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.