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Omiyale and Venyo: Primary well-differentiated neuroendocrine tumour (carcinoid tumour) of the urinary bladder


Neuroendocrine tumour (NET) represents a heterogeneous group of neoplasms with a diverse clinical presentation involving different anatomical sites that have similar histological features. NETs are epithelial tumours with predominant neuroendocrine differentiation, which arise from various sites in the body.1,2

Two broad categories, based on differentiation, are identified: (1) well-differentiated NETs and (2) poorly differentiated NETs. Differentiation is a description of the extent to which neoplastic cells resemble the normal non-neoplastic cells, while grading refers to the characteristic biological aggressiveness of the tumour. Although differentiation is usually associated with grading, the terms are distinct. The subtle distinction between these terms is reflected in the World Health Organization (WHO) and European Neuroendocrine Tumour Society (ENETS) classification of gastroenteropancreatic (GEP) NETs (Table 1).


Pathologic classifications of GEP NETs

Grade GEP NETs (WHO, 2010) GEP NETs (ENETS)
Low Neuroendocrine neoplasm Neuroendocrine tumour
Grade 1 Grade 1 (G1)
Intermediate Neuroendocrine neoplasm Neuroendocrine tumour
Grade 2 Grade 2 (G2)
High Neuroendocrine carcinoma Neuroendocrine carcinoma
Grade 3, small-cell carcinoma Grade 3 (G3), small-cell carcinoma
Neuroendocrine carcinoma Neuroendocrine carcinoma
Grade 3, large-cell carcinoma Grade 3 (G3), large-cell carcinoma

Well-differentiated NETs have classic carcinoid architectural arrangements with varying patterns. Diffuse and intense immunoexpression of neuroendocrine markers is exhibited by well-differentiated NETs because of the large number of secretory granules. Poorly differentiated NETs have a more sheet-like architecture, irregular nuclei and fewer cytoplasmic granules.2

Broadly speaking, well-differentiated NETs are either low or intermediate grade, and poorly differentiated NETs are considered high grade. Low-grade NETs exhibit a relatively indolent clinical course, whilst high-grade tumours are extremely aggressive and intermediate-grade tumours exhibit moderately aggressive behaviour with a less predictable clinical course.2

Proliferative activity of the tumours forms the basis of the WHO and ENETS grading systems. The proliferative rates are assessed by counting the number of mitoses per unit area of the tumour expressed as mitoses per 10 high-power field (HPF) or as the percentage of immunostaining for Ki-67 (MIB-1) antigen, which is a marker for proliferation.35 The ENETS and WHO grading systems, using the Ki-67 index and mitotic count, are G1 (< 2% or < 2 mitoses/10 HPF), G2 (3–20% or 2–20 mitoses/10 HPF) and G3 (> 20% or > 20 mitoses/10 HPF).

Neuroendocrine cells are widely distributed in the body and are known to produce neurotransmitters, neuromodulators and neuropeptide hormones.6 NETS predominantly occur in the gastrointestinal tract and the respiratory airway, which account for 73.7% and 25.1%, respectively, of carcinoid tumours, and very rarely in the genitourinary systems.7 The kidney and bladder account for 19% and 9%, respectively, of all genitourinary carcinoids reported.8

This paper seeks to review the literature for primary well-differentiated NETs of the bladder and to highlight their epidemiology, clinical features, histopathological characteristics, immunohistochemical features and prognosis.


An extensive literature search of PubMed, EMBASE, Ovid SP, Clinical Evidence Online and Cochrane Database of Systematic Reviews for primary NETs of the urinary bladder was carried out. A further search of the literature was carried out by manually searching the relevant references of the studies retrieved. The inclusion criterion for our review was any relevant publication published in English.

Case reports of bladder NETs mixed with other carcinomatous elements, such as adenocarcinoma and small-cell carcinoma, were excluded. Carcinoid tumour metastases emanating from other sites to the urinary bladder were also excluded from the review. All studies were assessed for epidemiological, histological, clinical, diagnostic, therapeutic and prognostic data. The search terms used include ‘primary bladder carcinoid tumour’, ‘primary neuroendocrine tumours of the bladder’, ‘primary tumours of the bladder’ and other similar terms.


