PTU - Polskie Towarzystwo Urologiczne

Usefulness of histological homogeneity estimation of muscle-invasive urinary bladder cancer in an individual prognosis: a mapping study
Artykuł opublikowany w Urologii Polskiej 2006/59/3.


Wojciech Jóźwicki 1, Jan Domaniewski 1, Zdzisław Skok 1, Zbigniew Wolski 2, Ewa Domanowska 1, Grażyna Jóźwicka 1
1 Katedra i Zakład Patomorfologii Klinicznej Collegium Medicum im. L. Rydygiera w Bydgoszczy, Uniwersytetu Mikołaja Kopernika w Toruniu
2 Katedra i Klinika Urologii Collegium Medicum im. L. Rydygiera w Bydgoszczy, Uniwersytetu Mikołaja Kopernika w Toruniu

słowa kluczowe

rak pęcherza, cystektomia, różnicowanie klasyczne, różnicowanie nieklasyczne, biologia guza, biologiczna stabilnoœść guza, rokowanie


Objectives. To examine the histological homogeneity of the muscle invasive urothelial cell carcinoma of the bladder, with conventional and nonconventional (eg, squamous, glandular, or variants) differentiation, to asses its influence on prognosis.
Material and methods. With organ mapping we, investigated 38 cystectomy specimens. Each entire bladder was cut into 88 slices according to an identical topographic scheme. From all the bladder slices, only 1231 slices that included tumor were chosen for histological study. We examined the diagnostic significance, extension and number of histological differentiation types.
Results. The extension of nonconventional differentiation, with any proportion of histological type, had an unfavourable impact on survival time. The number of nonconventional differentiation types increases in the presence of a sarcomatoid, an undifferentiated, a nested or a micropapillary pattern. The increased number of differentiation types had an unfavourable influence on survival time. Patients with a more than 80% classic urothelial cell carcinoma pattern had a favourable prognosis, which increases further with increasing percentage of this differentiation type.
Conclusions. Muscle-invasive urinary bladder cancers are not a homogenous group of tumors. Our results suggest that a precise assessment of the extension and number of histological differentiation types may be an individual prognostic factor. Conventional differentiation with at least 80% extension seems to be prognostically favourable. Nonconventional differentiation, especially with greater extension and a greater number of types, could imply a worse prognosis.

„Reprinted from: UROLOGY Vol.66, Wojciech Jóźwicki, Jan Domaniewski, Zdzisław Skok, Zbigniew Wolski,Ewa Domanowska, Grażyna Jóźwicka: Usefulness of histological homogeneity estimation of muscle-invasive urinary bladder cancer in an individual prognosis: a mapping study, Pages No.1122-1126, Copyright 2005, with permission from Elsevier.”

The investigation into urinary bladder cancer is dominated by the search for, and identification of, factors of tumor induction, promotion and progression, which may influence the clinical course and prognosis. The categorization of lamina propria invasion depth may prove a helpful prognostic factor in Stage T1 tumors [1-3]. However, in muscle-invasive cancers, the present TNM and histological grading systems are diagnostically insufficient [4]. The clinical course of these cancers varies, and an individual prognosis is only weakly predictable [5-7].

A biological characteristic of bladder cancer is the ability to differentiate histologically. This differentiation was used as a criterion to distinguish 12 histological subtypes and variants of invasive urothelial cell carcinoma (UCC) [8]. Previous reports have demonstrated that cases with sarcomatoid, nested, micropapillary, lymphoepithelial-like, and, probably lymphoid differentiation have a worse prognosis [9-14]. If, with an occurrence of different histological differentiation types the prognosis changes, it can not be excluded that the new cancer cell phenotype is an expression of a new cancer malignancy. We decided to examine, using organ mapping, whether the diversity of subtypes and variants of muscle invasive bladder cancer may be valuable as a prognostic factor.

Material and methods

We examined 38 urinary bladder specimens obtained from cystectomy for UCC collected from January 1996 to December 1998. Before cystectomy, none of the patients had received either radiotherapy or chemotherapy. The selection criteria for all the patients were invasive cancer graded histologically at Stage T2-T4 and the presence of conventional (transitional) or nonconventional (squamous, glandular, and variant) differentiation. The average patient age was 65.5 years and the male/female ratio was 5.33: 1. An autopsy was performed only in patients who died in hospital. The dates and causes of death of the remaining patients were determined according to clinical data, follow-up observations, and Registry Office data.

