Successful management of small cell neuroendocrine carcinoma of the ureter with neoadjuvant chemotherapy and adjuvant chemoradiation: case report and literature review

Abstract

Neuroendocrine tumours (NETs) of the urinary tract are rare, and the urinary bladder is the the most common primary site. Primary ureteric NET is rarer with under 80 cases reported in the literature thus far. Most of these tumours are of the high-grade small cell neuroendocrine carcinoma subtype, which has a worse prognosis. Neoadjuvant chemotherapy has a proven role in the management of NET of the bladder as it downstages the tumour, which may add to significant recurrence-free survival and overall survival. We report the successful management of a patient with locally advanced small cell neuroendocrine carcinoma of the ureter, who had a pathological complete response after neoadjuvant chemotherapy with etoposide and cisplatin. He subsequently received adjuvant chemotherapy followed by radiation and is recurrence-free at a follow-up of 1 year.

Background

Urothelial carcinoma of the upper urinary tract accounts for only 5%–10% of urothelial carcinomas. Those with non-urothelial histology like neuroendocrine tumours (NETs) are an extremely rare entity and have been described as sporadic case reports only. Most of the described urinary NETs have been reported in the bladder.¹ The ureteric NETs can be classified as well-differentiated (carcinoid), moderately differentiated (atypical carcinoid) and poorly differentiated (large cell and small cell) NETs based on their behaviour and histology.² Small cell carcinoma (SmCC) is the most common type (95.7%) of upper urinary tract NET.³ SmCC has aggressive clinical behaviour and most patients present with metastasis.⁴ The gastrointestinal tract is the most common site of NET (74%), followed by the lungs (10 %).⁴ The potential benefit of improved recurrence-free and overall survival after neoadjuvant chemotherapy (NACT) in bladder primary NET has been suggested in retrospective series,^{5 6} as well as in a prospective phase II trial by Siefker-Radtke et al.⁷ It leads to pathological downstaging and improves long-term outcomes.⁸ Therefore, NACT is recommended in both limited and extensive small cell neuroendocrine carcinomas (NECs) of the bladder.⁹

To our knowledge, only around 71 cases of ureteric NETs have been reported in the literature so far, among which six cases (table 1) were managed with NACT. We report successful management of a 57-year-old man with NACT and adjuvant chemoradiation for locally advanced SmCC of the ureter. This patient had a pathological complete response to NACT, which has never been reported before.

Table 1.

Selected case reports of ureter neuroendocrine tumours managed with neoadjuvant chemotherapy

	Case	Age/gender	Presentation	Clinical stage	Histopathology	NACT	Surgery	Pathological stage	Adjuvant therapy	Follow-up outcome
1	Nishiyama etal9 (2011)	70/M	Gross haematuria	T3N2M0	SmCC of the ureter on cytology and radiology	GP	NUx with open bladder cuff	(yPT3N2) SmCC of the renal pelvis	EP + RT	5 months, alive, disease-free
2	Ahsaini etal21 (2013)	54/M	Gross haematuria	T2N0M0 in the bladder T1N0M0 in the ureter	SmCC of the bladder and ureter on initial TURBT and ureteroscopic biopsy	EP and IA × four cycles	NUx and RC	SmCC of the bladder (pT2N0) and ureter (pT1N0)	Nil	24 months, alive, disease-free
3	Osaka etal18 (2015)	70/M	Left flank pain	cT3N0M0	SmCC of the ureter on initial ureteroscopic biopsy	IrP × three cycles	NUx	pT2N0 Urothelial carcinoma without a small-cell component	Nil	38 months, alive, disease-free
4	Acosta etal22 (2015)	71/M	Right flank pain	T1NxM0 on MRI*	SmCC of the ureter on initial ureteroscopic biopsy	EC	Salvage NUx	pT3N1M0 SmCC of the ureter	Nil	Dead at 6-month follow-up
5	Sood17 (2016)	55/F	Right lower back pain and haematuria	cT3N2M0	SmCC of the ureter on initial ureteroscopic biopsy	EP	Not mentioned	Not known	Nil	3 months post NACT Partial response (50% reduction in lymph node burden)
6	Nakasato etal3 (2018)	76/M	Gross haematuria	cT3N0M0	SmCC of the ureter on initial ureteroscopic biopsy	GP×2	NUx	pT3N0 SmCC of the ureter	Nil	5 months Died of disease
7	Our case	55/M	Gross haematuria, pain	CT4N2M0	SmCC of the ureter on initial ureteroscopic biopsy	EP×4	NUx	ypT0N0	EPX2 RT (50 Gy)	12 months Disease-free

*Raised creatinine.

A, doxorubicin (adriamycin); C, carboplatin; E, etoposide; G, gemcitabine; I, ifosfamide; Ir, irinotecan; NACT, neoadjuvant chemotherapy; NUx, nephroureterectomy; P, cisplatin; RC, radical cystoprostatectomy; RT, radiotherapy; SmCC, small cell carcinoma; TURBT, transurethral resection of bladder tumour.

