Group Title: CytoJournal 2005, 2:18
Title: Primary small cell neuroendocrine carcinoma of the urinary bladder with coexisting high-grade urothelial carcinoma: a case report and a review of the literature
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Title: Primary small cell neuroendocrine carcinoma of the urinary bladder with coexisting high-grade urothelial carcinoma: a case report and a review of the literature
Series Title: CytoJournal 2005, 2:18
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Creator: Bui M
Khalbuss WE
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Case Report

Primary small cell neuroendocrine carcinoma of the urinary
bladder with coexisting high-grade urothelial carcinoma: a case
report and a review of the literature
Marilyn Bui*l and Walid E Khalbuss2


Address: 'Department of Interdisciplinary Oncology, Division of Anatomical Pathology, H. Lee Moffitt Cancer Center and Research Institute,
Tampa, Florida, USA and 2Department of Pathology, University of Florida Health Science Center (UFHSC), Jacksonville, Florida, USA
Email: Marilyn Bui* buimm@moffitt.usf.edu; Walid E Khalbuss walid.khalbuss@jax.ufl.edu
* Corresponding author


d Central


Published: 04 November 2005
Cytojournal 2005, 2:18 doi:10.1 186/1742-6413-2-18


Received: 08 July 2005
Accepted: 04 November 2005


This article is available from: http://www.cytojournal.com/content/2/1/18
2005 Bui and Khalbuss; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.






Abstract
Primary neuroendocrine carcinomas of the urinary bladder are rare. Here, we report a case of an
82-year-old man who presented with hematuria and was found to have an ulcerated lesion in the
bladder. A diagnosis of small neuroendocrine cell carcinoma with coexisting minor high-grade
urothelial components was rendered. In this report, the clinical, cytological, histological, and
immunohistochemical features of this case are described, and a review of the literature about this
neoplasm is presented. The differential diagnoses of small cell tumor in urinary bladder washing
specimens are discussed.


Neuroendocrine carcinoma comprises carcinoid tumors,
large cell neuroendocrine carcinomas, and small cell car-
cinomas. Primary neuroendocrine carcinomas of the uri-
nary bladder are rare. They usually involve male patients
and coexist with urothelial carcinoma [1]. Among neu-
roendocrine tumors of the urinary bladder, small cell car-
cinomas are most common with more than 100 cases
having been described [2-4]; carcinoid tumors are much
less common; and large cell neuroendocrine carcinomas
are very rare with only 3 cases reported [5 The rare nature
of a primary neuroendocrine carcinoma, especially in a
cytology specimen, should be included in consideration
as part of the differential diagnosis of the far more com-
mon urothelial carcinoma.


Case Reports
The patient was an 82-year-old male who presented with
hematuria for 3 months. Cystoscopy revealed an ulcerated
lesion in the bladder trigone. A bladder washing and a
bladder biopsy were performed. The patient underwent
bladder tumor resection and subsequent cystoprostatec-
tomy. The patient's recovery was complicated by gastroin-
testinal bleeding, and he eventually expired within 3
months of his initial diagnosis. Autopsy concluded that
the patient died from extensive upper gastrointestinal
bleeding secondary to small bowel involvement with met-
astatic small cell carcinoma superimposed by DIG.

The cytological features of cytospin smears and cellblock
of the bladder washing are presented in Figures 1, 2, 3, 4,
&6. The specimen was hypercellular and consisted of


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Figure I
Bladder washing, cytospin preparation, Papanicolaou stain,
x400. Mixed small undifferentiated carcinoma and large
urothelial carcinoma cells. The small cells are seen singly and
in clusters with scanty cytoplasm, moderate cellular pleo-
morphism, nuclear molding, dark chromatin, irregular
nuclear contour, and background of blood and necrosis con-
sistent with a small cell carcinoma. In addition, there are a
few atypical cells with a moderate amount of cytoplasm,
small nucleoli, and irregular nuclear contours consistent with
high-grade urothelial carcinoma. Figure 2 inset: comparison
of two small cell carcinoma cells and one large urothelial car-
cinoma cell.


highly atypical cells with two distinct populations: small
cells and large cells.

The small cell population was the predominant one. It
showed undifferentiated malignant small cells ranging in
size and shape from lymphocyte-like to intermediate type
(see Figure 4 for comparison with RBC size). The cells
demonstrated a moderate degree of cellular pleomor-
phism, nuclear molding, finely granular chromatin,
hyperchromatic nuclei, and inconspicuous nucleoli in a
bloody and necrotic background (Figures 1, 2, 3). Occa-
sional elongated cells and occasional rosette formation
were also noted. These cytomorphologic features were
indicative of small undifferentiated cell carcinoma. The
cellblock (Figure 4) findings recapitulated the findings in
the smears and were useful in subsequent immunohisto-
chemical evaluations.

The large cell population was a minor component and
showed highly atypical cells with central nuclei, small
nucleoli, irregular nuclear contour, and dense cytoplasm
in a bloody and necrotic background (Figures 1 &2).
These cytomorphologic features were indicative of a high-
grade urothelial carcinoma component. The cell block


Figure 2
Bladder washing, cytospin preparation, Papanicolaou stain,
x400. Mixed small undifferentiated carcinoma and large
urothelial carcinoma cells. The small cells are seen singly and
in clusters with scanty cytoplasm, moderate cellular pleo-
morphism, nuclear molding, dark chromatin, irregular
nuclear contour, and background of blood and necrosis con-
sistent with a small cell carcinoma. In addition, there are a
few atypical cells with a moderate amount of cytoplasm,
small nucleoli, and irregular nuclear contours consistent with
high-grade urothelial carcinoma. Figure 2 inset: comparison
of two small cell carcinoma cells and one large urothelial car-
cinoma cell.





