Neuroendocrine tumour of urinary bladder: a rare case of aggressively behaving primary well-differentiated neuroendocrine tumour with review of literature

Abstract

Neuroendocrine tumour (NET) of the urinary bladder (UB) is a rare entity and comprises of well-differentiated, small cell and large cell types. Small and large cell NET like that in lung and gastrointestinal tract have an aggressive nature and are considered high-grade disease. Well-differentiated NET has been thought to be localised and having a good prognosis. We report the first case of metastatic well-differentiated NET of the UB. Our case is a 44-year-old man with well-differentiated NET of UB presented with hepatic and peritoneal metastases on initial diagnosis. He was treated with metaiodobenzylguanidine (MIBG) therapy and had a modest survival of 16 months. The primary well-differentiated NETs can present as a metastatic disease with an aggressive nature. MIBG therapy can be considered as a useful option but overall prognosis is poor. Further research is needed for better understanding and better treatment protocol.

Background

Urinary bladder cancer (BCa) is the 7th most common cancer in men, and it is the 11th most common cancer overall. The worldwide age-standardised incidence rate (per 100 000 people/years) is 9.0 for men and 2.2 for women.¹ In India, the incidence of BCa is 2.25 (per 100 000 annually) with males and females having an incidence of 3.67 and 0.83, respectively.²

Male patients have three to four times higher risk of developing BCa. The morbidity and mortality of BCa in male patients is the second highest among all urinary tumours, first being the prostate cancer.³ Urothelial carcinoma is the most common bladder tumour of the UB. Adenocarcinoma, squamous cell carcinoma, signet cell carcinoma and sarcomas are the other histological types of UB tumours.

Primary neuroendocrine tumour (NET) is a rare type of bladder tumour and comprises 0.35%–1% of all UB neoplasms. The subtypes of NET have been extensively studied for gene expression and molecular basis.^{4 5} Diagnosis is primarily based on clinical presentation, microscopic evaluation and immunohistochemistry (IHC) results. 2016 WHO classify NET of UB into small cell, large cell, paraganglioma and well-differentiated NET.⁶ These histological subtypes have variable clinical history and require different treatment strategies thereby increasing the importance of understanding the correct histopathological subtype. We here discuss the unusual behaviour of a well-differentiated primary NET of UB with diagnosis and treatment strategy.

Case presentation

A 44-year-old man presented with lower abdominal pain, altered bowel habits (increased frequency of defecation) with anorexia and weight loss for the last 3 months. There was no haematuria, dysuria or any urinary complaints. For initial evaluation ultrasound (USG) abdomen showed a gall bladder calculus of size 3.5 cm with multiple hypoechoic solid and cystic masses in both the lobes of the liver.

Investigations

USG-guided core needle biopsy from the liver mass was suggestive of poorly differentiated carcinoma. A contrast-enhanced CT showed enlarged liver with multiple variable sizes enhancing hypodense lesions involving both lobes and a UB mass of size 2.1×1.9 cm enhancing polypoidal in nature located in the left posterolateral wall with enlarged left iliac lymph node of size 2.2 cm. The patient underwent a transurethral biopsy of bladder growth. Intraoperatively, there was a growth of size 2×2 cm in the left posterolateral wall with intact mucosa over it with normal bilateral ureteric orifice (figure 1). On resection, a solid looking homogenous growth with broad base was seen. Histopathological examination of the tumour was suggestive of a well-differentiated primary NET-infiltrating muscle fibres of the UB which was immunopositive for chromogranin, synaptophysin and CD56 while negative for CK20, CK7 and p40 with Ki67 index being 5%. The core needle biopsy from the liver lesion was re-evaluated by two independent pathologists and IHC was done to correlate the findings. After the consensus of both the pathologist’s diagnosis of primary well-differentiated NET was made (figure 2).

Figure 1.

Solid looking lesion (arrow) in the left posterolateral wall of urinary bladder with intact mucosa.

Figure 2.

Microscopic picture of urinary bladder wall growth with immunohistochemistry marking.

Ga68-DOTANOC whole-body positron emission tomography and CT (PET/CT) was done postoperatively which revealed intensely tracer avid lesions in UB, multiple hypodense lesions in both the lobes of liver (largest 6×7.2 cm in segment II and III), lesion in intercostal muscle in 11th intercostal space and multiple left peripancreatic, para-aortic, retrocaval, left perigastric, internal mammary and paraesophageal lymph nodes. Intensely tracer avid multiple peritoneal and omental deposits were also noted (figure 3).

