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A 71-year-old man presented to hospital in November 2014 upon referral after reporting pain and evidence of blood on urination. Imaging and cystoscopy assessments identified a vegetative lesion of the bladder wall.

The patient reported being a heavy smoker for the past 30 years. His medical history over the past 3 decades included high blood pressure, elevated cholesterol, and psoriasis. His surgical history included a right hip prosthesis treatment for ankylosing spondylitis and an open partial colon resection for diverticulitis.

Clinicians performed a transabdominal ultrasound scan, which showed a 3-cm mass located on the left side of the anterior bladder wall. A subsequent contrast-enhanced abdominal CT scan was performed, which confirmed the presence of a 34 × 24-mm vegetative lesion of the bladder on the left lateral and anterior wall; both sides of the upper urinary tract were unaffected.

The patient underwent cystoscopy, followed by diagnostic transurethral resection of the bladder tumor. Examination of the biopsied tissue identified a pT2 high-grade urothelial carcinoma with widespread neuroendocrine differentiation affecting more than 80% of cells.

The immunohistochemical staining of the specimen noted positivity for synaptophysin and neuron-specific enolase. This provided confirmation of the tumor's neuroendocrine origin, while chromogranin A and somatostatin staining were both negative. A Ki-67 assessment found that the proliferation index was 70%.

A multidisciplinary team evaluated the patient and decided that a full-body CT scan was needed to determine clinical staging of this rare disease. The CT scan revealed an increase in the size of the bladder lesion, which had a diameter of 45 mm and evidence of thickening of the left bladder wall. There were no suspicious lymph nodes or evidence of distant metastasis.

In light of the patient's age and comorbidities, clinicians performed a multidimensional geriatric assessment prior to initiating chemotherapy, which determined that he was an appropriate candidate for neoadjuvant chemotherapy with cisplatin/etoposide every 21 days for 3 cycles.

The patient was treated with cisplatin 75 mg/m² intravenously on day 1 of the 3-week cycle and etoposide 100 mg/m² intravenously on days 1 to 3 every 3 weeks.

No high-level toxicity was noted; there was evidence of low-grade nephrotoxicity observed during the first cycle. Throughout the treatment, clinicians also noted grade 1 and 2 anemia, grade 1 thrombocytopenia, and grade 1 nausea.

At the end of chemotherapy, a full-body CT scan was performed, which showed no remaining evidence of the vesicle lesion and no signs of distant metastasis. Evidence of wall thickening of the bladder dome was associated with the previous resection.

One month after the patient had undergone the last cycle of chemotherapy, he underwent a radical cystectomy and lymphadenectomy, with placement of bilateral ureterocutaneostomy (Figure A). There were no complications following the surgery, and the patient's recovery was uneventful. Examination of the bladder specimen showed no microscopic signs of tumor in the bladder or in any dissected lymph nodes (Figure B).

Clinicians concluded that the neoadjuvant chemotherapy had resulted in a complete response of the neuroendocrine tumor.

One month after surgery, the patient underwent another full-body CT scan, which was completely negative for local and metastatic recurrence. Clinicians determined that there was no need for adjuvant chemotherapy and planned a close follow-up. At the time of the case report 1 year from diagnosis, the patient was still alive.

Discussion

Clinicians reporting this of successful treatment of rare small cell carcinoma of the urinary bladder (SCCUB) wished to share the complete response achieved with neoadjuvant chemotherapy and radical cystectomy, in order to show the effectiveness of the currently available treatment.

SCCUB represents less than 1% of all carcinomas originating in the bladder. Furthermore, it tends to occur along with transitional cell carcinoma. Neuroendocrine tumors affecting the bladder are noted to be more aggressive and have a worse prognosis than transitional cell carcinomas of the urinary bladder. In addition, they often develop in other organs. At the time of diagnosis, 95% of patients with SCCUB are in an advanced local stage (pT2 or pT3), and also at greater risk for metastatic disease than those with transitional cell carcinoma.

An of the Surveillance, Epidemiology, and End Results (SEER) limited database (1991-2005) found that median overall survival was 11 months for patients with SCCUB, with older Caucasian men most commonly affected (ratio of Caucasians to non-Caucasians 10:1; ratio of men to women 3:1; median age 73 years).

Gross hematuria, with or without dysuria depending on the site of the lesion, is the most common symptom of SCCUB.

Aside from case reports, there are sparse data on the treatment approaches for SCCUB, the authors noted, adding that most clinicians have based their approach to treatment on recommendations for small cell lung cancer.

In cases of limited disease, the authors said that clinical studies have reported better clinical response to strategies that combine local treatment and chemotherapy compared with local strategies alone.

"Multimodality therapies included neoadjuvant chemotherapy followed by radical cystectomy, radical cystectomy followed by adjuvant chemotherapy, and sequential chemoradiation," they wrote. In terms of median overall survival, they suggested that outcomes with neoadjuvant chemotherapy appear to be better than with surgery alone or adjuvant chemotherapy.

The group cited a that found that neoadjuvant chemotherapy was associated with a 5-year disease-free survival rate of 78% versus 36% with surgical treatment alone.

These findings inspired those clinicians to conduct the first of SCCUB, which alternated neoadjuvant doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in surgically resectable SCCUB and palliative therapy in unresectable patients. Median overall survival was 58 months in patients with resectable disease who received neoadjuvant chemotherapy compared with 13.3 months for patients with unresectable disease.

A subsequent confirmed that neoadjuvant chemotherapy was associated with a median overall survival of 159.5 months versus 18.3 months with cystectomy alone, and a 5-year disease-specific survival rate of 79% versus 20%, respectively. This study also found that neoadjuvant chemotherapy was associated with pathologic downstaging to ≤pT1N0 in 62% of tumors versus 9% of tumors in patients treated with surgery alone.

In surgically resectable SCCUB, neoadjuvant chemotherapy followed by radical surgery is the , given that it achieves cure in 78% to 80% of patients, the authors noted. "The rationale behind this approach relies on the rapid growth and upstaging after initial surgery; the advantage of neoadjuvant chemotherapy is the possibility to treat micrometastatic disease at an early stage and downstage the disease, facilitating radical surgery," they explained. When surgery is not an option, sequential chemoradiotherapy is reported to cure 36% to 70% of cases.

The authors cited the from the Canadian Association of Genitourinary Medical Oncologists, which advised treating limited-disease SCCUB with neoadjuvant or adjuvant chemotherapy; their recommendations reflect the regimens used in treating small cell lung cancer: cisplatin and etoposide, followed by cystectomy, or radiation as an alternative bladder-sparing approach.

The National Comprehensive Cancer Network guidelines recommend use of concurrent chemoradiotherapy or neoadjuvant chemotherapy followed by either cystectomy or radiation therapy for non-metastatic cancers with small cell component (or neuroendocrine features). Recent case studies have reported responses with checkpoint inhibition in patients with or disease.

Regarding their patient, the authors said that they performed a literature review to determine the best treatment regimen, and "the complete response obtained confirms the role of neoadjuvant chemotherapy [especially cisplatin plus etoposide] in downstaging limited-disease SCCUB before radical surgery and the efficacy of the neuroendocrine regimens used for small cell lung cancer in extrapulmonary NETs."

"In the absence of a multi-institutional comparative trial, it is very difficult to establish authoritative treatment guidelines, and there is no definitive conclusion regarding the best multimodality therapy strategy for the different stages of SCCUB. However, the improved clinical outcomes found in the literature and the positive result obtained in the present case suggest the utility of neoadjuvant chemotherapy, especially the regimen of cisplatin plus etoposide in limited-disease SCCUB," they concluded.

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