Accepted Manuscript PUNLMP in the Upper Urinary Tract: Endoscopic Treatment Hakan Ercil, Nevzat Can Şener, Adem Altunkol, Fulya Adamhasan, Suleyman Yesil, Ferhat Ortoglu, Ergun Alma, Zafer Gokhan Gurbuz PII:
S1558-7673(14)00108-6
DOI:
10.1016/j.clgc.2014.04.006
Reference:
CLGC 278
To appear in:
Clinical Genitourinary Cancer
Received Date: 17 February 2014 Revised Date:
2 April 2014
Accepted Date: 3 April 2014
Please cite this article as: Ercil H, Şener NC, Altunkol A, Adamhasan F, Yesil S, Ortoglu F, Alma E, Gurbuz ZG, PUNLMP in the Upper Urinary Tract: Endoscopic Treatment, Clinical Genitourinary Cancer (2014), doi: 10.1016/j.clgc.2014.04.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
PUNLMP in the Upper Urinary Tract: Endoscopic Treatment
Hakan Ercil1, Nevzat Can Şener1, Adem Altunkol1, Fulya Adamhasan2,
RI PT
Suleyman Yesil3, Ferhat Ortoglu1, Ergun Alma4, Zafer Gokhan Gurbuz5
1: Ministry of Health, Numune Teaching and Research Hospital,
SC
Department of Urology, Adana, Turkey
2: Ministry of Health, Numune Teaching and Research Hospital,
M AN U
Department of Pathology, Adana, Turkey
3: Department of Urology, Gazi University School of Medicine, Ankara, Turkey.
4: Ministry of Health, Cukurova Askim Tufekci State Hospital,
TE D
Department of Urology, Adana, Turkey
5: Ministry of Health, Haseki Teaching and Research Hospital,
EP
Department of Urology, Istanbul, Turkey
AC C
Corresponding Author: Nevzat Can Sener Ministry
of
Health,
Numune
Teaching
and
Research
Department of Urology, Adana, Turkey. Tel:
+905053328474
e-mail: [email protected]
Keywords: PUNLMP, upper urinary tract, endoscopic treatment
Hospital,
ACCEPTED MANUSCRIPT Editorial Office “Clinical Genitourinary Cancer”
PUNLMP in the Upper Urinary Tract: Endoscopic Treatment Title Page Authors: Hakan Ercil1, Nevzat Can Şener1, Adem Altunkol1, Fulya Adamhasan2,
RI PT
• •
Suleyman Yesil3, Ferhat Ortoglu1, Ergun Alma4, Zafer Gokhan Gurbuz5
SC
1: Ministry of Health, Numune Teaching and Research Hospital, Department
M AN U
of Urology, Adana, Turkey. 2: Ministry of Health, Numune Teaching and Research Hospital, Department of Pathology, Adana, Turkey. Department of Urology, Gazi University School of Medicine, Ankara, Turkey. 4: Ministry of Health, Cukurova Askim Tufekci State Hospital, Department of Urology, Adana, Turkey. 5: Ministry of Health, Haseki Teaching and Research Hospital,
EP
•
Financial Disclosure: The authors have nothing to disclose financially. Running Title: Endoscopic treatment of PUNLMP. Corresponding author: Nevzat Can Sener, M.D. Numune Teaching and Research Hospital, Department of Urology, Adana, Turkey. Adress: Numune Teaching and Research Hospital, Yuregir, Adana Number of Words: Abstract: 268, Manuscript: 1166.
AC C
• • •
TE D
Department of Urology, Istanbul, Turkey.
17.02.2013 Nevzat Can Sener
1
ACCEPTED MANUSCRIPT Clinical practice points: -
Papillary uretelial neoplasm of low malignant potential (PUNLMP) is rare disease.
-
Differential diagnosis is hard to exclude from other malignant pathologies
-
RI PT
that require radical nephroureterectomy. The purpose of this article is to report the first findings of PUNLMP in the upper urinary tract.
Because the lesion is the lowest grade of malignant uretelial tumors,
EP
TE D
M AN U
SC
endoscopic organ sparing technique may be a safe and feasible approach.
