—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 2 - Atypical Urothelial Proliferation, Concerning for Nested Urothelial Carcinoma

Donna E. Hansel
The Cleveland Clinic
Cleveland, OH





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Introduction:
Patient summary: The patient is a 72 year old male with a progressive history of nocturia and urinary urgency. The patient has had no prior urinary tract history and no evidence of gross or microscopic hematuria. His past medical history includes a diagnosis of benign prostatic hyperplasia (BPH), which has been treated with Flomax. A prior prostate biopsy revealed only benign glands and his current prostate specific antigen (PSA) is 1.62. The patient has been a long-time smoker, with a 30 pack year history of cigarette use. A urinalysis performed at the urologist's office did not reveal any abnormalities and a urine cytology was normal. A cystoscopy was performed, which revealed a raised, reddened patch on the posterior wall of the bladder. No exophytic component was identified. The remainder of the bladder, ureteral orifices, and urethra appeared unremarkable. A biopsy was performed, which was superficial in nature and lacked muscularis propria.

Case 2 - Figure 1
Case 2 - Figure 2
H&E
Case 2 - Figure 3
H&E

Case 2 - Figure 4
H&E
Case 2 - Figure 5
Ki67
Case 2 - Figure 6


Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Pathology: The pathology is presented in the accompanying powerpoint presentation. In brief, superficial portions of bladder mucosa were available for analysis. In the majority of tissue fragments, a urothelial proliferation was present in the lamina propria and was characterized by: 1) densely packed nests and glandular structures, 2) mild nuclear atypia, with the majority of nuclei demonstrating open chromatin and small nucleoli, 3) occasional cells with more abundant, eosinophilic cytoplasm – likely squamoid differentiation - scattered throughout the lesion, 4) occasional dense eosinophilic secretions in von Brunns-like structures, and 5) occasional vacuolization of the cytoplasm. The associated overlying urothelium was not strikingly abnormal, but did contain similar large cells with abundant pink cytoplasm.

Differential Diagnoses:
The differential diagnosis at this point includes a nested urothelial carcinoma, as well as inverted papilloma, a florid proliferation of von Brunns nests and cystitis cystica et glandularis.

Final Diagnosis:
The final diagnosis in this case was "atypical urothelial proliferation, concerning for nested urothelial carcinoma." Due to the lack of marked atypia and inability to survey the base of the lesion, a definitive diagnosis of carcinoma cannot be definitely rendered. Although the p53 immunoreactivity is striking, a diagnosis should not be rendered solely on the basis of immunohistochemical stains.

Case Discussion:
Unfortunately, deeper levels of the lamina propria and the muscularis propria were absent from the specimen, which would significantly aid in parsing the differential diagnosis. More specifically, if the atypical proliferation extended deep into the lamina propria or the muscularis propria, a diagnosis of nested urothelial carcinoma would be more likely. In contrast, if the lesion were well-circumscribed and paralleled the urothelium, a benign diagnosis would be favored. In this case, immunohistochemical stains for Ki67 and p53 were performed. Ki67 stains are non-specific, but are typically increased in neoplastic proliferations. In this case, a mild increase in proliferation was present. p53 nuclear immunoreactivity is a hallmark of p53 mutation and is frequent in urothelial neoplasia. This lesion demonstrates an almost uniform, strong expression of nuclear p53 – a finding that strongly favors a neoplastic process.

Differential diagnosis:
1. Florid proliferation of von Brunns nests. von Brunn nests are invaginations of the surface urothelium into the underlying lamina propria and may occur as a response to injury [1]. von Brunn nests appear as smooth invaginations of the urothelium located directly below – parallel to - the luminal surface. Occasionally, the presence of von Brunn nests may be extensive, a condition termed florid proliferation of von Brunn nests. A marked proliferation of von Brunns nests may appear as a submucosal nodule and are defined by urothelial nests that closely approximate one another within the superficial lamina propria, but do extend into the deep lamina propria or muscularis propria. The urothelial cells have minimal to no cytologic atypia, limited to no mitotic activity, and generally contain open chromatin with occasional pinpoint nucleoli. Florid proliferation of von Brunns nests is a benign diagnosis. The most common differential diagnosis associated with a florid proliferation of von Brunn nests is nested urothelial carcinoma (below) [2].

