Discussion
Primary neuroendocrine tumors of the bladder are very uncommon, representing less than 1% of bladder tumors. Among the four types of neuroendocrine tumors recognized in the WHO/ISUP 2016 classification, small cell is the most common, whereas large cell is extremely rare. However, small or large cell neuroendocrine tumors can be pure or mixed with urothelial carcinoma or other histological types [1, 2, 7]. In this case, both types were present, with a large cell component comprising approximately 20%.
It is important to note that our patient developed a bladder tumor on a bladder previously affected by bilharzial cystitis. This unique case not only showcases a rare histological type of bladder tumor but also highlights the uncommon coexistence of bilharzia, which is often associated with squamous cell carcinoma. Existing literature has established an association between bilharzia and the development of neuroendocrine tumors in the gastrointestinal tract [4]. It is probable that chronic inflammation from bilharzial cystitis played a role in the development of neuroendocrine tumors in our patient’s bladder.
From a histological perspective, large cell neuroendocrine carcinoma consists of large polygonal tumor cells exhibiting abundant cytoplasm, prominent nucleoli, and high mitotic activity. It displays growth patterns including solid, trabeculated, nested, pseudoglandular, organoid, and palisading structures [8].
Conversely, small cell neuroendocrine carcinomas are characterized by sheets or nests of small to intermediate cells with a high nuclear-to-cytoplasmic ratio, molding, scant cytoplasm, inconspicuous nucleoli, and evenly dispersed ”salt and pepper” chromatin [8].
Immunohistochemical staining plays a crucial role in confirming the impression of the light microscopic appearance of both small and large cell carcinomas. Markers that are typically expressed include CD56, synaptophysin, chromogranin A, and AE1/3. Our case demonstrated positivity for synaptophysin, CD56, and AE1/3 consistent with neuroendocrine differentiation [1,2,6-9].
Both small cell and large cell neuroendocrine tumors are aggressive and can present either as localized disease, as is the case in our patient, or as metastatic disease. However, since large cell neuroendocrine carcinoma is rare, its biological and clinicopathologic characteristics are largely unknown. This lack of understanding hinders the development and assessment of effective therapeutic approaches. Existing knowledge about this disease is restricted, primarily derived from small series and case reports. As of now, there is no established consensus on the standard treatment for patients affected by this aggressive malignancy [7,8]. A study at a single center found a difference in disease-free survival rates between 5 patients treated with adjuvant chemotherapy versus surgery alone, but the small number of cases limited the conclusiveness of the finding. Chemotherapeutic regimens are often adapted from those used for pulmonary neuroendocrine tumors, making neoadjuvant or adjuvant combination etoposide and platinum-based therapy the preferred treatment option. While surgery alone is not advised, it remains crucial in the comprehensive care of these patients [8].
Establishing a standard treatment guideline for small cell neuroendocrine carcinoma is also challenging due to its rarity. Patients are classified into those with localized or metastatic disease. For patients with localized disease, systemic chemotherapy followed by either radical cystectomy or radiation therapy is suggested. This approach found that patients undergoing preoperative chemotherapy had better cancer-specific survival rates compared to those who underwent immediate cystectomy (78% vs. 36%). Due to the absence of specific guidelines for small cell carcinoma, most chemotherapy regimens are adapted from protocols used for small cell lung cancer. Typically, a platinum-based chemotherapy agent is combined with etoposide. While cisplatin is recommended, carboplatin can be considered as an alternative if cisplatin is contraindicated or unavailable [7-9]. Based on this literature review, our patient was referred to the medical oncology team for assessment and potential adjuvant chemotherapy, as optimal treatment strategies remain uncertain.
In terms of prognosis, the pure form of large cell neuroendocrine cancer could possibly carry a worse prognosis than mixed forms based on a study with a small sample size by Wang et al. The worse outcome of pure large cell neuroendocrine carcinoma, compared with mixed types, could be due to the disease stage at the time of diagnosis [9]. However, for these conditions, long-term follow-up is crucial for monitoring recurrence and disease progression.