Figure 3.

Ga68-DOTANOC PET/CT maximum intensity projection (A), PET/CT fused (B–D) and CT only (E–G) images shows intensely tracer avid hypodense lesions in the liver (B,E), enlarged left-sided pelvic lymph nodes (C,D) and tracer avid lesion in the urinary bladder (D,G). ¹³¹I- MIBG scan (H) revealed increased tracer avidity in the lesions seen in Ga68-DOTANOC PET/CT. MIBG, metaiodobenzylguanidine; PET/CT, positron emission tomography and CT.

¹³¹I MIBG scan done for academic purpose showed concentrating mass in UB, liver and peritoneum corresponding to the lesions that were seen in Ga68-DOTANOC PET/CT (figure 3).

Differential diagnosis

1. The differential diagnosis of metastatic UB mass includes multiple tumours. These masses can be correctly identified on microscopy (both with cytology and IHC marking) as described.

2. High-grade papillary urothelial carcinoma—spindle, pyramidal and racquet-shaped cells with pleomorphism with enlarged hyperchromatic nuclei coarse chromatin, increased N/C ratio and prominent nucleoli. These stain positive for CK7, CK20, HMW keratin, uroplakin, GATA3 and S100 and stain negative for PSA, P501S and WT1.

3. Variants of urothelial neoplasm (nested, sarcomatoid, micropapillary, plasmacytiod and so on)

   • Sarcomatoid—round to polygonal cell with large round to oval nucleus with coarse chromatin and inconspicuous nucleoli. Diffuse cytokeratin and smooth muscle actin positivity seen on IHC.

   • Micropapillary—micropapillary architecture, high-nuclear grade with positive marking for CD 31 (endothelial marker) and D2-40 (lymphatic endothelial marker).

   • Nested—irregular and confluent small nests and abortive tubules composed of urothelial cells. IHC staining shows CK7, CK20, p63, Ki67, CK903 is positive.

   • Plasmacytoid—scattered discohesive cells with a plasmacytoid appearance, characterised by abundant cytoplasm, eccentric nuclei and inconspicuous nucleoli typically positive for cytokeratin and CD138+.

4. Squamous cell carcinoma—resembles epidermal tumours with keratin pearls and intercellular bridges. IHC positive staining for CK5/6 and CK5/14 but negative staining for CK20 and uroplakin III.

5. Adenocarcinoma—it has got glandular components resembling colonic carcinoma with IHC positivity for CK7, CK20, CEA, EMA, villin and CDX2.

6. Metastasis—metastasis to UB is rare and is typically seen in adenocarcinoma arising from prostate, colorectal, breast and lung. Adenocarcinoma on biopsy amount for metastatic workup including whole body CT, upper and lower gastrointestinal tract endoscopy serum prostate-specific antigen (PSA) and breast examination. In our patient, none of the above mentioned features were seen.

Microscopic evaluation of tumour in this patient showed small round cells with finely granular cytoplasm-infiltrating muscle fibres of UB. The tumour was immunopositive for chromogranin, synaptophysin and CD56 while negative for CK20, CK7 and p40 with Ki67 index being 5%. As the patient presented with hepatic metastasis which were confirmed by liver biopsy, the above-mentioned findings were consistent with well-differentiated primary NET-infiltrating muscle fibres of the UB with hepatic metastasis.

Treatment

As an initial treatment, a transurethral biopsy from the UB mass was taken. The histopathological examination was inconclusive; hence, diagnosis was made by IHC marking as stated earlier. To date, there are no standard treatment guidelines for the management of metastatic well-differentiated NET of the UB. The patient had poor performance status and was deemed unfit for chemotherapy; hence, based on the good uptake of tracer in tumour patient was planned for MIBG therapy.

Outcome and follow-up

The patient received three cycles of therapy over the next 7 months in the interval of 3–4 months. 200mCi of ¹³¹I MIBG was injected intravenously in each cycle and response assessed with post-therapy MIBG scan done at the time of discharge after 2–3 days. Post-therapy scans showed stable disease but in the meantime, succumbed to the illness 16 months after the first diagnosis was made.

As this is the first case of well-differentiated NET of UB with metastasis, we cannot comment whether the survival was better than chemotherapy but as the patient had stable disease after three cycles it becomes clear that MIBG therapy may offer survival benefit in carefully selected patients especially those who are unfit for chemotherapy.