2. Cystitis cystica et glandularis. Cystitis cystica and cystitis glandularis occur when von Brunns nests undergo cystic dilation, with cystitis glandularis defined by glandular change of the urothelium [3, 4]. More specifically, in cystitis cystica, the urothelium is lined by an umbrella cell layer that may appear reactive in nature, whereas the urothelium in cystitis glandularis may appear cuboidal or columnar in nature. Cystitis cystica et glandularis is a benign condition and is often associated with proliferation of von Brunns nests. Again, these lesions may appear as a submucosal nodule in the urothelium. Microscopically, cystitis cystica et glandularis appears as rounded urothelial nests demonstrating cystic dilation and present within the lamina propria, parallel to the urothelial surface. The cystically dilated lumens often contain prominent eosinophilic secretions. Similar to florid proliferation of von Brunns nests, the cells in cystitis cystica et glandularis maintain their polarity to the luminal surface and have minimal to no atypia or mitotic activity.

3. Inverted papilloma. Inverted papillomas are well- recognized entities that are defined by anastomosing cords of bland-appearing urothelial cells within the lamina propria. Often, the cells show a prominent polarization to the exterior surface of the cords and appear to demonstrate a "streaming" effect in the center of the urothelial cords. On rare occasions, foamy or vacuolated cytoplasm may be present within the cells [5]. Cystoscopically, these lesions appear as submucosal nodules. Considered an indolent neoplasm, inverted papillomas typically lack mutations of the p53 protein, making nuclear localization of this protein by immunohistochemistry unlikely [6]. In addition, Ki67 proliferation indices are minimal at most [7].

4. Nested urothelial carcinoma. Nested urothelial carcinoma is an uncommon and diagnostically challenging variant of bladder cancer [8, 9]. Per its name, this form of invasive carcinoma is defined by small, occasionally irregular, nests of bland urothelial cells. The invasive nature of this entity is often only defined by the identification of nests infiltrating well below the surface urothelium, often involving the muscularis propria. Atypia, if present, is often most conspicuous in these deepest regions of the carcinoma. Nested urothelial carcinoma often pursues an aggressive course and is likely due to the delay in diagnosis resulting from the bland morphology of this entity. p53 immunoreactivity, however, is present in only approximately 25% of cases and is often not diffusely present, making this case unusual [10, 11].

Conclusion(s):
Limited biopsies often present significant challenges to the pathologist, especially when a proliferative process is present. Systematic examination of the surface urothelium, organization of the submucosal proliferation (nodular, infiltrative, confined immediately below the surface urothelium), and careful review of the cytologic features is of primary importance. Although immunohistochemical stains can provide some guidance, the final diagnosis ultimately rests on the H&E features and comfort of the pathologist with the diagnosis.

References:
  1. Wiener DP, Koss LG, Sablay B, Freed SZ. The prevalence and significance of Brunn's nests, cystitis cystica and squamous metaplasia in normal bladders. J Urol 1979;122:317-21.

  2. Volmar KE, Chan TY, De Marzo AM, Epstein JI. Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol 2003;27:1243-52.

  3. Goldstein AM, Fauer RB, Chinn M, Kaempf MJ. New concepts on formation of Brunn's nests and cysts in urinary tract mucosa. Urology 1978;11:513-7.

  4. Davies G, Castro JE. Cystitis glandularis. Urology 1977;10:128-9.

  5. Fine SW, Epstein JI. Inverted urothelial papillomas with foamy or vacuolated cytoplasm. Hum Pathol. 2006 Dec;37(12):1577-82.

  6. Lott S, Wang M, Zhang S, MacLennan GT, Lopez- Beltran A, Montironi R, Sung MT, Tan PH, Cheng L. FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations. Mod Pathol. 2009; 22:627-32.

  7. Jones TD, Zhang S, Lopez-Beltran A, Eble JN, Sung MT, MacLennan GT, Montironi R, Tan PH, Zheng S, Baldridge LA, Cheng L. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis. Am J Surg Pathol. 2007;31:1861-7.

  8. Nigwekar P, Amin MB. The many faces of urothelial carcinoma: an update with an emphasis on recently described variants. Adv Anat Pathol. 2008 Jul;15(4):218-33.

  9. Wasco MJ, Daignault S, Bradley D, Shah RB. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 30 pure and mixed cases. Hum Pathol, in press.

  10. Volmar KE, Chan TY, De Marzo AM, Epstein JI. Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol. 2003 Sep;27(9):1243-52.

  11. Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson B, Reuter VE. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases. Mod Pathol. 2003 Dec;16(12):1289-98.