Inverted variant of urothelial carcinoma of the urinary bladder: a report of three cases and a proposal for a new clinicopathologic entity

Abstract

Inverted urothelial carcinoma (UC) without papillary areas is very rare; only 31 cases of three papers have been reported. The author herein reports three additional cases, and proposes the term “inverted variant” (IV) of UC. The materials were 3 cases of IV of UC, 5 cases of inverted papilloma (IP), and two cases of nested variant (NV) of UC. The three cases of IV of UC consisted of 56-year-old woman, 63-year-old man, and 78-year-old man. Presenting symptoms were hematuria in all cases. The cystoscopic findings were elevated tumors without papillary proliferations in all cases. The treatment was transurethral tumor resection (TUR-BT) in all cases. The sizes was 0.6 cm, 0.5 cm, and 3 cm. Microscopically, IV of UC showed inverted growth of atypical cells without papillary proliferations. Compared to IP, the inverted growth pattern was similar, but cytological atypia and thick trabeculae were noted in IV of UP while they were absent in IP. Compared to NV of UC, the growth pattern is different; NV of UC showed nested and vague tubular pattern. The cellular atypia is more pronounced in IV of UC than NV of UC. Immunohistochemically, p53 expression was seen in all the cases of IV of UC and in all the cases of NV of UC, while p53 expression was negative in all the cases of IP. Ki-67 labeling index was 25, 30 and 40% in IV of UC, 15 and 30% in NV of UC, and 3, 5, 6, 7, 9% in IP. Invasive features were seen in 1 case of IV of UC and 2 cases of NV of UC. In all cases of IV of UC, IP, and NV of UC, the TUR-BT, but one case of IV of UC, showed no recurrence after TUR-BT, while one case of IV of UC showed a recurrence. In conclusion, the IV and UC were structurally and cytologically very different from the NV of UC. The IV of UC was structurally similar to IP, but cellular atypia and thickened trabeculae were seen in IV and UC. p53 expression and Ki-67 labeling status were entirely different between in IV of UC and IP. The author proposes the term of IV of UC as a new clinicopathological entity.

Introduction

Most of the urinary bladder malignancies are urothelial carcinoma (UC). The urothelial carcinoma may show variable histologies, although most of them are papillary UC. In WHO blue book [1], the variants of UC include infiltrating UC squamous differentiation, infiltrating UC with glandular differentiation, nested variant (NV), microcystic variant, micropapillary variant, lymphoepithelioma-like carcinoma, lymphoma-like variant, plasmacytoid variant, sarcomatoid variant, UC with giant cells, UC with trophoblastic differentiation, clear cell variant, lipid cell variant, and undifferentiated carcinoma. However, inverted variant (IV) of UC is not listed in the WHO blue book. However, to the best of the author’s knowledge, 31 cases of UC with an inverted growth and without papillary areas have been reported in three papers [2-4]. The author herein reports 3 cases of UC composed only of inverted tumor growth without papillary areas, and propose the term of “inverted variant” (IV) of UC as a clinicopathologic entity. As controls, 5 cases of inverted papilloma (IP) and 2 cases of NV of UC were used.

Materials and methods

The author corrected 3 cases of IV of UC, 5 cases of IP, and 2 cases of NV of UC from the recent 13 years files of our laboratory. Clinicopathologic features in these 10 cases were investigated. An immunohistochemical study of p53 and Ki-67 was performed.