The clinical and histological characteristics, treatments and outcomes of the 18 cases of primary well-differentiated NETs of the urinary bladder reviewed are summarized in Table 2.


Features of reviewed cases of primary NETs (carcinoid) of the urinary bladder

Case Age (years) Sex Clinical features Size (mm) Location Associated pathology Mitosis Necrosis Metastasis Tx Follow-up (months) Outcome
Chang et al.28 55 F Incidental 15 Lateral wall Niln NR NR NR TUR 12 NED
Martignoni and Eble17 47 M Haematuria 7 Posterior wall and neck junction Nil Rare NR TUR NR NR
Martignoni and Eble17 69 M Haematuria 3 Neck Cystitis glandularis Rare NR TUR NR NR
Sugihara et al.29 73 M Incidental 10 Posterior wall NR TUR 22 NED
Burgess et al.16 61 F Haematuria 3 Trigone NR NR NR NR NR NR NED
Chen and Epstein9 60 M Incidental 4 Neck Cystitis glandularis, cystitis cystica NR TUR 4 NED
Chen and Epstein9 60 F Haematuria 2 Ureteral orifice Cystitis glandularis, cystitis cystica NR TUR 53 NED
Chen and Epstein9 58 M Haematuria 6 Trigone Cystitis glandularis, cystitis cystica NR TUR 7 NED
Chen and Epstein9 49 F Haematuria 3 Neck Cystitis glandularis, cystitis cystica NR TUR 48 NED
Chen and Epstein9 45 M Renal stones 2 Neck Cystitis glandularis, cystitis cystica NR TUR 48 NED
Colby18 30 M Haematuria 3 Neck von Brunn nests Rare NR NR TUR 12 NED
Stanfield et al.27 54 F Haematuria, voiding difficulty 9 Neck Inverted papilloma Rare NR NR TUR 6 NED
Baydar and Tasar15 49 F Haematuria 30 Trigone TUR 6 ?recurrence
Walker et al.14 62 F Haematuria, frequency 12 Trigone von Brunn nests, cystitis glandularis, cystitis cystica Rare NR NR TUR 12 NED
Mascolo et al.19 68 M Haematuria 4 Neck von Brunn nests NR TUR 14 NED
Kaplan et al.13 71 F Incidental 28 Trigone NR TUR NR NED
Zozumi et al.11 72 M Incidental 8 Trigone Cystitis glandularis TUR 72 NED
DeSouza and Schmeeckle31 34 M Haematuria 50 Neck NR TUR 24 NED

NED, no evidence of disease; NR, not reported; TUR, transurethral resection of the bladder; Tx, treatment.


Primary well-differentiated NETs of the urinary bladder are very rare. To the best of our knowledge, fewer than 20 cases of this tumour have been reported in the English literature.


The tumour commonly occurs in adults. The mean age of presentation of patients in our review was 56 years (range: 30–73 years).

There was no sex predilection in our review. Males accounted for 55% of cases. This is in contrast to previous reports that suggested male predominance with a male-to-female ratio of 1.8:16 and 1.6:1.9


The pathogenesis of primary NETs of the bladder is not clear, but some hypotheses have been suggested. One theory is the development from proliferative precursor lesions; von Brunn nests, cystitis glandularis and cystitis cystica.6,10,11 In support of this theory is the observation that these proliferative lesions are commonly present in the trigone of the bladder,11,12 and primary NETs of the bladder have been documented to have a predilection for the bladder trigone.9,11,1316

Further support for this theory is the observation that bladder carcinoid tumours often coexist with cystitis glandularis and cystitis cystica. This is consistent with the findings of our review, which show 10 case reports of primary NETs of the bladder coexisting with these lesions.9,11,14,1719 A plausible explanation for this observation is the finding that 70% of cystitis glandularis cases have neuroendocrine differentiation.20 Of note is the observation that eight cases of primary bladder NETs in our review were not associated with these proliferative lesions.

