Contemporary Issues in Bladder Neoplasia
Section 2 -
Variants of urothelial carcinoma
Cordoba University Medical School
Urothelial carcinoma has a propensity for divergent differentiation with the most common being
squamous, followed by glandular . Virtually the whole spectrum of bladder cancer variants may be seen
in variable proportions accompanying otherwise typical urothelial carcinoma
The clinical outcome
of some of these variants differs from typical urothelial carcinoma; therefore, recognition of these
variants is important (Table 1) for the surgical pathologist.
Table 1. Variants of urothelial carcinoma (WHO, 2004)
| ||With squamous differentiation|
With glandular differentiation
Other (specify type and %)
| Small cell carcinoma|
| Nested variant|
| Micropapillary carcinoma|
| Microcystic carcinoma|
| Plasmocytoid/Lymphoma-like carcinoma|
| Inverted papilloma-like carcinoma|
| Urothelial carcinoma with syncitiotrophoblastic giant cells|
| Giant cell carcinoma|
| Clear cell (glycogen-rich) urothelial carcinoma|
|Sarcomatoid carcinoma (Carcinosarcoma)|
| Undifferentiated carcinoma|
| Urothelial carcinoma with unusual stromal reactions|
| ||Pseudosarcomatous stroma|
Stromal osseous or cartilaginous metaplasia
| Osteoclast-type giant cells|
Prominent lymphoid infiltrate
Urothelial carcinoma with mixed differentiation
About 20% of urothelial carcinomas contain areas of glandular or squamous differentiation.
Squamous differentiation, defined by the presence of intercellular bridges or keratinization, occurs in
21% of urothelial carcinomas of the bladder. Its frequency increases with grade and stage, and the
proportion of the squamous component may vary considerably . These cases may have a less favorable
response to therapy than pure urothelial carcinoma. Of 91 patients with metastatic carcinoma, 83% with
mixed adenocarcinoma and 46% with mixed squamous cell carcinoma experienced disease progression despite
intense chemotherapy, whereas it progressed in <30% of patients with pure urothelial carcinoma.
Low-grade urothelial carcinoma with focal squamous differentiation has a higher recurrence rate .
Tumors with any identifiable urothelial element are classified as urothelial carcinoma with squamous
differentiation. Cytokeratin 14 and L1 antigen have been reported as immunohistochemical markers of
Glandular differentiationis less common and may be present in
about 6% of urothelial carcinomas of the bladder . Glandular differentiation is defined as the
presence of true glandular spaces within the tumor. These may be tubular or enteric glands with mucin
secretion. A colloid-mucinous pattern characterized by nests of cells "floating" in extracellular mucin,
occasionally with signet ring cells, may be present.. The expression of MUC5AC-apomucin may be useful as
immunohistochemical marker of glandular differentiation in urothelial tumors.
The nested variant of urothelial carcinoma is an aggressive neoplasm with fewer than 50
There is a marked male predominance, and 70% of patients died 4-40 months after
diagnosis, in spite of therapy. This rare pattern of urothelial carcinoma was first described as a tumor
with a "deceptively benign" appearance that closely resembles Brunn's nests infiltrating the lamina
Some nests have small tubular lumens that eventually can predominate. Nuclei generally
show little or no atypia, but invariably the tumor contains foci or unequivocal cancer with cells
exhibiting enlarged nucleoli and coarse nuclear chromatin.
Small cell carcinoma
Small cell carcinoma is a malignant neoplasm derived from the urothelium which mimics its pulmonary
(see the following section of this hand-out).
