Elsevier

Human Pathology

Volume 38, Issue 5, May 2007, Pages 741-746
Human Pathology

Original contribution
Muscle-invasive urothelial cell carcinoma of the human bladder: multidirectional differentiation and ability to metastasize

https://doi.org/10.1016/j.humpath.2006.11.001Get rights and content

Summary

Few published studies have addressed the correlation between multidirectional differentiation in muscle-invasive bladder cancer and its ability to metastasize. We demonstrated that histologic differentiation within a single tumor affects lymph node metastasis. We examined cystectomy specimens from 93 bladder tumors and 1085 lymph nodes. In this study, urothelial cell carcinomas (UCCs) with divergent differentiation, excluding pure divergent patterns such as squamous cell carcinoma and adenocarcinoma that tend toward a distinct biologic behavior, were subjected to histopathologic estimation. The positive lymph node ratio increased with the nonconventional differentiation number (NDN) within a tumor from 8.7% for an NDN of 0 (pure conventional UCCs) to 35.5% for an NDN of 2 or higher (mixed conventional and nonconventional [NC] UCCs showing >2 NC patterns). The positive lymph node number (PLN) was more than twice as high for an NDN of 3 or higher as compared with cases with an NDN of 0. Lymph node positivity (LP) was associated with the presence of micropapillary, lymphoma-like, plasmacytoid, giant cell, or clear cell–type tumors, and increasing PLN was associated with the presence of glandular, nested, lymphoma-like, plasmacytoid, or undifferentiated types in the primary tumor. By multivariate analysis, NDN status was determined to be an independent predictor of PLN (P = .032). Tumor stage had impact on LP (P = .002); however, in cases with a PLN of 4 or higher, the NDN became the only predictor of further dissemination (P = .016). No significant tumor grade impact on LP or PLN was found. Our results indicate that NC differentiation in the primary tumor is a good predictor of lymph node dissemination.

Introduction

The T2 to T4 urothelial cell carcinomas (UCCs) of the bladder are considered to belong to a prognostically homogeneous group of tumors with a poor prognosis. Prognosis in muscle-invasive bladder cancer (MIBC) is still only weakly predictable with the use of existing tumor grade and stage estimation systems [1], [2], [3]. The contributions of many investigators to the areas of recurrence, progression, metastases, treatment response, and survival time prediction are still clinically insufficient [4]. Although advances in methodology based on the molecular basis-of-disease approach have provided a better understanding of the neoplastic process in the urinary bladder, a histopathologic evaluation of tumor biology remains the gold standard [5].

Some reports have indicated that several histologic features that are not considered in a routine examination may have a significant prognostic value, such as the type of tumor infiltration (estimated within tumor borders), extension of classic differentiation (as the percentage of all histologically investigated tumor areas), and the tumor nonconventional differentiation number (NDN; ie, the number of all diagnostically important, other than transitional, histologic patterns within a tumor) [6], [7], [8]. As shown in our recent study, patients with MIBC can be stratified prognostically using the NDN [8]. The indicated criteria are based on the biologic properties of invasive UCCs, which tend toward multidirectional differentiation [5], [6], [7], [8], [9]. As described in previous studies, the variant differentiation of bladder cancer affecting prognosis [10], [11], [12], [13], [14], [15], [16] is probably associated with the progression of tumor malignancy. The appearance of divergent differentiation in a tumor indicates its tendency toward malignant progression, whereas the presence of 3 or more nonconventional (NC) types has an unfavorable influence on survival time [8].

Regional lymph node status is a well-known prognostic factor [17]. Both the percentage of positive nodes and the number of removed lymph nodes affecting prognosis are factors. Cases with a positive lymph node ratio (PLR) lower than 20% are prognostically favorable [18], [19]. The surgical procedures intended for the excision of a maximum number of lymph nodes seem to be favorable in patients with negative nodes [20], [21], [22], [23] and in those with positive nodes [24], [25]. However, the patient stratification system based on lymph node status seems to be going through a crisis since the suggestion of the absence of prognostic differences according to the quantity criteria of TNM (N1, N2, N3) was described [18], [25].

The possibility of a prognostically favorable application of adjuvant chemotherapy prompts the search for a method of evaluating the presence of lymph node metastases before or at least during a cystectomy [26]. Can the histologic pattern of a primary tumor be helpful in typing patients with a high risk for positive lymph nodes? We examined whether the multidirectionality and number of NC-type differentiations in MIBC could be useful criteria in the assessment of lymph node positivity (LP).

Section snippets

Material and methods

We examined 101 urinary bladder specimens, all with excised lymph nodes, that were obtained from patients who underwent a cystectomy for a primary UCC between 2000 and 2006. Before the cystectomy, none of the patients had received radiotherapy or chemotherapy. Patients with a diagnosis of invasive cancer staged between T2 and T4 as well as with conventional (transitional) or NC (squamous, glandular [but not pure squamous or glandular as these tend to have different biologic behaviors], and

Results

Within the entire set of tumors, the conventional and 11 NC types of differentiation were diagnostically important. The diagnosis of a conventional differentiation and that of an NC differentiation were established in 19% (18/93) and 81% (75/93) of the tumors, respectively (Table 1). All 16 tumors with a giant cell pattern had only scattered giant cells and were not the osteoclast-rich undifferentiated carcinomas as described by Baydar et al [27]. In 34 (45%) of the NC tumors, more than one

Discussion

The distribution of conventional and NC patterns in UCCs in this work was similar to that in our recent study [8]. In a review of the recent literature, we only found information about the incidence of squamous (21%) and glandular (6%) patterns in urothelial bladder cancer [30]. Other histologic types were described exclusively in only short series [9]. In our set of cases, 19% of the MIBCs retained a pure classic pattern; the rest developed a more or less nonclassic histologic pattern. The

References (30)

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