AC C
-
2
ACCEPTED MANUSCRIPT Abstract
Introduction: Papillary uretelial neoplasm of low malignant potential (PUNLMP) is a rare diagnosis, and has not yet been reported in the upper urinary tract. In this study,
RI PT
we aimed to present our experience in managing a very rare diagnosis, PUNLMP in the upper urinary tract, with endoscopic treatment. Material and Methods: Files of patients operated between January 2007 and January 2013 for upper urinary tract
SC
tumors were reviewed and patients treated for PUNLMP in the upper urinary tract in four urology clinics were reviewed. Patients included in the study had at most two
M AN U
tumors in the ureter and had a pathology of PUNLMP. Results: The study included eleven patients with a mean age of 58.5 years. There were 9 males, 2 females with a smoking rate of 81.8%. Nine patients (eight in distal and one in mid ureteral) were managed with a semirigid ureteroscope. Two patients (one mid ureteral and one
TE D
proximal) were treated with flexible ureteroscopy. The mean hospital stay was 1.56 days. Mean operative time was 37.18± 7.14 minutes. The mean follow up was 31.5 (7-72) months. In the follow-ups, three patients had recurrences of three, two and four
EP
mm in 9, 15 and 17 months, respectively. Conclusion: For tumors with a low risk of progression and relatively low risk of recurrence, organ-sparing treatments should be
AC C
the choice of preference. To support our initial findings, randomized controlled studies on larger cohorts should be designed.
3
ACCEPTED MANUSCRIPT Introduction Uretelial carcinomas were described in 1973 WHO classification and classified as Grades 1-3. In 2004, a modification was made to include terms, such as papillary uretelial neoplasm of low malignant potential (PUNLMP), low and high
RI PT
grades. Grades 1 and 2 (partial) were combined to low grade and Grades 2 (partial) and 3 were combined to high grades. PUNLMP was described as the grey zone between ureteral polyps and low-grade carcinomas 1. PUNLMP has a negligible low
SC
progression risk, but it is not a benign disease and recurrences may occur 2.
M AN U
PUNLMP has an incidence of 3 patients in 100,000 people every year. Male/female ratio is 5/1. Mean age at diagnosis is 64.6 years. The most common presentation is microscopic hematuria 3.
Efficacy of endoscopic treatment in treatment of upper ureteral tumors were demonstrated in literature 4. Report suggest that endoscopy can be the first line
TE D
treatment option for low grade urethelial tumors 5. Endoscopic treatment may be performed via retrograde or antegrade approaches 6. Tumor localization, grade and
EP
size are the most important factors for tumor prognosis 7. Depending on tumor grade, a recurrence rate between 34.8%-88% were reported 8. Close follow up is indicated,
AC C
and diagnostic ureteroscopy is needed. Researchers revealed that one thirds of patients had to be managed by nephroureterectomy because of high recurrence rates and disease progression
9,10
. All these data were acquired using the old classification.
To our knowledge, there is not a study focusing on PUNLMP in upper urinary tract. In this study, we aimed to present our experience in managing PUNLMP in the upper urinary tract with endoscopic treatment.
4
ACCEPTED MANUSCRIPT Patients and Methods Files of patients operated between January 2007 and January 2013 for upper urinary tract tumors were reviewed and patients treated for PUNLMP in the upper urinary tract in four urology clinics were reviewed. Patients with a diagnosis with
RI PT
PUNLMP were re-evaluated by a pathologist (FA). Patients included in the study had at most two tumors in the ureter and had a pathology of PUNLMP.
SC
The patients were diagnosed with intravenous urography (IVU) or urinary ultrasonography (USG) and Computerized Tomography Urography (CTU).
M AN U
All the patients had undergone cystoscopy for possible bladder tumor and ureteroscopy for the visualization of the disease. A biopsy was obtained from the tumor and the operation was ended.
To diagnose pathologically, PUNLMP was differentiated from papilloma and non-
TE D
invasive low-grade urethelial carcinoma. PUNLMP lesions resemble urethelial papilloma but without increased cellular proliferation resulting in thicker urothelium. Furthermore, when compared to urothelial papilloma, limited nuclear growth should
EP
be demonstrated. PUNLMP lesions should be distinguished from non-invasive lowgrade urothelial carcinoma by existing uniform nuclei without mytotic figures and
AC C
pleomorphism, and low Ki67 proliferation index. After the final pathology specimens confirmed the disease as PUNLMP (Figure 1), the patients were re-operated and a full diagnostic ureterorenoscopy was performed. Tumors were removed by biopsy and ablated and fulgurized with Ho:YAG laser ( 272 µm fiber sphinx, LISA,USA). Laser level was set to 0.5-1 joule at a frequency of 5-10 Hz. Fulguration and ablation was performed by semirigid ureteroscopy if the tumor could be reached. If not, a flexible ureterorenoscope was used (Flex-X2, Karl Storz,
5
ACCEPTED MANUSCRIPT Tuttlingen, Germany). Following the procedure, 40 mg of intraureteral Mitomycin-C instillation was performed by an ureteral catheter. An indwelling double J ureteral stent was placed and removed after two weeks. Patients then were followed-up with urinary cytology and CTU in third and sixth
RI PT
months. Cystoscopy and ureteroscopy were performed at months three and six. For
SC
two years, the follow-up was in semi annually and then annually for five years.
