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Urothelial carcinoma - invasive

Nested variant

Reviewer: Rugvedita Parakh, M.D. (see Reviewers page)
Revised: 9 February 2013, last major update June 2010
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.


● Rare tumor of irregular and confluent small nests and abortive tubules composed of urothelial cells infiltrating the lamina propria or muscularis propria, usually without surface involvement
● First described in 1989 (Am J Surg Pathol 1989;13:374)


● Usually men > 60 years, similar to classic urothelial carcinoma

Clinical features

● Either rare or underreported; estimated incidence is less than 0.3% of invasive bladder tumors
● Aggressive behavior despite bland cytologic features (Mod Pathol 2003;16:1289)
● Similar clinical outcome if pure or mixed with usual urothelial carcinoma (Hum Pathol 2010;41:163)
● Often advanced stage at presentation
● Tumor often at ureteral orifices
● Neoplasm resembles proliferation of Brunn's nests (Mod Pathol 1992;5:240); may be misinterpreted as benign (Am J Surg Pathol 1996;20:1448)

Case reports

● 71 year old man with recurrent tumor (Actas Urol Esp 2009;33:90)
● Two cases with aggressive behavior (Pathol Oncol Res 2006;12:105)


● Radical surgical resection

Gross description

● Often no clearly defined tumor

Micro description

● Irregular and confluent small nests and abortive tubules composed of urothelial cells infiltrating the lamina propria or muscularis propria, usually without surface involvement (Arch Pathol Lab Med 2007;131:1725)
● Tumor cells have only mild atypia (mild pleomorphism, slightly increased N/C ratios, occasional prominent nucleoli, rare mitotic figures) and resemble cystitis glandularis et cystica
● Deep tumor-stroma interface is jagged and infiltrative
● Often more atypia and focal anaplasia with increasing depth of invasion
● Typical urothelial carcinoma is often present (Mod Pathol 1996;9:989)
● Retraction artifact may be seen
● By definition, these tumors cannot be high grade or have overlying surface carcinoma in situ

Micro images

Nests of bland urothelial cells in lamina propria

Fig 1: Lamina propria infiltrated by neoplastic proliferation of fairly homogeneous nests
Fig. 2: Tumor cells are small/medium and uniform, with a low N/C ratio and a low mitotic index; nuclei are slightly irregular with occasional prominent nucleoli
Fig. 3: Tumor cells infiltrate muscularis propria

Confluent small nests and abortive tubules

Various images

Various images

Histological appearance of the urinary bladder
AFIP 2-30: The tumor usually presents as multiple, deceptively benign appearing nests in the lamina propria. In contrast to cystitis glandularis, the nests lack cellular organization around lumina, and appear to infiltrate rather than cluster. At high power, the cellular disorganization and atypia are prominent. AFIP images courtesy of Dr. Daniel M. Lundblad, Parkersburg, West Virginia

Cytology description

● Subtle features are not diagnostic by themselves; include medium sized round/polygonal cells with abundant, dense, slightly granular basophilic cytoplasm and well defined cell borders; irregular nuclear contours, increased N/C ratio, coarse chromatin, occasional prominent nucleoli (Cancer 2003;99:23)

Positive stains

● CK7, CK20, p63, Ki-67, CK903 (Arch Pathol Lab Med 2003;127:e333)
● Variable p53

Negative stains

● bcl2, EGFR, PSA

Differential diagnosis

Adenocarcinoma: colonic differentiation; more prominent atypia
Cystitis cystica / glandularis: no atypia, no invasion
Inverted papilloma: no deep invasion
Nephrogenic metaplasia / adenoma: usually has papillary component, prominent tubular or cystic structures lined by single layer of cuboidal cells, no atypia, no invasion
Prostatic adenocarcinoma: centered in prostate, PSA+, PSAP+
Urothelial carcinoma with small tubules: invasive carcinoma with small gland-like spaces lined by urothelial cells without intracellular mucin or columnar lining; some consider this part of nested variant (Hum Pathol 2004;35:769)
von Brunnís nests: no invasion, no prominent atypia; no focal anaplasia (Am J Surg Pathol 2003;27:1243)

End of Bladder > Urothelial carcinoma - invasive > Nested variant

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