Introduction
Small cell carcinoma of the urinary bladder (SCCB) is a rare, high-grade, malignant, and poorly differentiated neuroendocrine neoplasm that accounts for only 0.35%-0.7% of all bladder tumors [
1,
2]. Cramer and colleagues first described the disease in 1981 [
3]. Majority of SCCB patients typically present with painless gross hematuria as the initial clinical symptom, and 65% of patients have a history of smoking [
1]. In the present paper, we report a case of SCCB without gross hematuria, in contrast to previously reported cases. This case was diagnosed by histopathological examination.
Case presentation
The patient was a 68-year-old man who was diagnosed with urothelial carcinoma according to the pathological characteristics of the removed tissue after a local resection of the bladder in December 2012. Six months later, the patient underwent a follow-up examination after the operation. Routine blood and urine analyses revealed no abnormalities. A color Doppler ultrasound revealed a hypoechoic nodule measuring 20 mm × 18 mm × 16 mm at the posterior wall of the bladder with a clear border, regular configuration, exophytic growth, and no obvious blood signal. A CT scan revealed a rounded tubercle with a high parenchymal density located in the posterior wall that had infiltrated the muscle layers (Fig. 1A). The results of cystoscopy showed local elevation of the surgical scar; however, no tumor cells were found in the biopsy tissue.
Diagnosis and treatment
A partial cystectomy was performed on the patient, and an exogenous mass (3 cm × 2 cm in size) adhering to the adjacent peritoneum was found (Fig. 1B). A pathological examination revealed that the entire thickness of the involved bladder wall had been invaded by tumor cells. Hematoxylin and eosin (H&E) stain showed that the tumor cells were distributed as a sheet; these cells were small and exhibited darkened heterotypical nuclei. The peripheral mucosa of the tumor exhibited epithelial dysplasia and exfoliation with local lymphocytic infiltration (Fig. 2A). In addition, the immunohistochemistry results showed that the tumor cells were positive for neural cell adhesion molecule 1 (NCAM1/CD56), epithelial membrane antigen (EMA), pan-cytokeratin (CK-PAN), and synaptic element (SYN). However, the tumor cells were negative for cytokeratin 20 (CK20), CD45, and chromogranin A (CgA) (Fig. 2B–2H). The above results confirmed that the tumor cells were small neuroendocrine cells, and the patient was diagnosed with SCCB.
A postoperative CT scan revealed that the resection of the neoplasm was complete. Given that the general condition of the patient gradually improved, he was discharged one week after the surgery. To prevent the recurrence or metastasis of the carcinoma, the patient underwent chemotherapy. The patient underwent follow-up examinations for one year without recurrence of the tumor.
Discussion
Small cell carcinoma can occur in almost all epithelium-containing organs; however, a tumor in the urinary bladder is rare. In 1989, Blomjous
et al. performed a retrospective study of 3778 primary bladder malignancy cases, in which 0.48% (18/3778) of the 3778 primary bladder cancers were SCCBs [
4]. In 2005, Choong
et al. conducted a retrospective study at the Mayo Clinic (Rochester, MN) to characterize the clinical and pathological features of patients diagnosed with SCCB between 1975 and 2003; they found that 0.53% (44/8345) of the 8345 patients with malignant bladder neoplasms had SCCBs [
5]. Hou
et al. reviewed the charts of patients with bladder tumors at the Chang Gung Memorial Hospital from January 1995 to December 2012, and they found that 0.74% (18/2421) of the 2421 patients with malignant bladder tumors were diagnosed with primary SCCB [
6]. The incidence of SCCB in males is known to be significantly higher than that in females; the gender ratio of SCCB is 5:1 (ranging from 1:1 to 16:1), and the average onset age of SCCB is approximately 67 years (ranging from 32 to 91 years) [
1,
7].
SCCB patients usually have a poor prognosis; they usually present in advanced stage when diagnosed. Cheng
et al. reported that among 64 patients with SCCB, 98% had muscle-invasive disease, and 66% had lymph node metastasis at the time of cystectomy [
1]. A retrospective study performed by Choong
et al. indicated that out of 27 patients with SCCB, 27.3% (12/27) were in stage II, 29.6% (13/27) were in stage III, and 43.2% (19/27) were in stage IV [
5]. Ismaili
et al. showed that the average survival duration was approximately nine months for patients with pure SCCB [
8]. The most common symptom of SCCB is gross hematuria, with dysuria being the second most common symptom [
9]. Urinary obstruction, abdominal pain, urinary tract infection, and weight loss may also be concomitant symptoms [
4,
10]. Cases with paraneoplastic syndromes and hypercalcemia are rarely reported [
11]. SCCB is mainly diagnosed by cystoscopy and transurethral resection of bladder tumor (TURBT) [
6]. The tumors are usually large and nodular with an ulcerated surface [
6].