Within 20-60 minutes after removal from the body, the urinary bladder specimens were immediately transported to a biopsy room, where they were opened through the urethra along the midline of the anterior wall, and, after being pinned on a corkboard, they were soaked in 10% buffered formalin. The entire bladder was cut into 88 slices according to an identical and repeatable topographic scheme. Each slice was embedded in paraffin, cut into 5-ěm-thick sections and stained with hematoxylin-eosin. Of all the 3344 slices, only those with cancer (n=1231) were chosen for additional histological examination. In each section, two elements were evaluated: the type of differentiation according to World Health Organization histological classification [8], and the percentage of each type of differentiation using a subjective method of the succeeding approximations, dividing the microscopic view of the cancer in each entire section into successive halves, up to fourth division inclusive, with a method accuracy of approximately 6.5%. The number of nonconventional differentiation types was also noted. Each of these was considered diagnostically important if they were in at least 6.5% of tumor area of the section. Subsequently, conventional differentiation was considered diagnostically important if it covered 93.5%. In the case of presence of several differentiations per section complying with the requirements described above, all were considered diagnostically important. The criteria excluded the coexistence of diagnostic importance of conventional and nonconventional differentiation in the same section. The data from each section (histological type, diagnostic importance and a number of nonconventional differentiation types) were recorded separately in appropriate forms. The extension of any histological differentiation type was marked in the tumor as a number or percentage of sections with diagnostic importance. In our study, the term „survival” was always used to mean „disease-free survival”. Data sorting and the initial calculations were performed with a licensed version of Microsoft Office 2003. The means, correlations and survival statistics were performed with a licensed version of StatSoft (1997) STATISTICA for Windows. A P value less then 0.05 was considered to be statistically significant.


In the entire set of specimens, the conventional differentiation type and 10 nonconventional differentiation types were diagnostically important (Table I). In 72 sections of the sample (5.8%), the diagnostic importance of more than one nonconventional differentiation type was established. The tumor extension of conventional differentiation greater than 80% correlated significantly with survival time. The survival curves show the different prognosis for the two groups (Fig. 1). Of all the nonconventional types, only squamous extension alone correlated negatively with survival time (Table II). Extension of the remaining types correlated with survival time only with the presence of the squamous type (Table II). We observed a constant tendency for the strength of this correlation to increase as the number of other nonconventional types (with the exception of microcystic one) increased in association with the squamous type (Table II). The strongest survival dependence of extension of the nonconventional pattern was composed of the squamous type with one or more of the following: nested, micropapillary, lymphoid, and sarcomatoid. The number of nonconventional differentiation types strongly depended on presence of sarcomatoid, undifferentiated (r=0.51), and nested or micropapillary types (r=0.48). Also, the survival rate depended on the number of nonconventional differentiation types in the entire group of patients (Fig. 2). In the entire set of cases, we also found a negative correlation between the number of nonconventional differentiation types and the presence of conventional pattern in tumor (Fig. 3).