M AN U
Results
The study included eleven patients with a mean age of 58.5 years. There were 9 males, 2 females with a smoking rate of 81.8%.
Two patients were diagnosed incidentally, while a planned ureteroscopy had
TE D
been performed for distal ureteral stones. Five patients had a history of colic pain and microscopic hematuria and two patients were presented with microscopic hematuria only.
EP
Two of the patients were already in follow up because of a bladder tumor
AC C
history. Six patients had distal ureteral, two patients had mid ureteral and one patient had upper ureteral tumors. One patient had a previous history of high-grade renal pelvis tumor and was
under follow-up. That patient had been treated via radical nephroureterectomy. Another patient applied to our clinic with high grade hydroureteronephrosis and diagnosed with ureterovesical junction obstruction. Patient had been treated with a Double J catheter before he applied to our clinic. That patient was treated
6
ACCEPTED MANUSCRIPT endoscopically and a tumor of 5 mm was noticed in this operation. After the biopsy was confirmed with PUNLMP, the tumor was treated endoscopically. Visually assessed mean tumor size was 6.13 mm. Two patients had tumors in two sites and the others, in one site.
RI PT
Nine patients (eight in distal and one in mid ureteral) were managed with a semirigid ureteroscope. Two patients (one mid ureteral and one proximal) were treated with flexible ureteroscopy. The mean hospital stay was 1.56 days. Mean
SC
operative time was 37.18± 7.14 minutes. The mean follow up was 31.5 (7-72) months. In the follow-ups, three patients had recurrences of three, two and four mm in
M AN U
9, 15 and 17 months, respectively. They were all PUNLMP. The recurrences were managed endoscopically. The recurrence rate was 27.3%. No progression was detected and none of the patients underwent nephroureterectomy. When recurrent patients were analyzed, all pathologies were also PUNLMP.
TE D
The pathologist noted no specific difference for both recurrent or previous pathologies.
AC C
EP
Patient demographics and outcomes were summarized in Table 1.
Discussion
Gold
standard
treatment
of
upper
urinary
system
tumors
is
nephroureterectomy and bladder cuff excision. High morbidity and kidney loss prompted urologists to have second thoughts when dealing with low risk tumors
11,12
.
With technologic advances, small caliber devices and development of fiber technology, endoscopic treatment became more popular in treatment of upper ureteral tumors 13,14. Especially in small tumors and resectable tumors, in a solitary site, with a
7
ACCEPTED MANUSCRIPT low grade in cytology and pathology, and the lack of proof of invasion are the indications of endoscopic treatment 1. All our patients had at most two tumors with a size less than one cm. All our patients were treated with holmium laser ablation and fulguration.
RI PT
In literature, a conflict is present in whether a biopsy should be obtained. Childs et al indicated that with radiologic and ureteroscopic findings, a carcinoma cannot be distinguished and proposed a mandatory biopsy
15
. Sun et al pointed out
16
. In another study, authors reported 30% discordance
and indicated a biopsy for diagnosis
17
M AN U
performed in suspected cases
SC
that in fibroureteral polyps, a biopsy is not indicated but a frozen section can be
. With biopsy, researchers proposed 88%
success in prediction and risk assessment 18. In our nine patient cohorts, we performed a biopsy and a treatment modality was chosen according to the outcome. We believe in less invasive tumors like PUNLMP, a less invasive approach should be taken into
TE D
account.
In an ureteroscopy series performed by Daneshmand et al, 88% recurrence rate was reported. The authors performed mandatory organ sparing approach in 17 of
EP
the 26 cases because of a solitary kidney. They had seven grade 1 patients. The
AC C
remaining patients were grade 2 or 3 4. Chen and Bagley revealed 65% recurrence rates in routine ureteroscopic follow-ups. They reported 1-3 mm recurrences in most cases. They underlined the importance of routine ureteroscopic controls 9. We reported 33% recurrence. Because we only included PUNLMP patients, unlike in the earlier reports, our recurrence rate is lower. Ureteral perforation and stricture are the most serious complications in endoscopic treatment in upper urinary lesions. With the advances in technology, development of smaller endoscopes and laser technology, complication risk is
8
ACCEPTED MANUSCRIPT minimized where success rate is maximized
19
. We did not encounter any
intraoperative complications. In the follow up, there were no ureteral strictures. It may be because of the Double J stent placement following the surgery. Fuji et al reported their experience of PUNLMP of the bladder. They reported
recurrence rates
20
RI PT
an 11.7-year follow up of 50 cases. They did not report any progression with 60% . Literature reveals no studies on PUNLMP in the upper urinary
tract. We found a recurrence rate of 27% in 31.5 months of follow-up.