Another theory is the transformation of innate neuroendocrine cells in the bladder. It has been previously suggested that cells with neuroendocrine features are present in the bladder, especially in the bladder trigone, from which bladder NETs preferentially arise.6,14

Associated pathologies

Cystitis glandularis refers to a benign glandular differentiation in the von Brunn nests,21 while cystitis cystica refers to cystic dilatation of glandular structures. Proliferative lesions, such as von Brunn nests and cystitis cystica, have been reported in more than 90% of grossly normal bladder during autopsies.22 They are asymptomatic lesions and usually found incidentally. Cystitis glandularis may occasionally appear as nodular, irregular masses on cystoscopy examination, mimicking a neoplasm.23,24 Bladder NETs have been reported to coexist with high-grade invasive adenocarcinoma with metastasis25,26 and inverted papilloma.27

Clinical presentation

Primary NETs of the bladder have been reported as an incidental finding in 28% of cases in our review.9,11,13,28,29 The most common presentation of the cases in our review was haematuria, which is consistent with previous reports.30 Voiding difficulty and frequency occurs less frequently. Voiding difficulty is believed to be caused by transient ball valve occlusion of the vesicourethral junction by the pedunculated carcinoid tumour.27 An association with carcinoid syndrome has not been reported.6,11,30


Urine cytology usually demonstrates haematuria and is negative for atypical cells.11 Excretory urography shows polypoid filling defect in the bladder. Cystoscopy examination often shows a small rounded or sessile polypoid mass, which may be pedunculated.1618,27,29

Macroscopic features

Primary NETs of the bladder are histologically similar to carcinoid tumours in other sites of the body and have been reported to commonly involve the bladder trigone.6,10 This is consistent with the findings of our review, which demonstrated involvement of mostly the trigone and the bladder neck.

The diameters of these tumours have been previously documented as small, with a mean diameter of 5 mm.9 Our review, however, suggests relatively larger diameters, which range from 2 to 50 mm (mean diameter: 11 mm). Baydar and Tasar15 reported a diameter of 30 mm while De Souza and Schmeeckle31 reported a diameter of 50 mm.

These tumours often present as round or sessile polypoid lesions (Figure 1A) with smooth surfaces or sometimes surface changes consistent with an inflammatory process.9,17 The cut surface is solid, tan to slightly reddish in colour, homogeneous and covered with slightly attenuated normal urothelium.19,28 They are mostly subepithelial and confined to the lamina propria; however, Baydar and Tasar15 reported a case of primary carcinoid tumour widely infiltrating the muscularis propria.


Pathological features of carcinoid tumour of the urinary bladder. (A) Ovoid mass which contains small cystic spaces [haematoxylin and eosin (HE) stain ×4]. (B) The tumour is composed of columnar and cuboidal cells forming anastomosing cords and acini (HE stain ×10). (C) The neoplastic cells have a granular eosinophilic cytoplasm, which is most visible at the base of the cells. The nuclei are round to oval, with finely stippled chromatin and generally inconspicuous nucleoli (HE stain ×40). (D) Larger and slightly pleomorphic nuclei are infrequently present (HE stain ×10). (E) Approximately 80% of the cells have a positive reaction to the antibody for chromogranin (immunoperoxidase ×10). (F) Approximately 90% of the cells contain synaptophysin. The intracytoplasmic reaction is particularly evident in the basal poles of the columnar cells (immunoperoxidase ×20). (G) An antibody to the β-subunit of human chorionic gonadotropin decorates 20% of the tumour cells (immunoperoxidase ×40). (H) Thyroid transcription factor 1 is expressed in 20% of the nuclei (immunoperoxidase ×40). Reprinted from Martignoni G, Eble JN. Carcinoid tumours of the urinary bladder: immunohistochemical study of two cases and review of the literature. Arch Pathol Lab Med 2003; 127:e22–e24,17 with permission from Archives of Pathology and Laboratory Medicine. Copyright 2003 College of American Pathologists.


