A 73-year-old man, who had previously presented with angina and interstitial pneumonia, developed left lower back pain and attended our hospital. Peri–pelvic extravasation of urine was observed with magnetic resonance imaging. Contrast–enhanced computed tomography confirmed a left renal pelvic tumor. The patient’s tumor marker serum levels, such as those for carcinoembryonic antigen, carbohydrate antigen 19–9, and squamous cell carcinoma, were within the normal range. No malignant cells were identified in the patient’s urine cytology. A left nephroureterectomy was subsequently performed with a clinical diagnosis of left pelvic renal cancer.
Left nephroureterectomy specimens were obtained that were originally prepared from 10% buffered formalin–fixed, paraffin–embedded tissue according to our routine hospital procedure. A histopathological examination was performed using hematoxylin and eosin staining. Immunohistochemistry was conducted using an autoimmunostainer (Leica BOND–III system: Leica Biosystems, Newcastle, UK). The antibodies we employed are listed in Table 1.
There was well–circumscribed solid and low–papillary mass in the renal pelvis that measured 42 x 25 mm. The cut surface of the tumor showed a whitish mass with a partially myxoid change (Fig. 1A). Microscope observations revealed that the tumor was mainly located in the renal pelvic mucosa (Fig. 1B). The tumor exhibited two distinct morphological components. The tumor surface comprised a noninvasive urothelial carcinoma, which included a high-grade papillary urothelial carcinoma and a carcinoma in situ (CIS) (Fig. 1C and 1D). Whereas the invasive urothelial carcinoma was composed of cells that were dyscohesive, lacked cell adhesion and were set in a loose myxoid stroma (Fig. 1D and 1E). The transition of CIS and the invasive urothelial carcinoma was seen (Fig. 1D). The invasive tumor cells had an eccentrically placed nucleus and abundant amphophilic to eosinophilic cytoplasm and exhibited a striking morphologic overlap with plasma cells (Fig. 1F). A plasmacytoid urothelial carcinoma was diagnosed based on the morphology findings.
Immunohistochemically, the noninvasive urothelial carcinoma was positive for cytokeratin and E–cadherin, whereas it was negative for vimentin (Fig. 2A–C). CD138 and CD38, which are immunohistochemical markers for plasma cells, showed opposite immunostaining, and this noninvasive urothelial carcinoma was positive for CD138 and negative for CD38 (Fig. 2D and 2E). These cells were also negative for ZEB1 (Fig. 2F). On the other hand, the component of the plasmacytoid urothelial carcinoma was immunoreactive for cytokeratin, suggesting that these findings indicated the characteristics of an epithelium (Fig. 2A). However, E–cadherin was negative, and vimentin, CD138 and CD38 were positive for this component (Fig. 2B–E). In addition, ZEB1 expression was diffuse positive for this component (Fig. 2F). The immunohistochemical results are summarized in Table 2. Taken together, these immunohistochemical findings suggest that the expression of ZEB1 promotes a plasmacytoid transformation by repressing the E–cadherin in plasmacytoid urothelial carcinoma.
Discussion and Conclusions
Our work revealed the following two important suggestions. Increased ZEB1 expression and the loss of E–cadherin expression are associated with the tumorigenesis of a plasmacytoid urothelial carcinoma. CD38 as well as CD138 is a useful immunohistochemical marker for the diagnosis of a plasmacytoid urothelial carcinoma.
First, ZEB1 expression and the loss of E–cadherin expression in an invasive urothelial carcinoma contributed to the plasmacytoid transformation. The mechanism of the plasmacytoid transformation in an invasive urothelial carcinoma is not well documented in the literature. Recently, EMT has provided a new basis for understanding the progression of a carcinoma towards dedifferentiated and more malignant states, and a specific molecular mechanism underlying EMT has been identified . ZEB1 is a key EMT nuclear transcription factor that binds to the E–cadherin promoter E–box region and plays an important role in regulating E–cadherin expression [9, 13]. Furthermore, increased ZEB1 expression and the loss of E–cadherin have been shown to be involved in the transformation from a carcinoma to a sarcomatous component in other cancers . In this case, the plasmacytoid tumor cells were negative for E–cadherin and positive for vimentin and ZEB1, suggesting that ZEB1 might be involved and play an important role in the tumor transformation of a plasmacytoid urothelial carcinoma through the EMT mechanism. In addition, a plasmacytoid urothelial carcinoma has a worse prognosis than a usual infiltrating urothelial carcinoma . The expression of ZEB1 has been reported in various human cancers and increases the resistance of cancer cells to chemotherapy and radiation therapy , indicating that ZEB1 is a transcription factor not only involved in the tumorigenesis of cancers but also in the prognosis for cancer patients. The results of this case suggest that ZEB1 expression in plasmacytoid tumor cells may be associated with a poor prognosis as regards plasmacytoid urothelial carcinomas.
Second, CD38 is an appropriate immunohistochemical marker for confirming a plasmacytoid transformation in a urothelial carcinoma. Several studies have shown that the plasmacytoid tumor cells of a urothelial carcinoma are immunoreactive for CD138 [3–6]. CD138 is a highly sensitive and specific marker for normal and neoplastic plasma cells . However, CD138 expression has also been observed in the urothelial epithelium and in various urothelial carcinoma cells . It has been mentioned that the staining of CD138 might make it difficult when diagnosing plasmacytoid urothelial carcinomas and the other diseases . In this case, CD138 immunostaining could not distinguish between the tumor transformation of the noninvasive urothelial carcinoma and the plasmacytoid component. In contrast, CD38 was positive for plasmacytoid tumor cells and negative for noninvasive urothelial carcinoma cells. Although few studies have reported the use of CD38 to diagnose plasmacytoid urothelial carcinomas, CD38 is one of the most widely used plasma cell markers . Furthermore, to the best our knowledge, CD38 immunoreactivity for carcinoma cells has not been reported. Accordingly, CD38 immunostaining was efficient for confirming the plasmacytoid transformation in urothelial carcinomas.
In conclusion, the results of the present study suggest that ZEB1 is involved in the tumor transformation in plasmacytoid urothelial carcinomas showing CD38 expression. Further investigation is needed to substantiate this finding and determine whether the ZEB1 expression is associated with a poor prognosis for a plasmacytoid urothelial carcinoma.