SC
Our study has many limitations. It is retrospective and refers to a very small
we believe this study is valuable.
Conclusion
M AN U
cohort. However, because literature presents no data about upper urinary tract tumors,
TE D
In conclusion, for tumors with a low risk of progression and relatively low risk of recurrence, organ-sparing treatments should be the choice of preference. To support
AC C
designed.
EP
our initial findings, randomized controlled studies on larger cohorts should be
Conflict of Interest None.
Reference: 1.
Rouprêt M, Babjuk M, Compérat E, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013;63(6):1059–1071. doi:10.1016/j.eururo.2013.03.032.
9
ACCEPTED MANUSCRIPT Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64(4):639–653. doi:10.1016/j.eururo.2013.06.003.
3.
Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease, Professional Edition. 8th ed. Saunders Elsevier; 2013.
4.
Daneshmand S, Quek ML, Huffman JL. Endoscopic management of upper urinary tract transitional cell carcinoma: long-term experience. Cancer 2003;98(1):55–60. doi:10.1002/cncr.11446.
5.
Aboumarzouk OM, Somani B, Ahmad S, et al. Mitomycin C instillation following ureterorenoscopic laser ablation of upper urinary tract carcinoma. Urol Ann 2013;5(3):184–189. doi:10.4103/0974-7796.115746.
6.
Park BH, Jeon SS. Endoscopic management of upper urinary tract urothelial carcinoma. Korean J Urol 2013;54(7):426–432. doi:10.4111/kju.2013.54.7.426.
7.
Niţă G, Georgescu D, Mulţescu R, et al. Prognostic factors in laser treatment of upper urinary tract urothelial tumours. J Med Life 2012;5(1):33–38.
8.
Martínez-Piñeiro JA, García Matres MJ, Martínez-Piñeiro L. Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors. J Urol 1996;156(2 Pt 1):377–385.
9.
Chen GL, Bagley DH. Ureteroscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. J Urol 2000;164(4):1173–1176.
TE D
M AN U
SC
RI PT
2.
10. Elliott DS, Blute ML, Patterson DE, et al. Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. Urology 1996;47(6):819–825. doi:10.1016/S0090-4295(96)00043-X.
EP
11. Rouprêt M, Traxer O, Tligui M, et al. Upper urinary tract transitional cell carcinoma: recurrence rate after percutaneous endoscopic resection. Eur Urol 2007;51(3):709–713; discussion 714. doi:10.1016/j.eururo.2006.07.019.
AC C
12. Iborra I, Solsona E, Casanova J, et al. Conservative elective treatment of upper urinary tract tumors: a multivariate analysis of prognostic factors for recurrence and progression. J Urol 2003;169(1):82–85. doi:10.1097/01.ju.0000040589.56827.4a. 13. Deligne E, Colombel M, Badet L, et al. Conservative management of upper urinary tract tumors. Eur Urol 2002;42(1):43–48. 14. Lam JS, Gupta M. Ureteroscopic management of upper tract transitional cell carcinoma. Urol Clin North Am 2004;31(1):115–128. doi:10.1016/S00940143(03)00099-5. 15. Childs MA, Umbreit EC, Krambeck AE, et al. Fibroepithelial polyps of the ureter: a single-institutional experience. J Endourol Endourol Soc 2009;23(9):1415–1419. doi:10.1089/end.2009.0403. 10
ACCEPTED MANUSCRIPT 16. Sun Y, Xu C, Wen X, et al. Is endoscopic management suitable for long ureteral fibroepithelial polyps? J Endourol Endourol Soc 2008;22(7):1459–1462. doi:10.1089/end.2008.0060. 17. El-Hakim A, Weiss GH, Lee BR, et al. Correlation of ureteroscopic appearance with histologic grade of upper tract transitional cell carcinoma. Urology 2004;63(4):647–650; discussion 650. doi:10.1016/j.urology.2003.10.076.
RI PT
18. Shiraishi K, Eguchi S, Mohri J, et al. Role of ureteroscopic biopsy in the management of upper urinary tract malignancy. Int J Urol Off J Jpn Urol Assoc 2003;10(12):627–630.