Results

The results are shown in Table 1. The age and gender are shown in Table 1. The initial symptom was hematuria in all cases except for one case of IP whose symptom was dysuria. All cases were subjected to transurethral endoscopy and transurethral resection of bladder tumor (TUR-BT). The endoscopic appearance was elevated lesion in 9 cases and polypoid in 1 case. The size was 0.5, 0.6 and 3 cm in IV of UC, 0.7, 0.7, 0.9, 1.2 and 3.5 cm in IP, and 2.0 and 3.2 cm in NV of UC. Papillary features were absent in all cases. Histologically, the IV of UC and IP showed inverted papillary growth of urothelial epithelium. Figure 1 shows low power view of the IV of UC (Figure 1A) and IP (Figure 1B), which is useful for the comparison. The trabeculae of inverted growth were thick in IV of UC, but were relatively thin in IP. Von-Brunn’s nest-like and cystitis glandularis-like features were seen in 2/5 of IP, while they were not seen in IV of UC. The NV of UC showed nested or microglandular patterns dissimilar to IV of UC and IP. Submucosal invasion (pTa) was seen in 1/3 of the IV of UC and in all cases (2/2) of the NV of UC. No apparent lymphovascular permeation was seen in all cases. Higher magnification showed that the cells of IV of UC had cellular atypia such as nuclear hyperchromasia, high cellularity, increased nucleocytoplasmic ratio, nucleoli, scattered mitotic figures, and thickened cell nests (Figure 2A), while cells of IP showed little or none cellular atypia and cells nests were not thickened (Figure 2B). The NV of UC shows mild cellular atypia. An immunohistochemical study was performed with the use of Dako’s envision method, as previously described [5,6]. Immunohistochemically, p53 expression was seen in all cases of the IV of UC (Figure 3A) and the NV of UC, while it was consistently negative in the IP (Figure 3B). Ki-67 labeling index was high in IV of UC (Figure 4A) and NV of UC, while Ki-67 labeling was very low in IP (Figure 4B) (Table 1). The treatment of choice was TUR-BT in all cases. The outcome was good in all cases except for one case of IV of UC which showed recurrence after 9 months of the TUR-BT. Nine patients were now alive, while one patient with NV of UC died of acute myocardial infarction.

Table 1.

Clinicopathologic features

	Inverted variant of Urothelial carcinoma			Inverted papilloma					Nested variant of urothelial carcinoma
Case No.	1	2	3	1	2	3	4	5	1	2
Age (years)	56	63	78	60	61	61	35	54	78	80
Gender	M	F	M	M	F	M	F	M	F	M
Symptons	HU	HU	HU	HU	HU	HU	DU	HU	HU	HU
Gross features	E	E	E	E	E	P	E	E	E	E
Size	0.5 cm	0.6 cm	3 cm	0.9 cm	0.7 cm	1.2 cm	0.7 cm	3.5 cm	2.0 cm	3.2 cm
Papillary structure	-	-	-	-	-	-	-	-	-	-
Histology	IP	IP	IP	IP	IP	IP	IP	IP	Nested	Nested
Celllar atypia	++	++	+++	-	-	-	-	-	+	+
Trabecular Thickening	+	+	+	-	-	-	-	-	-	-
Invasion	-	-	+	-	-	-	-	-	+	+
Lymphatic permeation	-	-	-	-	-	-	-	-	-	-
Vascular permeation	-	-	-	-	-	-	-	-	-	-
P53	+	++	++	-	-	-	-	-	++	++
Ki-67	25%	30%	40%	3%	4%	7%	6%	9%	15%	30%
Treatment	TUR	TUR	TUR	TUR	TUR	TUR	TUR	TUR	TUR	TUR
Outcome	good	good	recurrence	good	good	good	good	good	good	good
Present status	alive	alive	alive	alive	alive	alive	alive	alive	alive	Dyed of MI

HU: hematuria. DU: dysuria. E: elevated. IP: inverted papillary. TUR: Transurethral resection. MI: myocardial infarction. Invasion is up to submucosa (pTa).

Figure 1.

Low power view of inverted variant of urothelial carcinoma (A) and inverted papilloma (A). Both show inverted growth of urothelium (A, B). The inverted trabeculae are more thick in inverted variant of urothelial carcinoma (A) than inverted papilloma (B). HE, x20.

Figure 2.

High power view of inverted variant of urothelial carcinoma (A) and inverted papilloma (B). The inverted papilloma has little or none atypia (B), while inverted variant of urothelial carcinoma shows hyperchromatic nuclei, nucleoli, a few mitosis, increased nucleocytoplasmic ratio, and hypercellularity (A). HE, x200.

Figure 3.

p53 expression. p53 expression is prominent in inverted variant of urothelial carcinoma (A), while it is almost negative in inverted papilloma (B). Immunostaining, x200.

Figure 4.