Case presentation

A 56-year-old man with a history of tobacco chewing and smoking was evaluated for left lower abdominal pain for 3 months and one episode of gross total. His initial evaluation at other centre with contrast-enhanced CT (CECT) showed left moderate hydroureteronephrosis with soft tissue tumour left distal ureter. He underwent ureteroscopy with biopsy of the lesion in the distal ureter, which was reported elsewhere as low-grade urothelial carcinoma. He came to our hospital for further management after 2 months.

Investigations

He underwent repeat CECT (figure 1A, B), which showed a 5.2×5.4 cm, soft tissue density lesion encasing the left mid to distal ureter extending up to the ureterovesical junction and loss of fat plane with the adjacent rectum, abutting the bladder with fat planes maintained in the distal part. Left obturator, left common iliac (~1.4 cm), left lower para-aortic (~2.5 cm) and lower precaval lymph nodes (~1.4 cm) were significantly enlarged. Metastatic workup was negative for focal lesions involving the liver/adrenals/bones and lungs. His clinical stage was T3N2M0 as per tumour–node–metastases staging system.

Figure 1.

(A and B) Prechemotherapy contrast-enhanced CT (CECT): 5.2×5.4 cm, soft tissue density lesion encasing the left mid to distal ureter extending up to ureterovesical junction (UVJ) and loss of fat plane with the adjacent rectum, abutting the bladder with fat planes maintained distal part. Significant left obturator, left common iliac, left lower para-aortic, and lower precaval lymph nodes. (C and D) Postchemotherapy 18 FDG PET(Fluorodeoxyglucose F 18 positron emission tomography) CT interval decrease in size of the ill-defined soft tissue density lesion encasing the left distal ureter just proximal to UVJ.

His left ureteric mass biopsy was reviewed in our institute. The histopathological slides showed multiple fragments of a poorly differentiated carcinoma located in the subepithelial connective tissue of the ureteric wall with overlying intact and benign urothelium. The tumour was arranged in sheets, closely packed clusters, cords and trabecular architecture (figure 2A) and composed of polygonal cells with moderate nuclear pleomorphism, hyperchromasia and scant cytoplasm with poorly defined margins. Nuclear moulding of the cells was evident (figure 2B). Mitotic activity was ~4–5/10 high power field. Extensive crush artefact and foci of necrosis were present. An immunohistochemical study was performed, which revealed tumour cells diffusely positive for synaptophysin (figure 2C) and CD56 and focally positive for chromogranin (figure 2D) and showed characteristic diffuse paranuclear positivity for pan-cytokeratin (figure 2E). The cells were negative for GATA3 (figure 2F). MIB-1 Proliferative Index was ~95%. The histomorphological features and immune profile were characteristic of high-grade NEC, and hence, a diagnosis of SmCC was rendered.

Figure 2.

A and B show highly cellular tumour arranged in sheet and small clusters with cells displaying moderate nuclear pleomorphism, hyperchromasia and scant cytoplasm. Nuclear moulding is evident. Immunohistochemistry (C–F) shows tumour cells with diffuse cytoplasmic positivity for synaptophysin, focally positive for chromogranin, diffuse paranuclear positivity for pan-cytokeratin and negative for GATA3 (the lining urothelium is highlighted by GATA3).

In view of the significant nodal disease burden, he received four cycles of NACT with etoposide (100 mg/m² days 1–3) and cisplatin (75 mg/m² day 1). Postchemotherapy 18 FDG PET(Fluorodeoxyglucose F 18 positron emission tomography) CT (figure 1C, D) showed interval decrease in size of the ill-defined soft tissue density lesion encasing the left distal ureter just proximal to ureterovesical junction measuring ~2.2×1.6 cm (prechemotherapy ~5.2×5.4 cm) and lower para-aortic 8.5 mm (prechemo ~2.5 cm).

Differential diagnosis

• Mixed ureteral neoplasms containing urothelial carcinoma and/or squamous carcinoma in addition to a NET have been well documented. Immunohistochemical stains for synaptophysin, chromogranin A, neuron-specific enolase and/or CD56 show positivity in ureteral NETs. At least one ureteral NET has demonstrated positivity for cytokeratin 20, cytokeratin 7, pan-keratin and epithelial membrane antigen, but uroplakin III and GATA3 invariably show negativity. Therefore, GATA3 seems to be an additional tool for differentiating ureteral NETs from urothelial carcinoma. Ki-67 Labelling Index is frequently greater than 50%–60%, which is consistent with the high mitotic rate normally found in these tumours.¹⁰

• It is difficult to differentiate between urothelial carcinoma and SmCC of the ureter based on imaging alone. Histological analysis with immunohistochemistry distinguishes SmCC from its differential diagnoses like poorly differentiated urothelial carcinoma, plasmacytoid carcinoma, lymphoepithelioma-like carcinoma, primitive neuroectodermal tumour or malignant lymphoma. The neuroendocrine nature can be confirmed by staining positively for neuroendocrine markers such as chromogranin A, synaptophysin and neuron-specific enolase.¹¹ GATA3 is usually negative, and this may help the differential diagnosis with urothelial carcinoma.

