Keywords
atypical - carcinoid - neuroendocrine tumor - ureter
Neuroendocrine tumors (NETs) of the ureter are very rare and represent less than 0.5%
of urinary tract cancers.[1] NETs can occur in any part of the urinary tract including the kidney, ureter, bladder,
and prostate. Majority of NETs of the urinary tract will present in the bladder, and
primary ureteric NETs are extremely rare.[1] Due to their rarity, the clinical presentation and origins of these tumors are poorly
understood.[2]
Less than 40 cases of neuroendocrine ureteric tumors have been reported in the literature,
with the vast majority being poorly differentiated NETs. These tumors commonly present
as aggressive tumors that metastasize early, leaving patients with a poor prognosis.
We present the case of a moderately differentiated neuroendocrine carcinoma of the
ureter with a good outcome postoperatively.
Case Description
An 88-year-old man presented with right-sided loin pain and microscopic hematuria,
without any urinary symptoms. Routine blood tests revealed derangement of his renal
function. An initial ultrasound scan of his urinary tract revealed right-sided hydronephrosis.
A further computed tomography of kidneys, ureters, and bladder scan revealed dilatation
of the ureter up to the vesicoureteric junction with an associated tight stricture
([Fig. 1]). He subsequently had a right rigid ureteroscopy, ureteric biopsy, and ureteric
stent insertion. The initial histology was reported as transitional cell carcinoma
of the ureter. No neuroendocrine markers were performed at the time, as the tumor
did not show any classical signs of a carcinoid tumor or a well-differentiated small
cell carcinoma. As demonstrated later, the histology revealed an atypical carcinoid
pattern. Further imaging of his chest did not reveal distant metastases and this man
underwent a right laparoscopic nephroureterectomy and open excision of bladder cuff.
Fig. 1 Coronal section: computed tomography of kidneys, ureters, and bladder showing the
hydronephrotic kidney and dilated lower end of the ureter with narrowing at the vesicoureteric
junction (arrows).
Macroscopically, the ureter showed a tumor obstructing the lumen toward its distal
end, covering a length of ∼18 mm and the resection margin was clear by at least 4
mm. Microscopy of the ureteric specimen revealed a positive immunohistochemical stain
with CD56, a common neuroendocrine marker ([Fig. 2]). Staining with other neuroendocrine markers was weakly positive ([Figs. 3] and [4]). The tumor was of intermediate to high grade, with a high Ki-67 proliferation index
of 25 to 30% ([Fig. 5]). Associated carcinoma in situ (CIS) was not seen. There was no definite lymphovascular
invasion. The tumor infiltrated through the muscle into the periureteric fat (T3).
The background kidney displayed patchy lymphocytic infiltrates in keeping with mild
interstitial nephritis. There was no tumor infiltration into the kidney. The urothelium
covering the renal pelvis did not show any evidence of CIS or tumor.
Fig. 2 (Left) Neuroendocrine tumor from luminal side of ureter with glandular formation
(arrow). (Right) Positive stain with CD56 (arrow).
Fig. 3 Chromogranin A staining.
Fig. 4 Synaptophysin.
Fig. 5 Ki-67 staining 25 to 30% positivity.
The patient made an unremarkable recovery. As he remained well and chromogranin levels
were only mildly elevated and stable, the oncologist decided there was no need for
adjuvant therapy. Over the past 12 months, his cystoscopies have not shown any signs
of recurrence. He also had a repeat computed tomography of his chest, abdomen, and
pelvis 12 months postoperatively which did not show any signs of recurrence.
Discussion
NETs of the ureter commonly present in the sixth decade.[3] Presenting symptoms are not dissimilar to other urothelial carcinomas and majority
of patients initially present with flank pain and hematuria ([Table 1]). Immunohistochemical staining with stains such as chromogranin, synaptophysin,
CD56, or Ki-67 is the key to diagnosing these tumors. Tumors are variably positive
to these stains.
