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CAS CLINIQUE / CASE REPORT

SMALL CELL NEUROENDOCRINE CARCINOMA OF THE URINARY BLADDER


Report on Two Cases and Review of the Literature
http://www.lebanesemedicaljournal.org/articles/58-1/case1.pdf

Camil J. CHOUAIRY1, Ali N. SALLOUM2, George Y. GHAZAL2

Chouairy CJ, Salloum AN, Ghazal GY. Small cell neuroendo- Chouairy CJ, Salloum AN, Ghazal GY. Carcinome vésical à
crine carcinoma of the urinary bladder : Report on two cases and petites cellules (neuroendocrinien). A propos de deux cas et
review of the literature. J Med Liban 2010 ; 58 (2) : 111-119. revue de la littérature. J Med Liban 2010 ; 58 (2) : 111-119.

ABSTRACT : Small cell (Neuroendocrine) carcinoma of RÉSUMÉ : Le carcinome vésical à petites cellules (neuro-
the urinary bladder is a rare but highly aggressive malig- endocrinien) est une entité rare mais très agressive. Les
nancy. The neoplastic cells exhibit both neuroendocrine cellules néoplasiques exhibent une différentiation à la fois
and epithelial differentiation. It is morphologically indis- neuroendocrinienne et épithéliale. Morphologiquement,
tinguishable from the more common pulmonary small il est impossible de le distinguer du carcinome pulmo-
cell carcinoma. It can occur either in association with naire à petites cellules, qui est plus fréquent. Il peut avoir
urothelial (transitional cell) carcinoma or in a pure form. lieu en association avec un carcinome transitionnel (uro-
Presenting signs and symptoms are non specific. Histo- thélial) ou de façon isolée (forme pure). Les signes et les
logically, it can mimic poorly differentiated urothelial symptômes ne sont pas spécifiques. L’histologie peut mi-
carcinoma and lymphoma. Muscle invasion is almost mer celle d’un carcinome urothélial peu différencié ou
invariably present at diagnosis and mortality is mainly celle d’un lymphome. L’invasion du muscle vésical est
due to metastases rather than loco regional recurrence. presque toujours présente. La mortalité est due principa-
The optimal therapeutic modality is still controversial. lement aux métastases plutôt qu’à la récidive locoré-
In this article, we report on two cases occurring in a pure gionale. L’approche thérapeutique optimale est toujours
form and we briefly review the published literature controversée. Dans cet article, on rapporte la présenta-
regarding the clinical presentation, morphology, differ- tion clinique et l’histologie de deux cas de forme « pure »
ential diagnosis, prognosis and treatment. et une revue des données publiées dans la littérature sur
la présentation clinique, l’immunophénotype, le diagnos-
tic différentiel, le pronostic et le traitement.
INTRODUCTION
mass, which appeared to invade the whole thickness of the
Small cell carcinoma of the urinary bladder is a rare but bladder wall. Cystoscopy revealed a large sessile and
highly aggressive malignancy. It was first reported in necrotic tumor. Transurethral resection (TUR) was per-
1981 and accounts for 0.5% to 1% of malignant bladder formed. A diagnosis of pure small cell (Neuroendocrine)
tumors [1-4]. The overall median survival is four months carcinoma invading the mucosa and Muscularis propria
for patients who do not receive chemotherapy, regardless (pT2) [6] was made.
of the stage and 15 months for those receiving chemo- He was a poor candidate for radical cystectomy due to
therapy [5]. The diagnosis has important implications in his cardiovascular condition. Follow-up cystoscopy was
terms of prognosis, survival and threpeutic approach. performed at 3 months and 6 months post TUR and failed
Differential diagnosis includes mainly poorly differ- to show any recurrence. One year after the transurethral
entiated urothelial carcinoma and lymphoma, both of resection, the painless gross hematuria reappeared. Abdo-
which have relatively better prognosis and different ther- mino-pelvic CT scan showed infiltrative bladder tumor in
apeutic approach. the right postero-lateral wall with extension to the right
seminal vesicle (Clinical T4a) [6]. Transurethral resection
CASE REPORTS was performed and the pathology was similar to that of
the tumor resected one year earlier. Metastatic workup
Case 1 showed lung metastases (Clinical Stage IV). He died one
A 68-year-old gentleman presented for painless gross month later of massive transmural myocardial infarction.
hematuria. Kidneys and bladder ultrasound showed a
3 x 2 cm sessile polypoid mass in the right postero-lateral Case 2
bladder wall. Computed tomography scan (CT scan) of An 83-year-old gentleman, known to have advanced
the abdomen and pelvis confirmed the presence of the stage prostatic acinar adenocarcinoma, Gleason score 9,