Discussion

NET is an exceedingly rare type of UB neoplasm and accounts for a small percentage (0.35%–1%).⁴ According to the current WHO grading system, NETs are divided into three subgroups depending on histopathological evaluation of the mitotic index and the Ki67 index. Tumours with grade 1 (low) or grade 2 (intermediate) are considered well-differentiated and have a better prognosis. Grade 3 (high) or poorly differentiated tumours, typically have a high mitotic and/or Ki67 index and display aggressive behaviour.^{4 7 8} Large cell and small cell tumours are considered high grade and have a poor prognosis often reported with fatal outcomes. For localised disease, cystectomy with adjuvant chemotherapy is considered the treatment of choice. On the other hand, the prognosis is excellent for typical well-differentiated NETs limited to the lamina propria. Since the number of cases reported is small with limited follow-up periods, not much is known about the course of the disease.^{9 10}

About 50 cases of mixed low-grade NET of UB have been described in the literature. The other components like urothelial, adenocarcinoma, squamous and sarcomatoid forms were seen along with low-grade NET.¹¹ If we isolate pure neuroendocrine forms, there are fewer than 15 cases described. Age of presentation is fifth to the seventh decade of life and is generally seen in the bladder neck and trigone of the UB but may be located anywhere in the bladder.^11–14 Most of the patients present with haematuria but it may be asymptomatic or may present as obstructive lower urinary tract symptoms if located in the prostatic urethra. Our patient was younger, 44 years old at the time of presentation and never had a recurrent cough, skin flushing which are symptoms associated with carcinoid syndrome.

Macroscopically, it may be of variable size and they often appear as polypoidal or smooth-surfaced submucosal nodules with normal bladder mucosa over it. The glandular pattern is the most common pattern, but acinar, trabecular and cribriform structures of monotonous small round cells with finely granular cytoplasm and small nucleoli with so-called ‘salt and pepper’ chromatin are also found. Cells are synaptophysin, chromogranin and neuron-specific enolase positive, as well as CD56 in a smaller percentage, as proof of neuroendocrine differentiation. Cytokeratin 20 is negative in carcinoid, and cytokeratin 7 staining can be strongly positive in most of the tumorous cells.¹⁵ Our patient’s tumour was positive for chromogranin, synaptophysin and CD56 while negative for CK20, CK7 and p40.

The few cases of pure primary NET tumour of the bladder reported in the literature to date have been small lesions that were excisable through cystoscopy. Other subtypes like small cell NET and large cell NET are also rare with both accounting for <1% of total BCa and there currently no standard treatment guidelines exist. For small cell type, National Comprehensive Cancer Network’s guidelines of 2015 recommend resection and chemotherapy (as for small-cell lung carcinoma) with or without radiotherapy for non-locally advanced tumours, radiotherapy and chemotherapy for locoregional advanced disease, and chemotherapy alone for metastatic disease. One study compared combined treatment modalities (neoadjuvant chemotherapy + cystectomy vs cystectomy + adjuvant chemotherapy), the median overall survival was 16 months in the first group and 18.3 months in the latter.¹⁶ Chemotherapy regimens depend on histology with mixed small-cell carcinoma responds to MVAC regimen (methotrexate, vinblastine, adriamycin, cisplatin), pure small-cell carcinoma responds to cisplatin-etoposide or etoposide or ifosfamide/doxorubicin regimen.¹⁷ Likewise large cell NET also has grave prognosis and treatment recommended is similar to that of small cell NET.

Our patient presented with high burden metastatic disease with well-differentiated NET histology and since he had MIBG concentrating lesion patient received MIBG therapy. The patient survived for 16 months after diagnosis and finally succumbed to the illness. To our knowledge, this the first case to be reported of primary well-differentiated NET of UB presenting with metastasis; hence, little is known about the disease and the treatment is still under study.

Learning points.

• Neuroendocrine bladder tumours are rare variants which can be well-differentiated, small cell or large cell varieties.

• Well-differentiated primary neuroendocrine tumour (NET) of urinary bladder (UB) was earlier considered to have an indolent course but now we know that it can metastasize to other organs.

• NET of UB is an aggressive entity and proper metastatic workup irrespective of pathological subtype is necessary.

• Metaiodobenzylguanidine therapy may offer some role in the adjuvant settings in selected cases especially those deemed unfit for chemotherapy.