Multidisciplinary treatment for small cell carcinoma of the bladder: a case report

Abstract

Small cell carcinoma (SCC) of the urinary bladder is a rare and highly aggressive subtype of bladder cancer. Most cases are diagnosed at advanced stages, and its therapeutic strategy remains unestablished. Here, we report a case of bladder SCC in which multidisciplinary treatment has resulted in relatively long-term survival. A 68-year-old man presented with gross hematuria. A cystoscopy revealed an invasive bladder tumor. A transurethral resection of bladder tumor (TURBT) was performed, and the pathological diagnosis was SCC. After systemic chemotherapy using etoposide and carboplatin and subsequent TURBT, a radical cystectomy and ileal conduit were performed. Three months postoperatively, the patient had a recurrence in the para-aortic lymph node. Systemic combination chemotherapy with carboplatin plus irinotecan (CBDCA + CPT-11) was administered, followed by amrubicin and an immune checkpoint inhibitor. In addition to this treatment, radiation therapy for the metastatic region led to the reduction of pain and shrinkage of the metastatic lesion. The patient survived for 2 years after the initial diagnosis. Our report indicates that multidisciplinary treatment can be effective for SCC of the bladder, and a therapeutic strategy including the identification of novel biomarkers should be established.

Introduction

Small cell carcinoma (SCC) is categorized as one of the subtypes of neuroendocrine carcinoma according to the WHO classification [1]. SCC has often been reported as a more aggressive subtype than the standard type, and patients with SCC have shown poor prognosis [1, 2]. In bladder cancer, SCC makes up 0.5–1.0% of them, while most of them are urothelial cancer. Because of the low incidence and insufficient data, there has been no consensus on the standard treatment of SCC [2]. Here, we present a multidisciplinary approach to treating a case of SCC of the bladder.

Case report

A 68-year-old man presented to his primary provider with the chief complaint of blood in his urine. He had no familial history of cancer, no history of serious illness, past surgeries, smoking, or alcohol consumption.

His urinalysis at presentation revealed > 100 RBCs, and the urinary cytology was class III. The cystoscopy revealed a nodular tumor on the left side of the bladder (Fig. 1). The CT and plain MRI also showed a tumor on the same side and a nodule outgrowth of the left aspect of the bladder (Fig. 2). There were no findings suggesting lymph node or visceral metastases. A biopsy and potential resection of the tumor were performed subsequently via a transurethral resection of bladder tumor (TURBT). Histopathology using hematoxylin and eosin (H&E) staining revealed sheets and nests of small-to-medium-sized cells with hyperchromatic nuclear with extensive areas of coagulative necrosis. Immunohistochemistry staining was positive for chromogranin A and synaptophysin; these positive markers are indicative of a tumor with a cellular subtype of a neuroendocrine origin (Fig. 3a–d). Based on the above, the patient was diagnosed with SCC of the bladder. The tumor invaded at least the muscle layer, and the pathological grade was high-grade carcinoma. Because the patient initially refused radical cystectomy, systemic chemotherapy was started with four courses of etoposide plus carboplatin. 80 mg/m² of etoposide as administered intravenously on days 1–3, repeated every 3 weeks, and 5 AUC of carboplatin was given intravenously on day 1. After the four courses, the subsequent TURBT showed a pathologically viable tumor (Fig. 3e), and the patient opted to undergo radical surgery. A robot-assisted radical cystectomy (RARC) and intracorporeal ileal conduit were performed. Pathology showed that the fatty tissue around the bladder was also infiltrated, and two of the ten lymph nodes extracted (one left closed lymph node and one left external iliac lymph node) were positive for cancer cells. Thus, the patient was diagnosed with small cell carcinoma of the bladder pT3bN2M0. Pathological finding also showed the infiltration of cancer cells into the peri-vesical fatty tissue mixed with necrotic tissue, indicating the effect of the chemotherapy. Three months after the RARC, retroperitoneal lymph node recurrence was observed (Fig. 4a), and combination therapy with carboplatin plus irinotecan (CBDCA + CPT-11) was administered. Irinotecan 60 mg/m² was administered intravenously on days 1, 8, and 15, repeated every 4 weeks. Carboplatin 5 AUC was given intravenously on day 1. Although the recurrent lesion significantly reduced in size after three courses of CBDCA + CPT-11 (Fig. 4b), the disease relapsed after the sixth course (Fig. 4c). Amrubicin was then administered as the third line option. Amrubicin 40 mg/m² was administered intravenously on days 1–3, repeated every 3 weeks. However, the patient experienced worsening pain, and the CT also showed increased lymph node involvement, so the treatment was discontinued after only one course. Because the recurrent lesion was localized to the para-aortic lymph node, radiotherapy (60 Gy/20 fraction) was performed as a local therapy to control pain and reduce the size of the tumor. As a result, the recurrent lesion was reduced, and pain was relieved.

Fig. 1.

Cystoscopy revealed a nodular tumor with 3.5 cm in size on the left lateral wall of the bladder

Fig. 2.

a Abdominal contrast-enhanced CT and b abdominal plain MRI also showed a tumor on the left wall of the bladder, which was suspicious for extravesical invasion

Fig. 3.

Microscopic findings of the bladder tumor. a Low-power view showing a solid mass of small cell carcinoma covered by mucosa with carcinoma in situ. b High-power view of the cancer cell component showing sheets and nests of small to medium-sized cells with hyperchromatic nuclei and extensive area of coagulative necrosis. Immunohistochemical staining for c chromogranin A and d synaptophysin. e Pathological findings after four courses of systemic chemotherapy showed viable tumor cells with necrotic tissue

Fig. 4.