1 2
Departments of Pathology and Urology, St George Hospital University Medical Center, Achrafieh, Beirut, Lebanon.
Correspondence : Camil J. Chouairy, MD. Saint George Hospital. Pathology Department. Youssef Sursock Street. Rmeil- Achrafieh
P.O. Box 166 378. Beirut 1100 2807. Lebanon. e-mail : camil.chouairy@balamand.edu.lb

Lebanese Medical Journal 2010 • Volume 58 (2) 111


presented for painless gross hematuria. PSA level was
393 ng/dl. Cystoscopy showed a 3 x 4 cm lobulated exo-
phytic polypoid tumor in the left postero-lateral wall of the
bladder. Transurethral resection and bilateral orchiectomy
were performed. A diagnosis of pure small cell (neuro-
endocrine) carcinoma invading the mucosa and Muscularis
propria (pT2) was made. Re-review of the prostatic biopsies
confirmed the diagnosis of high grade prostatic acinar ade-
nocarcinoma. There were no features of neuroendocrine
small cell carcinoma in the prostate biopsies.
Chemotherapy and radical cystectomy were not con-
sidered as therapeutic options given his age and medical
condition. Follow-up cystoscopy 6 months later showed
absence of tumor. One year after transurethral resection,
gross hematuria reappeared. CT scan of the abdomen and
pelvis showed a large sessile polypoid exophytic mass
arising from the left postero-lateral bladder wall with cir-
cumferential thickening. A large lymph node in the right
internal iliac chain measuring 6 x 5 x 5 cm with features
of necrosis was also noticed (Clinical Stage IV). Liver FIGURE 2. Infiltration of the Muscularis propria by neoplastic
cells. Case 2 (H&E 40x).
appeared normal. Cystoscopy revealed a large polypoid
mass arising from the left postero-lateral wall. A second was regular and flat with no evidence of neoplasia (Fig. 1).
transurethral resection was performed. Pathology was Nuclei varied in size from 2 to 4 times the size of a small
identical to the previous one obtained one year ago. He mature lymphocyte. Chromatin was finely granular. Open
died three months later. vesicular chromatin and conspicuous nucleoli were absent.
Nuclear contour was frequently angulated and nuclear
Pathology findings molding was prominent and well visible in some areas
All four specimens showed similar microscopic findings : (Fig. 3). PAS and PAS-Diastase failed to reveal any amount
Solid sheet like and nodular neoplastic proliferation of of glycogen or mucin. All of the following Immunohisto-
cells with high nucleo-cytoplasmic ratio and inconspicu- chemical stains were negative : Leukocyte common anti-
ous cytoplasm, imparting a “small round blue cell appear- gen (LCA), Vimentin, CD99, CD117 (c-kit), S-100, CEA,
ance” on low power (Fig. 1 & 2). The neoplasm occupied Cytokeratin 20, Cytokeratin 7, and High molecular weight
and infiltrated the Lamina propria (Fig. 1) and the thick cytokeratin (Clone 34ßE12).
smooth muscle bundles of the Muscularis propria (Fig. 2). Synaptophysin was diffusely positive in both cases
Areas of coagulative type necrosis, crush artifact and lym- (Fig. 4). Chromogranin A was negative in Case 1 and
phovascular invasion were also present. Mitotic figures expressed in Case 2 (Fig. 5). Table I shows the antibodies
were abundant and easily detected. Surface urothelium used, the source, their clones and the working concentration.