SC
19. Multescu R, Geavlete B, Geavlete P. A new era: performance and limitations of the latest models of flexible ureteroscopes. Urology 2013;82(6):1236–1239. doi:10.1016/j.urology.2013.07.022.
TE D
M AN U
20. Fujii Y, Kawakami S, Koga F, et al. Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential. BJU Int 2003;92(6):559–562.
Figure 1: Left: Papillary neoplasm lined with non-fused multilayered uretelial epithelium (H&Ex40). Right: Uretelial cells have no cytological atypia, only a few
AC C
EP
cells stained with Ki-67. (immunohistochemistryX100).
11
ACCEPTED MANUSCRIPT
64 53 43 62 48 57
7
64
M
L
8
1
8
56
M
L
8
1
9 10
69 72
F M
L R
6 4
1 1
11
55
M
L
5
1
Recurrence?
Tumor Site
Patient History
Negative Negative Negative Negative Negative Negative
Follow-up length (months) 72 15 13 31 53 34
15 months None None 9 months None None
Distal Distal Distal Proximal Mid Distal
Negative
7
None
Distal
None None Ureterolithiasis None None Bladder Tumor, Ureterolithiasis Diabetes Mellitus
Negative
50
None
Mid
Hypertension
Negative Negative
30 25
17 months None
Distal Distal
Negative
17
None
Distal
Bladder Tumor Renal Pelvis Tumor Ureterovesical Junction Obstruction
SC
1 2 3 4 5 6
Urinary Cytology
M AN U
Number of lesions 1 2 1 2 1 1
TE D
M M M F M M
Side Lesion Length (mm) R 8 L 8&4 L 5 L 7&5 R 5 R 7
EP
Sex
AC C
Patient Age (Years)
RI PT
Table 1: Patient demographics and follow-up data
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1558-7673(14)00108-6
DOI:
10.1016/j.clgc.2014.04.006
Reference:
CLGC 278
To appear in:
Clinical Genitourinary Cancer
Received Date: 17 February 2014 Revised Date:
2 April 2014
Accepted Date: 3 April 2014
Please cite this article as: Ercil H, Şener NC, Altunkol A, Adamhasan F, Yesil S, Ortoglu F, Alma E, Gurbuz ZG, PUNLMP in the Upper Urinary Tract: Endoscopic Treatment, Clinical Genitourinary Cancer (2014), doi: 10.1016/j.clgc.2014.04.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
PUNLMP in the Upper Urinary Tract: Endoscopic Treatment
Hakan Ercil1, Nevzat Can Şener1, Adem Altunkol1, Fulya Adamhasan2,
RI PT
Suleyman Yesil3, Ferhat Ortoglu1, Ergun Alma4, Zafer Gokhan Gurbuz5
1: Ministry of Health, Numune Teaching and Research Hospital,
SC
Department of Urology, Adana, Turkey
2: Ministry of Health, Numune Teaching and Research Hospital,
M AN U
Department of Pathology, Adana, Turkey
3: Department of Urology, Gazi University School of Medicine, Ankara, Turkey.
4: Ministry of Health, Cukurova Askim Tufekci State Hospital,
TE D
Department of Urology, Adana, Turkey
5: Ministry of Health, Haseki Teaching and Research Hospital,
EP
Department of Urology, Istanbul, Turkey
AC C
Corresponding Author: Nevzat Can Sener Ministry
of
Health,
Numune
Teaching
and
Research
Department of Urology, Adana, Turkey. Tel:
+905053328474
e-mail: [email protected]
Keywords: PUNLMP, upper urinary tract, endoscopic treatment
Hospital,
ACCEPTED MANUSCRIPT Editorial Office “Clinical Genitourinary Cancer”
PUNLMP in the Upper Urinary Tract: Endoscopic Treatment Title Page Authors: Hakan Ercil1, Nevzat Can Şener1, Adem Altunkol1, Fulya Adamhasan2,
RI PT
• •
Suleyman Yesil3, Ferhat Ortoglu1, Ergun Alma4, Zafer Gokhan Gurbuz5
SC
1: Ministry of Health, Numune Teaching and Research Hospital, Department
M AN U
of Urology, Adana, Turkey. 2: Ministry of Health, Numune Teaching and Research Hospital, Department of Pathology, Adana, Turkey. Department of Urology, Gazi University School of Medicine, Ankara, Turkey. 4: Ministry of Health, Cukurova Askim Tufekci State Hospital, Department of Urology, Adana, Turkey. 5: Ministry of Health, Haseki Teaching and Research Hospital,
EP
•
Financial Disclosure: The authors have nothing to disclose financially. Running Title: Endoscopic treatment of PUNLMP. Corresponding author: Nevzat Can Sener, M.D. Numune Teaching and Research Hospital, Department of Urology, Adana, Turkey. Adress: Numune Teaching and Research Hospital, Yuregir, Adana Number of Words: Abstract: 268, Manuscript: 1166.