(Figure 6) findings recapitulated the findings in the
smears and were useful in subsequent immunohisto-
chemical evaluations.

Immunohistochemical stains were performed on cell
blocks and showed positive staining of the small cell car-
cinoma component only for synaptophysin (Figure 5).
The diagnosis was rendered as small cell neuroendocrine
carcinoma with a high-grade urothelial carcinoma com-
ponent.

Subsequently, the patient underwent bladder tumor resec-
tion and a 4 cm tumor was rejected. The histology sec-
tions (Figures 7 and 8) demonstrated a small cell
carcinoma in about 80% of the tumor (Figure 7) and a
high-grade urothelial carcinoma in about 20% of the
tumor (Figure 8). Immunohistochemical stains were per-
formed and the tumor cells of the small cell carcinoma
component were positive selectively for synaptophysin
(Figure 9) and chromogranin, whereas, the high-grade
urothelial carcinoma stained selectively for CK7, and
CK20.


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Figure 3
Bladder washing, cell block, H&E, x400: clusters of pure,
small cell undifferentiated carcinoma of the bladder. The
small cell carcinoma cells are approximately twice the size of
the RBCs with finely granular chromatin and nuclear molding.


A subsequent radical cystectomy revealed a residual tumor
of 4 cm in the greatest dimension. The tumor also
appeared to have invaded through the muscularis propria
into the adjacent fat. There were fifteen out of twenty-one
bilateral lymph nodes involved by the small cell undiffer-
entiated carcinoma. The tumor stage was yT3N2 Mx.

The autopsy revealed an intra-abdominal mass showing
extensive metastatic small cell carcinoma (18 cm) with


Figure 4
Bladder washing, cell block, H&E, x400: clusters of pure,
small cell undifferentiated carcinoma of the bladder. The
small cell carcinoma cells are approximately twice the size of
the RBCs with finely granular chromatin and nuclear molding.


Figure 5
Bladder washing, cell block, synaptophysin immunostain of
small cell carcinoma, x400. The tumor cells demonstrated
cytoplasmic positivity.


involvement of the duodenum (the entire duodenal wall
including the mucosa) with extensive adhesions to the ret-
roperitoneum, descending aorta, periaortic lymph nodes,
and mesenteric fat. Tumor also involved peripancreatic
and peri adrenal adipose tissue. Autopsy concluded that
the patient died from extensive upper gastrointestinal
bleeding secondary to small bowel involvement with met-
astatic small cell carcinoma superimposed by DIG.


Figure 6
Cell block, H&E, x400: Urothelial carcinoma cells with a
moderate amount of cytoplasm and small nucleoli.




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Figure 7
Tissue biopsy of the bladder tumor, H&E, x200. Figure 7;
Small cell carcinoma. Figure 8; Urothelial carcinoma with
active mitosis evident.


Figure 8
Tissue biopsy of the bladder tumor, H&E, x200. Figure 7;
Small cell carcinoma. Figure 8; Urothelial carcinoma with
active mitosis evident.


Figure 9
Tissue biopsy of the bladder tumor, synaptophysin immunos-
tain. The bottom half of the section is the small cell carci-
noma component of the bladder tumor which demonstrated
synaptophysin positivity. The top half of the section is
urothelial carcinoma that is negative for synaptophysin.



Discussion
Here, we present a case of primary small cell carcinoma of
the urinary bladder coexisting with a high-grade urothe-
lial carcinoma component. The cytomorphological pat-
tern of the bladder washing was that of a small, blue cell
neoplasm. The differential diagnoses included a high-
grade urothelial carcinoma, a small cell carcinoma of the
urinary bladder, and a lymphoma, as well as metastatic
lesions, especially from the lung. Lymphomas of the blad-
der are rare, and have a good prognosis with a good
response to chemotherapy [6]. The cytomorphological
features of bladder lymphoma include single pleomor-
phic cells with round to oval nuclei, increased nuclear/
cytoplasmic ratio, and centrally located nuclei often with
prominent nucleoli [7]. The cytomorphological features
of metastatic small cell carcinoma of lung origin are indis-
tinguishable from primary small cell carcinoma of the
bladder. However, the presence of a high-grade urothelial
carcinoma component in our case was suggestive evidence
of a primary bladder lesion. In conjunction with the
patient's clinical presentation and clinical work-up, the
cytomorphology and immunocytochemical features sup-
ported the diagnosis of a primary small cell carcinoma of
the urinary bladder. Subsequent surgical excision revealed
a high-grade urothelial carcinoma and small cell carci-
noma.

Making the diagnosis of a small cell carcinoma of the uri-
nary bladder on a cytology specimen is important. Pri-
mary neuroendocrine carcinomas of the bladder usually
are at an advanced stage at presentation. As in this case,


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the patient already had local invasion and lymph node
metastases at the time of diagnosis. Although bladder
neuroendocrine carcinoma is an aggressive tumor, the
prognosis is better than those patients with neuroendo-
crine carcinoma of other sites [8].


Acknowledgements
The authors are thankful to Dr. Steve Goodison for his critiques of this case
report.

Declaration of competing interests: The authors declare that they have no
competing interests.

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3. Grignon D, Ro J, Ayala A, et al.: Small cell carcinoma of the uri-
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