FIGURE 3. The neoplastic cells are dyshesive to poorly cohesive and


exhibit a high nucleo-cytoplasmic ratio. Chromatin is
FIGURE 1. Large nodule of neoplastic cells within the Lamina propria. granular. Nucleoli are absent. Notice the irregular angulated
Surface urothelium is normal. Case 2 (H&E 100x). nuclear contour and nuclear molding. Case 1 (H&E 400x).

112 Lebanese Medical Journal 2010 • Volume 58 (2) C. J. CHOUAIRY et al. – Small cell carcinoma of the bladder
FIGURE 4. Positive anti-synaptophysin immunohistochemical FIGURE 5. Positive anti-chromogranin A immunohistochemical
stain. Case 1 (400x). stain. Case 2 (400x).

TABLE I
LIST OF THE ANTIBODIES USED AND THEIR CLONES, AS WELL AS THE MANUFACTURER
AND WORKING CONCENTRATION

C. J. CHOUAIRY et al. – Small cell carcinoma of the bladder Lebanese Medical Journal 2010 • Volume 58 (2) 113
TABLE II • STAGE AT DIAGNOSIS OF BLADDER SMALL CELL CARCINOMA

u The N and M parameters were not specified in the study.


* Patients with limited disease (LD) are all those with a stage of any TN0M0 or any TN1M0.
Patients with extensive disease (ED) had a stage of TxN2M0, TxN3M0 or TxNxM1.
**Five patients were staged as D1 (Jewett-Strong-Marshall) system. It is not clear how many of these cases would be classified as T4a
(Stage III) or T4b (Stage IV) in the AJCC 2002 Bladder Cancer Staging System.

Immunohistochemistry was performed on deparaffinized most common clinical presentation [2]. Some patients
sections by Standard Avidin-Biotin-Complex (ABC) Im- present with irritative symptoms such as dysuria, noc-
munoperoxidase technique, with diaminobenzidine (DAB) turia, urgency, urinary obstructive symptoms or local-
as chromogen. When needed, antigen retrieval was per- ized abdominal pain [2]. Nonspecific signs and symp-
formed by boiling the slides for 10 minutes in a citrate toms of malignancy such as anorexia and weight loss are
buffer solution 0.01M, pH 6.0 in a pressure cooker. Sec- frequent. Occasionally, the patients have a paraneoplas-
tions were counterstained with hematoxylin. tic syndrome such as hypercalcemia, hypophosphatemia,
or ectopic secretion of adrenocorticotropic hormone
DISCUSSION (ACTH) [1, 9-12]. Table II shows the stage at presenta-
tion as reported in some studies.
Clinical features
The first case of small cell carcinoma of the urinary Pathology and differential diagnosis
bladder was reported in 1981 by Cramer et al. [1]. The Grossly, small cell carcinoma of the bladder most com-
epidemiology, risk factors and clinical presentations are monly presents as a large solid polypoid mass but it may
similar to those of urothelial (Transitional cell) carcino- also appear as ulcerated plaque like lesion [13].
ma, which is the most common malignancy of this organ Histologically, it is identical to small cell carcinoma of
[7]. The majority of patients are male (M/F ratio of the lung [4, 13-14]. Vascular invasion is almost always pre-
3.3:1), 36 to 85 years old, with a mean age at diagnosis sent and invasion of the Muscularis propria is very common
of 66 years [2, 8]. A history of smoking is frequently at presentation [13].There is often a second type of carcino-
present. Gross hematuria with or without dysuria is the ma that is intimately admixed with it (Urothelial carcinoma,