AC C
• • •
TE D
Department of Urology, Istanbul, Turkey.
17.02.2013 Nevzat Can Sener
1
ACCEPTED MANUSCRIPT Clinical practice points: -
Papillary uretelial neoplasm of low malignant potential (PUNLMP) is rare disease.
-
Differential diagnosis is hard to exclude from other malignant pathologies
-
RI PT
that require radical nephroureterectomy. The purpose of this article is to report the first findings of PUNLMP in the upper urinary tract.
Because the lesion is the lowest grade of malignant uretelial tumors,
EP
TE D
M AN U
SC
endoscopic organ sparing technique may be a safe and feasible approach.
AC C
-
2
ACCEPTED MANUSCRIPT Abstract
Introduction: Papillary uretelial neoplasm of low malignant potential (PUNLMP) is a rare diagnosis, and has not yet been reported in the upper urinary tract. In this study,
RI PT
we aimed to present our experience in managing a very rare diagnosis, PUNLMP in the upper urinary tract, with endoscopic treatment. Material and Methods: Files of patients operated between January 2007 and January 2013 for upper urinary tract
SC
tumors were reviewed and patients treated for PUNLMP in the upper urinary tract in four urology clinics were reviewed. Patients included in the study had at most two
M AN U
tumors in the ureter and had a pathology of PUNLMP. Results: The study included eleven patients with a mean age of 58.5 years. There were 9 males, 2 females with a smoking rate of 81.8%. Nine patients (eight in distal and one in mid ureteral) were managed with a semirigid ureteroscope. Two patients (one mid ureteral and one
TE D
proximal) were treated with flexible ureteroscopy. The mean hospital stay was 1.56 days. Mean operative time was 37.18± 7.14 minutes. The mean follow up was 31.5 (7-72) months. In the follow-ups, three patients had recurrences of three, two and four
EP
mm in 9, 15 and 17 months, respectively. Conclusion: For tumors with a low risk of progression and relatively low risk of recurrence, organ-sparing treatments should be
AC C
the choice of preference. To support our initial findings, randomized controlled studies on larger cohorts should be designed.
3
ACCEPTED MANUSCRIPT Introduction Uretelial carcinomas were described in 1973 WHO classification and classified as Grades 1-3. In 2004, a modification was made to include terms, such as papillary uretelial neoplasm of low malignant potential (PUNLMP), low and high
RI PT
grades. Grades 1 and 2 (partial) were combined to low grade and Grades 2 (partial) and 3 were combined to high grades. PUNLMP was described as the grey zone between ureteral polyps and low-grade carcinomas 1. PUNLMP has a negligible low
SC
progression risk, but it is not a benign disease and recurrences may occur 2.
M AN U
PUNLMP has an incidence of 3 patients in 100,000 people every year. Male/female ratio is 5/1. Mean age at diagnosis is 64.6 years. The most common presentation is microscopic hematuria 3.
Efficacy of endoscopic treatment in treatment of upper ureteral tumors were demonstrated in literature 4. Report suggest that endoscopy can be the first line
TE D
treatment option for low grade urethelial tumors 5. Endoscopic treatment may be performed via retrograde or antegrade approaches 6. Tumor localization, grade and
EP
size are the most important factors for tumor prognosis 7. Depending on tumor grade, a recurrence rate between 34.8%-88% were reported 8. Close follow up is indicated,
AC C
and diagnostic ureteroscopy is needed. Researchers revealed that one thirds of patients had to be managed by nephroureterectomy because of high recurrence rates and disease progression
9,10
. All these data were acquired using the old classification.
To our knowledge, there is not a study focusing on PUNLMP in upper urinary tract. In this study, we aimed to present our experience in managing PUNLMP in the upper urinary tract with endoscopic treatment.
4
ACCEPTED MANUSCRIPT Patients and Methods Files of patients operated between January 2007 and January 2013 for upper urinary tract tumors were reviewed and patients treated for PUNLMP in the upper urinary tract in four urology clinics were reviewed. Patients with a diagnosis with
RI PT
PUNLMP were re-evaluated by a pathologist (FA). Patients included in the study had at most two tumors in the ureter and had a pathology of PUNLMP.