The extension of squamous and glandular differentiation (17% and 3.2%, respectively) in our study is comparable with another report [15]. However, in our examinations, the percentage of tumors with diagnostically important squamous differentiation was more than double (Table I). The difference might have resulted from the improved accuracy of the method used. Our results better reflect the real presence of squamous and glandular differentiation in UCC. To our knowledge, no statistical elaboration concerning the frequency of other types of nonconventional differentiation has been done. The total percentage of the nonconventional pattern was 43.9% of all samples (Table I). A varied accumulation of genetic changes in UCC cells responsible for the occurrence of the sarcomatoid component has been previously described [16]. If we assume that the nonconventional pattern of bladder UCC derives from genetic changes, its extension, evaluated histopathologically, may be a range indicator of these changes. According to Koss [17], „bladder cancer is not a local disease but, in many patients at least, a local manifestation of a diffuse abnormality of the urothelium”. Perhaps the extension of nonconventional differentiation is expression of a similar tendency in the neoplastic urothelium. It can not be excluded that the large extension of this pattern reflects a range of genetic changes typical for muscle invasive cancer. Also, an increased number of histological types in these tumors may indicate their instable biology. To date, no reports concerning the subject have been published. The results of our study suggest that the existence of a threshold of conventional extension in the tumor has a decisive prognostic implication. In the group with a conventional pattern of more than 80%, its increasing extension, ranging from 80% to 100%, remained prognostically favourable (Fig. 1). Other than our study, this has not been evaluated in Stage T2-T4 bladder cancer. We observed a decrease in conventional extension with an increasing number of nonconventional differentiation types (Fig. 3). It could not be excluded that in the case of conventional extension of less than 80%, nonconventional differentiation may indicate an unfavourable prognosis. To date, this possibility has not being investigated. Of all estimated nonconventional differentiation types, only squamous extension was an independent unfavourable survival factor. This observation may be the result of both the greater frequency of squamous differentiation in bladder cancer [15] and the small number of our cases. That latter point is highlighted in that the strength of the dependence increased in association with other nonconventional types (Table II). Our results suggest that histological evaluation of T2-T4 cancer specimens may be a valuable source of additional information about the biological potential if the complexity of the estimation is allowed for. First, it was found that the presence of a single type of nonconventional differentiation, other than the squamous, did not influence survival. Second, the influence, or an increase of its strength, appears in compositions of nonconventional types (Table II). Third, we demonstrated that an increased number of nonconventional types in a tumor implies a worse prognosis (Fig. 2). These observations speak in favor of the greater value of joint estimation of all differentiation types as a single „nonconventional” type, in contrast to a diagnostic tumor classification as a single variant. We found no discussion of this subject in published studies we reviewed. To date, the search for finding a reference standard prognostic factor in UCC of bladder has been difficult. To recognize the true biological potential of urinary bladder cancers, it is necessary to identify a variety of potential prognostic markers, especially because of insufficiency of the grade and stage estimation in providing a precise prediction of the behaviour of most bladder cancer [4]. The histological malignancy in a nonconventional component also may not reflect its biological potential [18]. Thus, among others, the additional assessment of biological malignancy of Stage T2-T4 cancers according to a model of invasiveness has been previously proposed [19]. We found that extension and multidirectionality of histological differentiation in UCC of the bladder is a valuable predictor of prognosis. With regard to such circumstances as high grade, deep infiltration of the bladder wall, decreased percentage of conventional component and a decrease in survival time, each of nonconventional differentiation type should be treated as a probable progression indicator in muscle-invasive UCC of the bladder. It could not be excluded that with an increase of biological malignancy of a tumor, a tendency for nonconventional differentiation arises.


Stage T2-T4 UCC of the bladder is not a homogeneous group of neoplasms. A detailed histopathological examination shows the possibility of prognostic stratification within this group of patients. An estimation of the histological pattern of UCC, conventional, as well as nonconventional (type, extension, and number of histological lines of differentiation), may be a helpful prognostic criterion. A conventional component of UCC with more than 80% extension seems to be prognostically favourable. It is advisable to take into consideration all types of nonconventional differentiation because this may have greater prognostic value than classification of the tumor as a single type. A nonconventional part of the tumor, especially with greater extension and a higher number of differentiation lines, may imply a worse prognosis. Additional investigation is needed to define the prognostic rules and to confirm these results in a larger sample.

Acknowledgements: To Marco Baralle, Ph. D., for English revision of the manuscript; and to Zbigniew Wlodarczyk, Professor, and Marzena Lewandowska, Ph. D., for their support and encouragement.

Reprinted from: UROLOGY Vol. 66, Wojciech Jóźwicki, Jan Domaniewski, Zdzisław Skok, Zbigniew Wolski, Ewa Domanowska, Grażyna Jóźwicka: Usefulness of histological homogeneity estimation of muscle-invasive urinary bladder cancer in an individual prognosis: a mapping study, Pages No. 1122-1126, Copyright 2005, with permission from Elsevier.


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adres autorów

Wojciech Jóźwicki
Katedra i Zakład Patomorfologii Klinicznej Collegium Medicum
ul. M. Skłodowskiej-Curie 9
85-094 Bydgoszcz
tel. (052) 585 42 05