114 Lebanese Medical Journal 2010 • Volume 58 (2) C. J. CHOUAIRY et al. – Small cell carcinoma of the bladder
squamous cell carcinoma, adenocarcinoma). The pure form tectomy [29-31] and combination of chemotherapy and
is encountered in 12% to 61% of cases [2-3, 11, 13]. radiation therapy [32-33].
Differential diagnosis includes mainly lymphoma [15- The high growth rate had led sometimes to the abor-
16], plasmacytoid urothelial carcinoma [17-19], poorly tion of a planned cystectomy and adjuvant chemotherapy,
differentiated high grade urothelial carcinoma, invasion due to the discovery – at the time of surgery – of unre-
by prostatic small cell carcinoma, pulmonary small cell sectable tumor (i.e. higher stage than what was expected
carcinoma with bladder metastases and the extremely based on preoperative clinical staging) [27]. It is not clear
rare primary primitive neuroectodermal tumor (PNET) however whether this phenomenon reflected clinical
[20]. under staging or rapid growth rate [27]. Siefker-Radtke et
The cytological and histological features remain the al. from M.D. Anderson Cancer Center found that even in
gold standard for the diagnosis (as in pulmonary small cell the presence of potentially resectable tumor by radical
carcinoma). Immunohistochemistry is an adjunct and the cystectomy, pre-operative chemotherapy offered better
immunoprofile has to be interpreted with caution and in 5-year survival rate than initial cystectomy followed by
light of the morphological features, otherwise it can be chemotherapy (78% vs. 36%). In their study, preoperative
misleading rather than helpful. chemotherapy often resulted in pathological down staging
Pulmonary small cell carcinoma metastatic to the uri- while the opposite occurred in cases treated by initial
nary bladder is indistinguishable from primary small cell cystectomy. The authors concluded that surgery was still
carcinoma by morphology and immunohistochemistry needed after chemotherapy because residual tumor is
[21-23]. Clinical history and the presence of associated often present [27].
urothelial carcinoma, squamous cell carcinoma or adeno- The similarity between small cell carcinoma of the
carcinoma are much more helpful. lung and small cell carcinoma of the urinary bladder in
Small cell carcinoma of the prostate can occasionally terms of pathology, high growth rate, advanced stage at
invade the bladder. Its morphology and immunoprofile presentation, frequent subclinical metastases and chemo
are almost identical to its urinary counterpart [24]. The sensitivity, as well as the scarcity of small cell carcinoma
presence of an admixed regular type prostatic adenocar- of the bladder, prompted some authors to approach it the
cinoma in 43% of cases as well as the clinical and radio- same way as its pulmonary counterpart (which is much
logical features are helpful in reaching the correct diag- more frequent and better studied), i.e. as a systemic dis-
nosis [24]. ease from the onset, with no role for surgery [5, 32].
Primary primitive neuroectodermal tumor (PNET) of A combination of chemotherapy and radiotherapy –
the urinary bladder is extremely rare [20]. It is glycogen depending on the extent of the disease – was recommend-
rich, strongly expresses CD99 (MIC2 gene product) and ed (organ sparing treatment strategy) [5]. The authors sug-
Vimentin and it is usually negative for Synaptophysin and gested a two-tier staging system similar to the one used in
Chromogranin [20]. small cell carcinoma of the lung (i.e. limited disease and
extensive disease). Those with limited disease are defined
Treatment as those whose disease could be included within a radia-
The optimal treatment strategy for this type of tumor re- tion field [34] (i.e. disease limited to the pelvis, no distant
mains unknown and is still controversial [7]. Its scarcity metastases and involvement of maximally one loco-
precludes prospective randomized studies. It took 20 years regional lymph node less than 2 cm) [5, 32]. Otherwise,
for a single center to include 25 patients in a prospective the disease is considered to be extensive. The rationale for
study [5]. In another series, only four cases were diagnosed adding radiotherapy to systemic therapy is the small but
during a 19-year period [25]. All the currently available significant documented improvement in overall survival
data indicate that surgery alone (TUR or cystectomy) is in cases of lung small cell carcinoma [34-35]. Bex et al.
not an optimal therapy [26]. The majority of patients pre- [5] concluded that bladder preserving surgery (chemo-
sent with metastatic disease. Metastases rather than loco- therapy and radiotherapy) is an attractive and feasible ther-
regional tumor progression are the usual cause of death apeutic option. However, the high prevalence of elderly
[5, 25]. Metastases involve the regional lymph nodes, lung, patients with co-morbidities precludes chemoradiotherapy
liver, bone and brain [2, 13, 27]. Table III summarizes the in a significant portion (more than half the patients with
treatment modalities and outcome as reported in some of limited disease in their study).
the studies cited in this article. Chemotherapy with a neuroendocrine regimen contain-
Even in the setting of clinically localized and surgically ing etoposide and cisplatin (E/P) or ifosfamide and doxo-
resectable disease, many patients die within one year of rubicin was more likely to successfully eradicate the small
diagnosis, which indicates that these tumors have a high cell component compared with regimens typically used
metastatic potential and that a significant number of pa- for urothelial carcinoma [27]. Cisplatin chemotherapy
tients with presumed (apparent) localized disease have in particular was associated with a favorable prognosis
already undiagnosed micro metastases at presentation [8, [4, 8, 30, 36]. The possibility that the good performance
28]. Treatment strategies incorporate multimodality thera- status (required for cisplatin-based chemotherapy) is
py such as cystectomy and radiation therapy [28] or incor- mainly responsible for the improved survival was raised
poration of chemotherapy with local therapy such as cys- however [5].

