 bladder urothelial carcinoma: The value of recording millimetric depth of invasion, diameter of invasive carcinoma, and muscularis mucosa invasion. Hum Pathol 2013;44:95-102.  Back to cited text no. 8
    
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Segal R, Yafi FA, Brimo F, Tanguay S, Aprikian A, Kassouf W. Prognostic factors and outcome in patients with T1 high-grade bladder cancer: Can we identify patients for early cystectomy? BJU Int 2012;109:1026-30.  Back to cited text no. 9
    
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Cheng L, Neumann RM, Scherer BG, Weaver AL, Leibovich BC, Nehra A, et al. Tumor size predicts the survival of patients with pathologic stage T2 bladder carcinoma: A critical evaluation of the depth of muscle invasion. Cancer 1999;85:2638-47.  Back to cited text no. 10
    
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Leissner J, Koeppen C, Wolf HK. Prognostic significance of vascular and perineural invasion in urothelial bladder cancer treated with radical cystectomy. J Urol 2003;169:955-60.  Back to cited text no. 11
    
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Lotan Y, Gupta A, Shariat SF, Palapattu GS, Vazina A, Karakiewicz PI, et al. Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 2005;23:6533-9.  Back to cited text no. 12
    
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Cho KS, Seo HK, Joung JY, Park WS, Ro JY, Han KS, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009;182:2625-30.  Back to cited text no. 13
    
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Cheng L, Weaver AL, Neumann RM, Scherer BG, Bostwick DG. Substaging of T1 bladder carcinoma based on the depth of invasion as measured by micrometer: A new proposal. Cancer 1999;86:1035-43.  Back to cited text no. 14
    
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Lopez JI, Angulo JC. The prognostic significance of vascular invasion in stage T1 bladder cancer. Histopathology 1995;27:27-33.  Back to cited text no. 15
    
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Correspondence Address:
Sawkar Vijay Pramod,
Department of Urology, Hasan Sadikin Academic Medical Center, Jl. Pasteur 38, Bandung 40161
Indonesia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_112_21



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