The lateral bladder walls are the most common sites of SCCB. Using CT scanning, we can observe typical wall invasion and central necrosis or cystic changes, which often range in size from 2 cm to 10 cm [
1,
7,
12]. The ultrasonography and CT scan results of the present patient revealed that the neoplasm was an obviously exophytic nodular mass located at the posterior wall of the bladder, with involvement of the muscle layers, which indicated its invasive ability and malignancy. Therefore, tumor resection was necessary.
SCCB is combined with classic urothelial carcinomas or adenocarcinomas of the bladder in 68% of the cases [
1]. However, in the present case, we did not find evidence suggesting that the origin of the tumor cells was a urothelial carcinoma. In addition, distinguishing SCCB from metastatic small cell carcinomas of lung origin is difficult through histological examinations alone [
13]. Typical morphological features, including hypercellularity, necrosis, and nuclear chromatin crush, can be observed via H&E stain [
14]. The histological results of the present case revealed that the tumor cells were distributed as a sheet with small, darkened, heterotypical nuclei. However, morphological features alone cannot produce a definitive diagnosis in some cases. Immunohistochemistry can facilitate the differentiation of various tumor cell types and SCCB diagnosis [
13].
Medical scientists are exploring and rapidly developing quick, simple, and effective diagnostic methods for SCCB. The use of immunohistochemical methods to diagnose SCCB is becoming an area of interest for translational medicine research. At present, various molecular markers are often used for the clinical detection of SCCB, such as CD56, nerve-specific enolization enzyme (NSE), SYN, EMA, CK-PAN, CK20, CgA, thyroid transcription factor 1, and Ki-67, which is a marker of proliferation [
14,
15]. To date, no biomarkers have been found that can diagnose SCCB with 100% specificity. In most SCCBs, at least two positive neural markers exist, the most common being NSE, which is present in approximately 90% of SCCB cases. Furthermore, CHG and SYN are present in approximately half of all SCCB cases [
16]. Iczkowski
et al. reported that CHG can be used to diagnose SCCB with 97% specificity, whereas the specificity of NSE and SYN are 93% and 76%, respectively [
17,
18]. The immunohistochemical results of the present case showed that the tumor cells were positive for EMA, CD56, CK-PAN, and SYN. The presence of NCAM1/CD56- and SYN-positive cells suggests that the tumor cells are derived from neural cells, whereas the presence of EMA- and CK-PAN-positive cells suggests that the tumor cells are derived from epithelial cells. Moreover, H&E stain showed that the tumor cells were distributed as a sheet, small in size, and exhibited darkened heterotypical nuclei. After integration of the morphological features and molecular marker data, the patient was diagnosed with SCCB. The involved bladder wall was resected by cystoscopy to limit the diffusion of the tumor cells. SCCB patients are known to develop distant metastases or paraneoplastic syndromes [
19], in which oncologic surgery is the first choice of treatment but is not the most curative option unless the tumor is confined to the bladder. The surgical methods available are radical cystectomy, salvage cystectomy, and TURBT. Combination therapy with adjuvant or neoadjuvant chemotherapy can also benefit SCCB patients [
20].
All the evidence suggested that SCCB is a type of malignant carcinoma. Therefore, early identification and diagnosis are important, which are challenging for pathologists and urologists. Although gross hematuria is the most common symptom in SCCB patients, it is not exhibited in 12%-37% of patients [
2,
5,
21]. The present case had no urinary symptoms. However, upon re-examination with CT scan, the results revealed a lesion in the bladder.
The initial symptoms varies in all SCCB cases. Uroscopy is necessary and helpful for diagnosing SCCB as early as possible; nevertheless, one should also pay close attention to other initial symptoms, such as frequent hematospermia, recurrent urinary tract infection, urethral obstruction, urinary obstruction, dysuria, abdominal pain, and urinary tract infection [
5,
8]. Further examinations such as KUB, enhanced CT scan, and MRI results should attach great importance to these urinary abnormal symptoms. Therefore, the definitive diagnosis of SCCB should depend on the pathological and immunohistochemical results. We cannot rely on urinary symptoms alone to achieve a definitive diagnosis. Imaging studies and histopathological analyses must also be performed.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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