SC
The patients were diagnosed with intravenous urography (IVU) or urinary ultrasonography (USG) and Computerized Tomography Urography (CTU).
M AN U
All the patients had undergone cystoscopy for possible bladder tumor and ureteroscopy for the visualization of the disease. A biopsy was obtained from the tumor and the operation was ended.
To diagnose pathologically, PUNLMP was differentiated from papilloma and non-
TE D
invasive low-grade urethelial carcinoma. PUNLMP lesions resemble urethelial papilloma but without increased cellular proliferation resulting in thicker urothelium. Furthermore, when compared to urothelial papilloma, limited nuclear growth should
EP
be demonstrated. PUNLMP lesions should be distinguished from non-invasive lowgrade urothelial carcinoma by existing uniform nuclei without mytotic figures and
AC C
pleomorphism, and low Ki67 proliferation index. After the final pathology specimens confirmed the disease as PUNLMP (Figure 1), the patients were re-operated and a full diagnostic ureterorenoscopy was performed. Tumors were removed by biopsy and ablated and fulgurized with Ho:YAG laser ( 272 µm fiber sphinx, LISA,USA). Laser level was set to 0.5-1 joule at a frequency of 5-10 Hz. Fulguration and ablation was performed by semirigid ureteroscopy if the tumor could be reached. If not, a flexible ureterorenoscope was used (Flex-X2, Karl Storz,
5
ACCEPTED MANUSCRIPT Tuttlingen, Germany). Following the procedure, 40 mg of intraureteral Mitomycin-C instillation was performed by an ureteral catheter. An indwelling double J ureteral stent was placed and removed after two weeks. Patients then were followed-up with urinary cytology and CTU in third and sixth
RI PT
months. Cystoscopy and ureteroscopy were performed at months three and six. For
SC
two years, the follow-up was in semi annually and then annually for five years.
M AN U
Results
The study included eleven patients with a mean age of 58.5 years. There were 9 males, 2 females with a smoking rate of 81.8%.
Two patients were diagnosed incidentally, while a planned ureteroscopy had
TE D
been performed for distal ureteral stones. Five patients had a history of colic pain and microscopic hematuria and two patients were presented with microscopic hematuria only.
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Two of the patients were already in follow up because of a bladder tumor
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history. Six patients had distal ureteral, two patients had mid ureteral and one patient had upper ureteral tumors. One patient had a previous history of high-grade renal pelvis tumor and was
under follow-up. That patient had been treated via radical nephroureterectomy. Another patient applied to our clinic with high grade hydroureteronephrosis and diagnosed with ureterovesical junction obstruction. Patient had been treated with a Double J catheter before he applied to our clinic. That patient was treated
6
ACCEPTED MANUSCRIPT endoscopically and a tumor of 5 mm was noticed in this operation. After the biopsy was confirmed with PUNLMP, the tumor was treated endoscopically. Visually assessed mean tumor size was 6.13 mm. Two patients had tumors in two sites and the others, in one site.
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Nine patients (eight in distal and one in mid ureteral) were managed with a semirigid ureteroscope. Two patients (one mid ureteral and one proximal) were treated with flexible ureteroscopy. The mean hospital stay was 1.56 days. Mean
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operative time was 37.18± 7.14 minutes. The mean follow up was 31.5 (7-72) months. In the follow-ups, three patients had recurrences of three, two and four mm in
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9, 15 and 17 months, respectively. They were all PUNLMP. The recurrences were managed endoscopically. The recurrence rate was 27.3%. No progression was detected and none of the patients underwent nephroureterectomy. When recurrent patients were analyzed, all pathologies were also PUNLMP.
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The pathologist noted no specific difference for both recurrent or previous pathologies.
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Patient demographics and outcomes were summarized in Table 1.
Discussion
Gold
standard
treatment
of
upper
urinary
system
tumors
is
nephroureterectomy and bladder cuff excision. High morbidity and kidney loss prompted urologists to have second thoughts when dealing with low risk tumors
11,12
.
With technologic advances, small caliber devices and development of fiber technology, endoscopic treatment became more popular in treatment of upper ureteral tumors 13,14. Especially in small tumors and resectable tumors, in a solitary site, with a
7
ACCEPTED MANUSCRIPT low grade in cytology and pathology, and the lack of proof of invasion are the indications of endoscopic treatment 1. All our patients had at most two tumors with a size less than one cm. All our patients were treated with holmium laser ablation and fulguration.