Microscopic features

The patterns of the arrangement of the neoplastic cells are similar to carcinoids in other sites of the body. Tumour cells demonstrated classic carcinoid architectural arrangements or patterns, which include insular, glandular or pseudoglandular, anastomosing trabecular, nested or mixed.6,10,15,17,32 The pseudoglandular pattern within a vascular stroma is the predominant histological pattern.9,10,19,28 The neoplastic cells are uniform in size and shape, which may be cuboidal or columnar (Figure 1B), usually with finely granular moderate to abundant amphophilic cytoplasm, but which could also vary from basophilic to eosinophilic (Figure 1C) cytoplasm.911,29

Nuclei are round to oval in shape and exhibit salt-and-pepper chromatin. The nucleoli were not prominent. Basally located intracytoplasmic granules with a striking resemblance to Paneth cells were observed.9,15 Peculiar and prominent subnuclear eosinophilic granules have been reported.11 Mitotic activities are usually non-evident and rare (Figure 1D).

Calcification and foci areas of haemorrhage have not been reported. No foci of necrosis have been reported. Foci of epithelial von Brunn nests, cystitis glandularis and cystitis cystica have, however, been reported.9,11,14,1719 Intraluminal mucin and intracytoplasmic mucin have been reported.17

Immunohistochemical staining

Neuroendocrine tumours of the urinary bladder are immune-reactive to a panel of antibodies to neuroendocrine markers. They are strongly reactive to chromogranin (Figure 1E) and synaptophysin (Figure 1F). Reactions to calcitonin have been documented in the literature.19 NETs have also been reported as reactive to other immunohistochemical stains, such as neuron-specific enolase (NSE), cytokeratin 7 (CK7),11,13 beta-human chorionic gonadotropin (Figure 1G) serotonin and complement defence 59 (CD59)/neural cell adhesion molecule (NCAM). Tumour cells have negative reactions to p53 protein, prostate-specific antigen (PSA) and S-100 protein.17,19

Thyroid transcription factor-1 (Figure 1H) has been reportedly expressed in 20% of tumour cells.17 Antibodies to prostatic-specific acid phosphatase (PSAP) are usually negative; however, a diffuse and strong expression of PSAP has been observed in a female patient, which definitely excludes the possibility of metastasis from a prostatic malignancy.15 A focal weak positivity for PSAP has been observed in one of the cases reported by Chen and Epstein.9


Previous reports suggest that more than 25% of patients will have regional lymph node involvement or distant spread;30 however, metastases to distant sites have not been reported in cases of primary well-differentiated urinary bladder NETs15 and this is consistent with the findings of our review. Mixed NETs of the urinary bladder with carcinomatous elements have been reported as aggressive with the worse prognosis because of the malignant components, such as small-cell carcinoma and adenocarcinoma.10,25,26


The mainstay of treatment is transurethral resection of the bladder, which appears to be curative, to the best of our knowledge. Findings from our review of primary well-differentiated NETs of the urinary bladder suggest they have an excellent prognosis. The mean follow-up in our review was 24.3 months, with patients having no evidence of disease.

To the best of our knowledge, there is only one suspected case of recurrence in the literature: a 49-year-old woman with primary bladder NET who presented with haematuria and had transurethral resection of the bladder. Subsequent microscopic examination of the biopsy taken from the previous resection site during the second follow-up cystoscopy (6 months after diagnosis) demonstrated 1–2 mm NET in the mucosa.15 It is, however, difficult to ascertain if it was a true recurrence or a case of residual tumour.


Neuroendocrine tumours are broadly classified as low, intermediate or high grade. Low and intermediate grades are well-differentiated NETs with a predictable indolent clinical course compared with high-grade NETS. Primary well-differentiated NETs of the urinary bladder are very rare and they have a predilection for the trigone and bladder neck.

They have similar histopathological features with carcinoid tumours of other sites in the body. They have a similar clinical presentation to that of other tumours of the urinary bladder and, hence, primary well-differentiated NETs of the urinary bladder should be considered as a differential diagnosis for bladder tumours.

Diagnostic workup must include immunostaining for neuroendocrine markers, such as synaptophysin and chromogranin. Immunostaining for the cell cycle-dependent marker of proliferation – Ki-67/MIB-1 – must also be performed.

Clinicians need to be aware of the pathological classification, which affects management. The tumours are amenable to transurethral resection and they appear to have a good prognosis. Metastatic workup must be done to rule out metastasis from other sites of the body.


Many thanks to the editor-in-chief of Archives of Pathology and Laboratory Medicine for the kind permission to reprint the slides used in this review.



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