Ki-67 expression. The Ki-67 labeling in inverted variant of urothelial carcinoma is high (B), while it is very low in inverted papilloma (B). Immunostaining, x200.

Discussion

In the present study, clinicopathologies of the three similar lesions, i.e. IV of UC, IP, and NV of UC, were investigated. Clinically, there were no differences in the age and gender among the three groups. The presenting symptoms were hematuria in almost all cases in the three disorders. Endoscopic gross examination revealed that the lesions were elevated and that no apparent papillary structures were seen in the three groups. The size of tumor was mostly less than 3 cm. No difference in size was seen between the IV of UC and IP, while the tumor size was somewhat larger in NV of UC. These clinical findings suggest that clinical and endoscopic distinction of the three diseases is very difficult.

The outcome of IP was, of course, good. In the present study, the outcome of IV of UC was relatively good, although one case showed recurrence. In addition, the outcome of NV of UC was relatively good in the present study, although it has been thought that NV of UC had relatively poor prognosis despite of its benign-looking histologies [1]. In any way, because no comprehensive studies of clinical findings of IV of UC have been performed, accumulation of much more cases of this variant of UC is mandatory to determine the clinical features.

In the present study, the 3 cases of IV of UC were histologically quite different from NV of UC. The problem is the distinction between IV of UC and IP. In the present study, von-Brunn’s nests-like structures and cystitis glandularis-like structures are occasionally seen in IP, suggesting that the presence of these structures is in favor of IP rather than IV of UC. In the present study, IV of UC had structural and cytological atypia, while IP did not. The present IV of UC showed positive p53 and high Ki-67 labeling, while IP showed negative p53 and low Ki-67 labeling. These findings indicate that the present IV of UC was malignant. In fact, one case of IV of UC showed a recurrence. Jones et al [2] also described that urothelial carcinoma with an inverted growth pattern was positive for p53 and Ki-67, while IP was negative for p53 and Ki-67 by immunohistochemistry, FISH, and morphologic analysis. Pathologists should consider IV of UC when they show IP-like urothelial inverted proliferation.

A review of the literature using PubMed was performed. To the best of the author’s knowledge, there are only 3 reports (31 cases) of urothelial carcinoma with predominant inverted growth (IV of UC). Lazarevic and Garret [4] reported one case of IP and papillary transitional cell carcinoma in a single polypoid lesion of the bladder. They suggested that IP may transform into IV of UC. This is a very interesting observation. However, later studies have not shown such a case. Sudo et al [3] reported a case of UC with inverted papilloma-like endophytic growth pattern. They stated that the case had thickened trabeculae, cytological atypia, and many mitotic figures. There case is very similar to the 3 cases of IV of UC in the current study. They also described that the lesion showed high expression of p53, Ki-67 and cytoplasmic cyclin D1 [3]. They stated that to clarify the biologic activities of tumors with IP-like growth pattern, even when it appears as benign by routine pathologic examination, analyses of immunoreactivity of p53 and Ki-67 might be critical [3]. The author completely agrees with the opinion of Sudo et al [3]. Jones et al [2], who examined 29 cases of UC with an inverted growth pattern and 15 cases of IP, stressed that p53, Ki-67 and cytokeratin 20 can distinguish UC with an inverted growth pattern from IP by morphologic, FISH, and immunohistochemical analysis. In IP, p53, KI67 and cytokeratin 20 were all negative, while, in UC with an inverted growth pattern, their expression was seen in 59% (p53), 66% (Ki-67) and 59% (cytokeratin 20). In addition, they described that UroVision FISH produced normal results for all cases of IP while UroVision FISH demonstrated chromosomal abnormalities typical for UC. In any way, much more analyses for the distinction of IP and IV of UC are required.

In conclusion, the author reported clinicopathologies of 3 cases of IV of UC and compared with those of IP and NV of UC. IV of UC can be easily distinguished from NV of UC by only morphology. Distinction of IV of UC and IP can be made by histology and immunohistochemistry using p53 and Ki-67, but can be arbitrary. The author wants to stress that when pathologists or urologists encounter IP-like lesion, they should keep in mild of the IV of UC. Although it is not used, the author herein proposes the term of IV of UC.

Conflict of interest statement

The author has no conflict of interest.