C. J. CHOUAIRY et al. – Small cell carcinoma of the bladder Lebanese Medical Journal 2010 • Volume 58 (2) 115
TABLE III • REPORTED TREATMENT MODALITIES AND OUTCOME IN BLADDER SMALL CELL CARCINOMA

Abrahams [3]

116 Lebanese Medical Journal 2010 • Volume 58 (2) C.J. CHOUAIRY et al. – Small cell carcinoma of the bladder
Grignon [30]

SURG : Radical cystectomy RT : External beamradiotherapy CH : Chemotherapy TUR : Trans urethral resection

Potential role for targeted therapy (50%) of small cell carcinoma of the bladder.
CD117 (c-kit) is a type III transmembrane tyrosine kinase These data raise the question of whether therapy
growth factor receptor. Gain of function mutation (Activa- against these target molecules might prove beneficial in
tion mutation) of the receptor occurs in a large subset of patient management.
gastrointestinal stromal tumors (GIST), leading to consti- The successful treatment of some GIST tumors by
tutive (permanent) phosphorylation and activation of the imatimib mesylate (Gleevec®), which is an inhibitor
receptor, regardless of the presence of the ligand. of c-kit, raises the question of whether treatment against
Pan et al. [37] showed positive immunostaining for these target molecules (targeted therapy) might be bene-
c-kit in 14 of 52 cases (27%) of small cell carcinoma of ficial in the case of small cell carcinoma of the bladder.
the bladder. Additional studies are needed however, especially
Epidermal growth factor receptor (EGFR ; HER-1 ; regarding the status of the c-kit receptor. The large data
ERB-B1) and EGFR-2 (HER-2 ; ERB-B2) are transmem- obtained from the study of gastrointestinal stromal tumors
brane tyrosine kinase growth factor receptors, which are (GISTs) indicate that the expression of the c-kit antigen –
over expressed in many malignancies. Abrahams et al. [3] as detected by immunohistochemistry – can be associated
demonstrated expression of EGFR in 4 of 11 cases (36%) with either the wild type or the mutated form of the recep-
of small cell carcinoma of the bladder by immunohisto- tor [38]. The responsiveness of GIST to imatimib mesy-
chemistry. late is variable, depending on the presence or absence of
Soriano et al. [22] observed typical membranous stain- gain of function mutation and depending on the mutated
ing indicating over expression of EGFR-2 in 5 of 10 cases exon [39-41].

C. J. CHOUAIRY et al. – Small cell carcinoma of the bladder Lebanese Medical Journal 2010 • Volume 58 (2) 117
CONCLUSION production. Hum Pathol 1985 ; 16 (3) : 313-15.
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C. J. CHOUAIRY et al. – Small cell carcinoma of the bladder Lebanese Medical Journal 2010 • Volume 58 (2) 119