Micropapillary carcinoma is a distinct variant of urothelial carcinoma that resembles
papillary serous carcinoma of the ovary, and approximately 60 cases were reported in the literature
There is a male predominance. The first description of micropapillary carcinoma consisted of 18
patients whose ages ranged from 47 to 81 years (mean 67) with a male-to-female ratio of 5:1. Seven
patients died of carcinoma . The micropapillary component shows slender delicate filiform processes
or small papillary clusters of tumor cells and when present in invasive carcinoma, it is composed of
infiltrating tight clusters of micropapillary aggregates that are often within lacunae that are negative
for endothelial markers
Vascular and lymphatic invasion is common. Immunohistochemical
studies in one large series disclosed immunoreactivity in 20 of 20 cases for EMA, Cytokeratin 7 and 20,
and Leu M-1; but high molecular weight cytokeratin may be present. The presence of a surface
micropapillary component in bladder biopsy specimens is an unfavorable prognostic feature, and deeper
biopsies may be useful to determine muscle invasion. The prognosis seems to be related to the proportion
and location of the micropapillary component.. The main differential consideration is serous
micropapillary ovarian carcinoma in women or mesothelioma in both genders.
In the micropapillary pattern of invasive carcinoma, the expression of MUC1 is largely
limited to the basal surface of the cells in contrast to the conventional carcinomas in which MUC1 is
largely apical, intracytoplasmic, or intercellular. The MUC1 expression was predominantly in the aspect
of the cell clusters facing the stroma, accentuating the outlines of the micropapillary units by forming
a distinct band on this surface. This observation provides support for the hypothesis that the reversal
of cell polarity as an important factor in the pathogenesis of the invasive micropapillary carcinoma.
Since MUC1 is known to be involved in lumen formation and has an inhibitory effect on cell-to-stroma
interaction, it may play an important role in the detachment of cells from the stroma easing the spread
of neoplastic cells .
The microcystic variant of invasive urothelial carcinoma is characterized by the formation
of microcysts, macrocysts, or tubular structures with cysts ranging from microscopic up to 1-2 cm in
diameter. The cysts and tubules may be empty or contain necrotic debris or mucin
Carcinoma that histologically resembles lymphoepithelioma of the nasopharynx has been
described in the urinary bladder, with fewer than 50 cases reported. 
It is more common in men (mean:
69 years). Histologically, it may be pure or mixed with typical urothelial carcinoma. Glandular and
squamous differentiation may be seen . The tumor is composed of nests, sheets, and cords of
undifferentiated cells with large pleomorphic nuclei and prominent nucleoli. The cytoplasmic borders are
poorly defined, imparting a syncytial appearance. The background consists of a prominent T and B
lymphocyte infiltration, plasma cells, histiocytes; neutrophils or eosinophils may be present.
Epstein-Barr virus infection has not been identified in bladder cases. This tumor has been found to be
responsive to chemotherapy when it is encountered in its pure form. The epithelial cells of this tumor
stain with several cytokeratin markers. A relatively favorable prognosis has been reported when pure or
Lymphoma-like or plasmacytoma-like carcinoma
In this variant, the tumor cells were medium-sized, with eosinophilic cytoplasm and eccentric nuclei
producing a plasmacytoid appearance. In a series report of 6 cases, the age range was 54-73years.
All cases stained positively for cytokeratin AE1/AE3 and CK 20 and 7. Five of six patients died of
disease (mean survival, 23 months)
Inverted papilloma-like (inverted growth) carcinoma
The potential for misinterpretation of urothelial carcinoma with endophytic growth as
inverted papilloma is high. By definition, this variant of urothelial carcinoma has significant nuclear
pleomorphism, mitotic figures, and architectural abnormalities consistent with low- or high-grade
urothelial carcinoma. Large papillary tumors with prominent endophytic growth "invade" the lamina
propria with a pushing border. Unless this pattern is accompanied by true destructive stromal invasion
the likelihood of metastasis is minimal, because the basement membrane is not truly breached .
Urothelial carcinoma with syncytiotrophoblastic giant cells
Syncytiotrophoblastic giant cells are present in up to 12% of cases of urothelial
carcinoma, producing substantial amounts of beta-human chorionic gonadotropin (HCG) indicative of
Giant cell carcinoma
High grade urothelial carcinoma may contain epithelial tumor giant cells or the tumor may
appear undifferentiated, resembling giant cell carcinoma of the lung. The giant cells display
cytokeratin and vimentin immunoreactivity.