Table 1
Selected articles reporting cases of neuroendocrine tumors of the ureter
|
Case
|
Age/gender
|
Presenting symptoms
|
Site of tumor
|
Management
|
Pathology
|
Follow-up (mo)
|
Adjuvant treatment
|
Outcome of disease
|
|
1
|
Chuang and Liao (2003)[4]
|
57/M
|
Hematuria/pain
|
Ureter
|
Neph-uret
|
Small cell
|
17
|
Nil
|
Death from disease
|
|
2
|
Chuang and Liao (2003)[4]
|
50/M
|
Hematuria/pain
|
Ureter
|
Neph-uret
|
Small cell
|
>55
|
Nil
|
No recurrence
|
|
3
|
Lee et al (2006)[5]
|
70/F
|
Malaise
|
Ureter
|
Neph-uret
|
Atypical carcinoid
|
36
|
Nil
|
No recurrence
|
|
4
|
Sakuma et al (2008)[6]
|
73/F
|
Hematuria
|
Ureter
|
Neph-uret
|
Carcinoid
|
9
|
Nil
|
CT not done due to comorbidities. Death from disease
|
|
5
|
Masui et al (2008)[7]
|
69/M
|
Hematuria
|
Ureter
|
Neph-uret + bladder cuff
|
Small cell
|
14
|
CT (irinotecan, etoposide, cisplatin)
RT
|
No recurrence
|
|
6
|
Banerji et al (2008)[3]
|
55/M
|
Flank pain
|
Ureter
|
Neph-uret + bladder cuff + removal of nodes
|
Small cell
|
Not mentioned
|
CT (gemcitabine +carboplatin)
|
Not mentioned
|
|
7
|
Kozyrakis et al (2009)[8]
|
78/M
|
Hematuria
|
Ureter
|
Neph-uret + bladder cuff incision
|
Small cell
|
6
|
Nil
|
CT not done due to comorbidities. Death from disease
|
|
8
|
Oshiro et al (2013)[9]
|
78/M
|
Incidental
|
Ureter
|
Neph-uret + partial resection of bladder
|
Large cell
|
9
|
Nil
|
No recurrence
|
|
9
|
Ping et al (2014)[1]
|
65/F
|
Flank pain
|
Ureter
|
Neph-uret
|
Small cell
|
4
|
CT (irinotecan + cisplatin)
|
Tumor remains stable
|
|
10
|
Jang et al (2013)[10]
|
59/M
|
Hematuria
|
Ureter + bladder
|
Neph-uret + bladder cuff resection
|
Small cell
|
10
|
CT (etoposide + cisplatin)
RT
|
No recurrences
|
|
11
|
Osaka et al (2015)[11]
|
70/M
|
Flank pain
|
Ureter
|
Neph-uret
|
Small cell
|
38
|
CT (cisplatin + irinotecan)
|
No recurrences
|
|
12
|
Wang et al (2016)[2]
|
69/M
|
Flank pain+ hematuria
|
Ureter
|
Neph-uret
|
Small cell + atypical carcinoid
|
12
|
Nil
|
Pt declined CT/RT. Death from disease
|
|
13
|
Beddok et al (2016)[12]
|
80/M
|
Hematuria
|
Ureter
|
Neph-uret
|
Small cell
|
16
|
CT (carboplatin + etoposide)
RT
|
In remission
|
Abbreviations: CT, chemotherapy; Neph-uret, nephroureterectomy; Pt, patient; RT, radiotherapy
Due to low incidence, the development of ureteric NETs is poorly understood. Four
hypotheses have been put forward to suggest the origin of these tumors: (1) neuroendocrine
differentiation of the urothelium, (2) direct origin from the neuroendocrine cells
present in the urinary tract, (3) from the entrapped neural crest in the ureter during
embryogenesis, and (4) from undifferentiated stem cells that differentiate toward
an urothelial or squamous cell lineage.[3]
[13]
Based on their behavior and histology, neuroendocrine ureteric tumors can be divided
into the following categories: well differentiated (carcinoid), moderately differentiated
(atypical carcinoid), and poorly differentiated (small cell and large cell) ([Table 2]). These tumors can develop anywhere, with 74% of NETs originating from the gastrointestinal
tract, 10% from the lungs, and the remainder from other parts of the body.[2]
Table 2
Types of neuroendocrine tumors
|
Well differentiated
(Benign behavior)
|
Carcinoid
|
|
Moderately differentiated
(Atypical behavior)
|
Atypical carcinoid
|
|
Poorly differentiated
(High-grade malignant)
|
Small cell and large cell carcinoma
|
Poorly differentiated ureteric NETs are the most malignant among these tumors.[14] The clinical course of these tumors is aggressive, and most present with metastases
at the time of diagnosis, with a median survival of 8.2 months.[2] The mainstay of management in case of localized tumor is surgical removal which
involves nephroureterectomy. As there are few case reports, there is no standard recommendation
for adjuvant treatment. If the adjuvant treatment is used, most of the series recommend
a cisplatin-based chemotherapy ([Table 1]). In case of metastatic disease, cisplatin-based chemotherapy is the main modality
of treatment.
Most cases described in the literature fall under the category, which includes small
cell and large cell NETs ([Table 1]). Characteristics of small cell carcinoma include a small cell size, scant cytoplasm,
high mitotic rate, finely granular nuclear chromatin and faint or absent nucleoli,
and frequent necrosis.[15] Large cell carcinomas also exhibit a high mitotic rate and necrosis. They are differentiated
from small cell carcinomas by their large cell size, with a low ratio of nucleus to
cytoplasm and nuclei with coarse, fine or vesicular chromatin, and/or frequent nucleoli.[9]
Well-differentiated tumors such as carcinoids usually exhibit low-grade nuclear atypia,
small number of mitoses, and a low Ki-67 labeling index.[15] They generally behave in a benign manner. Atypical carcinoids or moderately differentiated
NETs are characterized by microscopic characteristics that are similar to carcinoids
but with an increased nuclear atypia and higher mitotic activity.[2]
[5] In this case, there was a high Ki-67 proliferative activity of 25 to 30%. A majority
of the atypical carcinoid tumors are poorly differentiated with metastasis seen in
55.6% of them.[14]
Conclusion
The optimal management of patients with NETs has not been well established due to
the rarity of cases. As seen in [Table 1], a multimodular therapeutic approach is often adopted, which includes surgery, radiation
therapy, and chemotherapy. There have been few documented cases of atypical carcinoid
ureteric tumors, and our case has shown that early surgical management can give rise
to a good clinical outcome.
Another learning point from our case is that initial biopsies of atypical carcinoid
tumors can have similar properties to transitional cell tumors. It is, therefore,
important to perform neuroendocrine stains to ensure correct diagnosis and appropriate
management of tumors.