Findings of abdominal contrast-enhanced CT. a Recurrence of retroperitoneal multiple lymph node metastasis at three months after radical cystectomy. b Volume reduction of retroperitoneal lymph node metastasis after three courses of CBDCA + CPT-11 therapy. c Recurrence of retroperitoneal lymph node metastasis after six courses of CBDCA + CPT-11 therapy

FoundationOne®CDx cancer genomic profiling testing was then performed but failed to identify any genetic findings that could lead to potentially effective treatment. Then, pembrolizumab (200 mg/body, every 3 weeks) was administered as the fourth line option; however, the patient died 2 years after surgery due to the progression of the disease.

Discussion

Primary bladder SCC is rare. Several studies have showed that the incidence is between 0.35% and 0.70% [1, 2]. Because of the low incidence and lack of data, standard guidelines for management are yet to be established. Many of the previous cases received systemic therapy using regimens for lung SCC, which showed poor prognosis [1–3]. In many of the previous cases, the patients underwent radical cystectomy, which is the treatment for urothelial carcinoma of the bladder [4]. However, the oncological outcome of total cystectomy alone is not sufficient for SCC of the bladder [2]. For locally invasive urothelial carcinoma of the bladder, neoadjuvant systemic chemotherapy has been shown to improve the prognosis [5, 6]. In addition, in SCC, several reports have shown that preoperative chemotherapy was associated with down-staging of tumors in 45% of cases, although few down-staged to pT2 or below [5, 7], indicating the potential for a better prognosis than radical cystectomy alone [4, 6]. A few reports have been published on neoadjuvant/adjuvant chemotherapy for SCC of the urinary bladder. One study showed that the 5-year survival rate for the patients who underwent neoadjuvant chemotherapy was 78%, which was significantly higher than that of the patients who underwent radical cystectomy (36%) [4]. Another study demonstrated the genetic analysis for predicting the sensitivity of neoadjuvant chemotherapy in patients with SCC [8]. Furthermore, the role of adjuvant chemotherapy after radical cystectomy for invasive SCC has been reported to potentially improve the chances of survival compared with cystectomy alone [9]. In addition, adjuvant chemotherapy has been recommended for patients whose cancer is in the advanced stages [2]. These studies indicate that perioperative chemotherapy may be effective for select patients with SCC. In our present case, six cycles of systemic chemotherapy were given before the patient made the decision to undergo surgical treatment, followed by radical cystectomy. However, the effectiveness of chemotherapy has not been fully clarified because of the rare pathological type of the cancer, and it progressed more rapidly than urothelial carcinoma, so some studies have recommended immediate radical cystectomy followed by postoperative adjuvant chemotherapy [2, 3]. Even when radical cystectomy is performed, the rate of recurrence is high, and substantial therapy is required.

The present case was treated with the second-line regimen, CBDCA + CPT11, and tumor shrinkage was observed after three cycles of treatment. According to reports of other organs, SCC was often reported to be relatively radiosensitive, which has been shown in previous studies [10–12]. Furthermore, the combination of radiation therapy and chemotherapy has been reported to potentially improve the outcomes. For instance, the combination therapy has been found to be beneficial in treating small cell lung cancer [12]. Likewise, Lohrisch et al. reported that a combination of local irradiation and chemotherapy was effective for bladder cancer with components with SCC, indicating the benefits of multidisciplinary treatment [13]. It is also suggested that the combination and timing of treatments is important in multidisciplinary treatment. A retrospective analysis indicated the potential role of a multi-modality approach with radiation therapy for patients with localized or locally advanced SCC. The analysis reported that surgical therapy with chemotherapy and/or radiation therapy was associated with prolonged overall survival [14]. Sved et al. also reported the importance of systemic chemotherapy in addition to cystectomy or radiation therapy for local disease control in a review of 123 patients with small cell carcinoma [15]. In the present case, irradiation of the para-aortic lymph node metastases was effective for pain control, but combining irradiation with preoperative chemotherapy at an early stage may have been even more beneficial. Thus, although various treatments for SCC have been reported to date, the effectiveness has been limited, and multidisciplinary treatment is considered necessary to achieve sufficient therapeutic effects. A retrospective study demonstrated that the 5-year survival rates of patients with stage II, III, and IV SCC were 63.6%, 15.4%, and 10.5%, respectively [2], and the median OS was 11 months. In contrast, OS in the present case was 24 months, indicating that a relatively better outcome could be obtained through multimodality treatment with surgical therapy, including TURBT and total bladder resection, as well as local control with radiation therapy. There is no established standard of care for SCC of the bladder, and previous reports have used various regimens of chemotherapy, surgery, and radiation therapy. In the present case, the patient underwent systemic treatment with these various regimens, and surgery and radiation therapy were administered. His relatively long survival may be attributed to such multidisciplinary treatment using almost all of these treatment options.

In summary, we have presented a case of multidisciplinary treatment for bladder SCC. The prognosis for patients with bladder SCC was poor in previous analyses. While no genetic abnormality was found in the present case, additional treatment strategies, including the identification of new therapeutic targets and biomarkers, will need to be explored in the future.

Author contributions

JT, YM, TY, RU, and IN performed and supervised the entirety of the treatment including operation and systemic therapy. YM and JT drafted the manuscript. TH performed the cancer genomic analysis. MF supervised the drafting of the manuscript. All authors have read and approved the final manuscript.

Funding

No funding was received for this case report.

Data availability

Data and materials will be available on request to the corresponding author.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All anticancer drugs were administered after approval by Pharmaceutical Affairs Committee in Kobe City medical Center West Hospital, and ethical approval for the report was obtained from the Research and Ethics Committee of the institute.

Informed consent

Informed consent was obtained from the patient for the publication of this case report.