Clear cell (glycogen-rich) carcinoma
Up to two-thirds of cases of urothelial carcinoma have foci of clear cell change resulting
from abundant glycogen.This variant consisting predominantly or exclusively of cells with abundant clear
cytoplasm that stains for cytokeratin 7 .
Sarcomatoid carcinoma with/without heterologous elements (carcinosarcoma, metaplastic carcinoma)
The term sarcomatoid variant of urothelial carcinoma should be used for all biphasic
malignant neoplasms exhibiting morphologic and/or immunohistochemical evidence of epithelial and
mesenchymal differentiation (with the presence or absence of heterologous elements acknowledged in the
The gross appearance is characteristically "sarcoma-like," and the tumors are often
polypoid. Microscopically, sarcomatoid carcinoma is composed of urothelial, glandular or small cell
component showing variable degrees of differentiation. Carcinoma in situ is present in 30% of cases and
occasionally is the only apparent epithelial component.. The mesenchymal component most frequently
observed is a undifferentiated high grade spindle cell neoplasm. The most common heterologous element is
osteosarcoma followed by chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma or
multiple types of heterologous differentiation may be present. By immunohistochemistry, epithelial
elements react with cytokeratins , whereas stromal elements react with vimentin or specific markers
corresponding to the mesenchymal differentiation. The sarcomatoid phenotype retains the epithelial
nature of the cells by immunohistochemistry. Recent molecular studies strongly argue for a monoclonal
origin of both components in sarcomatoid carcinoma and carcinosarcoma. Pathological stage is the best
predictor of survival in sarcomatoid carcinoma .
Lipoid cell variant, is a rare neoplasm defined by the WHO (1999, 2004)
 as an
urothelial carcinoma which exhibits transition to a cell type resembling signet-ring lipoblasts . It
is currently considered to be an ill-defined tumor variant. Clinicopathologic features and the
immunohistochemical findings in seven reported cases showed gross hematuria as the initial symptom. All
patients were elderly men. The immunohistochemical results showed an epithelial phenotype characterized
by diffuse staining with cytokeratins AE1/AE3.
This category contains tumors that cannot be otherwise classified.
Other uncommon morphologic variations in bladder cancer
Baldwin et al.  described a series of 10 cases of urothelial carcinoma with a
striking discohesive growth pattern that show morphological features that mimicked infiltrating lobular
carcinoma of the breast and diffuse carcinoma of the stomach.  In areas the tumor cells were arranged
in linear single-cell files (indian file pattern).
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- Nassar H, Pansare V, Zhang H, Grignon D, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol 2004;17:1045-50.
- Lopez-Beltran A, Luque RJ, Vicioso L, et al. Lymphoepithelioma-like carcinoma of the urinary bladder: a clinicopathologic study of 13 cases. Virchows Arch 2001;438:552-7.
- Tamboli P, Amin MB, Mohsin SK, Lopez-Beltran A, et al. Plasmocytoid variant of non-papillary urothelial carcinoma(Abstract). Mod Pathol 2000;13:107A.
- Amin MB, Gomez JA, Young RH. Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol 1997;21:1057-68.
- Oliva E, Amin MB, Jimenez R, et al. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol 2002;26:190-7.
- Lopez-Beltran A, Pacelli A, Rothenberg HJ, et al. Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. J Urol 1998;159:1497-503.
- Lopez-Beltran A, Luque RJ, Oliveira PS, et al. Urothelial carcinoma of the bladder, lipid cell variant (UCBLCV). Immunohistochemical and clinico-pathologic findings in seven cases(Abstract). Mod Pathol 2002;15:171A.
- Baldwin L, Lee AH, Al-Talib RK, et al. Transitional cell carcinoma of the bladder mimicking lobular carcinoma of the breast: a discohesive variant of urothelial carcinoma. Histopathology 2005;46:50-6.