• CT thorax should be done not only as a part of metastatic workup but also to rule out metastasis to ureter from primary small cell NET of the lung, which has been reported rarely.¹²

Treatment

He underwent left Laparoscopic nephroureterectomy with bladder cuff and open pelvic lymph node dissection after NACT with etoposide/cisplatin. Intraoperatively, there were dense adhesions of the lower ureter at the tumour site to surrounding structures, and pelvic lymph nodes were plastered to the vessels. No intraoperative frozen section assessment was done. Histopathological examination showed a complete response to chemotherapy (ypT0N0). He received two more cycles of adjuvant chemotherapy with etoposide and cisplatin. Fifty gray adjuvant radiotherapy in 25 fractions to the planning target volume (the pelvis) was given using the three-dimensional conformal radiotherapy technique over 5 weeks after adjuvant chemotherapy.

Outcome and follow-up

He is recurrence-free at a follow-up of 1 year.

Discussion

Neuroendocrine ureteric tumours are rare and are mostly high grade and present as haematuria or flank pain in the sixth decade.¹³ The majority of NETs are poorly differentiated and metastasise early and thus are associated with poor prognosis.^{2 4} Various hypothesis regarding the origin of NET cells in the urinary are (1) differentiation of urothelium, (2) directly from neuroendocrine cell present in the urinary tract, (3) from the entrapped neural crest during embryogenesis or (4) from the differentiation of stem cell.¹⁴ Among these, the most acceptable and recent theory is that SmCC originates from totipotent stem cells present in the urinary tract submucosa.¹⁵ These tumours have similar histomorphology to its counterpart in the lung. Cells are generally small-to-medium-sized with speckled chromatin, scant to moderate amounts of cytoplasm and a high nuclear to cytoplasmic ratio. The architecture shows patterns that are similar to NECs from other primary locations: rosettes, diffuse sheets and solid tumour nests. Necrosis and lymphovascular invasion have been reported.¹ Up to 50% of neuroendocrine ureteric tumours can have a urothelial carcinoma component also.³ Immunohistochemical stain positivity for synaptophysin, chromogranin A and neuron-specific enolase is crucial for a diagnosis of NEC.^{10 13}

Nakasato et al,³ in their systematic review of 70 patients, have shown that adjuvant treatment (chemotherapy and radiation) after surgery for T1–2 disease is likely to improve prognosis. Platinum-based chemotherapy is reported to improve prognosis when compared with other non-platinum-containing regimens.¹⁶ Additional therapy in the form of chemotherapy or chemoradiation or occasionally radiotherapy only was mostly given in an adjuvant setting.³ Among the six patients mentioned above (table 1), none had a complete pathological response despite receiving platinum-based chemotherapy. Sood et al¹⁷ reported partial response to NACT in the form of a reduction in lymph node burden. Osaka et al,¹⁸ after the initial diagnosis of SmCC of the ureter, treated the patient with neoadjuvant irinotecan and cisplatin, three cycles. This patient, however, had a pathological stage of ypT2N0 residual urothelial carcinoma without any small-cell component after nephroureterectomy. From this, we can infer that this patient had coexisting SmCC as well as urothelial carcinoma of the ureter, with SmCC component completely responding to the chemotherapy. Our patient had a pathological complete response without any evidence of tumour in the final nephroureterectomy specimen. This is an important observation, and therefore, neoadjuvant or adjuvant cisplatin-based chemotherapy should be considered whenever SmCC is found in solitude or in coexistence with urothelial carcinoma of the ureter.

Chemoradiotherapy is the standard treatment for localised, locally advanced or unresectable small cell NEC of the lung, and the management of NECs in other parts of the body is extrapolated from the above strategy.¹⁹ Radiotherapy has been given less often in the prior reported cases (less than 7%), mostly in combination with adjuvant chemotherapy.³ Beddok et al²⁰ reported complete remission at a follow-up of 16 months in a patient who had a partial response to adjuvant chemotherapy (carboplatin–etoposide) for a recurrence at 4 months post nephroureterectomy. Hence, radiotherapy may be considered in cases of partial responders to chemotherapy. The solid evidence and consensus regarding this are lacking like other treatment options because of the rarity of the disease.

Learning points.

• SmCC of the ureter is a rare tumour, that can some times coexist with urothelial carcinoma. A panel of neuroendocrine markers is a useful adjunct for accurate classification.

• A complete metastatic workup (contrast-enhance CT thorax/bone scan) to rule out lung, liver and bone metastases is mandatory.

• Platinum-based chemotherapeutic agents are valuable in treating SmCC of the upper urinary tract like bladder and lung SmCC and should be considered for downstaging the disease in the neoadjuvant setting as well for systemic control of the disease.

• Postoperative radiation can be considered for local control of the disease in case of partial response to chemotherapy.

• There is no consensus or guidelines on the treatment of SmCC of the ureter due to very low incidence, and further accumulation of evidence in the form of case reports may help to establish the same in the future.

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