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In literature, a conflict is present in whether a biopsy should be obtained. Childs et al indicated that with radiologic and ureteroscopic findings, a carcinoma cannot be distinguished and proposed a mandatory biopsy
15
. Sun et al pointed out
16
. In another study, authors reported 30% discordance
and indicated a biopsy for diagnosis
17
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performed in suspected cases
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that in fibroureteral polyps, a biopsy is not indicated but a frozen section can be
. With biopsy, researchers proposed 88%
success in prediction and risk assessment 18. In our nine patient cohorts, we performed a biopsy and a treatment modality was chosen according to the outcome. We believe in less invasive tumors like PUNLMP, a less invasive approach should be taken into
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account.
In an ureteroscopy series performed by Daneshmand et al, 88% recurrence rate was reported. The authors performed mandatory organ sparing approach in 17 of
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the 26 cases because of a solitary kidney. They had seven grade 1 patients. The
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remaining patients were grade 2 or 3 4. Chen and Bagley revealed 65% recurrence rates in routine ureteroscopic follow-ups. They reported 1-3 mm recurrences in most cases. They underlined the importance of routine ureteroscopic controls 9. We reported 33% recurrence. Because we only included PUNLMP patients, unlike in the earlier reports, our recurrence rate is lower. Ureteral perforation and stricture are the most serious complications in endoscopic treatment in upper urinary lesions. With the advances in technology, development of smaller endoscopes and laser technology, complication risk is
8
ACCEPTED MANUSCRIPT minimized where success rate is maximized
19
. We did not encounter any
intraoperative complications. In the follow up, there were no ureteral strictures. It may be because of the Double J stent placement following the surgery. Fuji et al reported their experience of PUNLMP of the bladder. They reported
recurrence rates
20
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an 11.7-year follow up of 50 cases. They did not report any progression with 60% . Literature reveals no studies on PUNLMP in the upper urinary
tract. We found a recurrence rate of 27% in 31.5 months of follow-up.
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Our study has many limitations. It is retrospective and refers to a very small
we believe this study is valuable.
Conclusion
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cohort. However, because literature presents no data about upper urinary tract tumors,
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In conclusion, for tumors with a low risk of progression and relatively low risk of recurrence, organ-sparing treatments should be the choice of preference. To support
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designed.
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our initial findings, randomized controlled studies on larger cohorts should be
Conflict of Interest None.
Reference: 1.
Rouprêt M, Babjuk M, Compérat E, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013;63(6):1059–1071. doi:10.1016/j.eururo.2013.03.032.
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ACCEPTED MANUSCRIPT Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64(4):639–653. doi:10.1016/j.eururo.2013.06.003.
3.
Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease, Professional Edition. 8th ed. Saunders Elsevier; 2013.
4.
Daneshmand S, Quek ML, Huffman JL. Endoscopic management of upper urinary tract transitional cell carcinoma: long-term experience. Cancer 2003;98(1):55–60. doi:10.1002/cncr.11446.
5.
Aboumarzouk OM, Somani B, Ahmad S, et al. Mitomycin C instillation following ureterorenoscopic laser ablation of upper urinary tract carcinoma. Urol Ann 2013;5(3):184–189. doi:10.4103/0974-7796.115746.
6.
Park BH, Jeon SS. Endoscopic management of upper urinary tract urothelial carcinoma. Korean J Urol 2013;54(7):426–432. doi:10.4111/kju.2013.54.7.426.
7.
Niţă G, Georgescu D, Mulţescu R, et al. Prognostic factors in laser treatment of upper urinary tract urothelial tumours. J Med Life 2012;5(1):33–38.
8.
Martínez-Piñeiro JA, García Matres MJ, Martínez-Piñeiro L. Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors. J Urol 1996;156(2 Pt 1):377–385.
9.
Chen GL, Bagley DH. Ureteroscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. J Urol 2000;164(4):1173–1176.
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SC
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2.
10. Elliott DS, Blute ML, Patterson DE, et al. Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. Urology 1996;47(6):819–825. doi:10.1016/S0090-4295(96)00043-X.
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11. Rouprêt M, Traxer O, Tligui M, et al. Upper urinary tract transitional cell carcinoma: recurrence rate after percutaneous endoscopic resection. Eur Urol 2007;51(3):709–713; discussion 714. doi:10.1016/j.eururo.2006.07.019.
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12. Iborra I, Solsona E, Casanova J, et al. Conservative elective treatment of upper urinary tract tumors: a multivariate analysis of prognostic factors for recurrence and progression. J Urol 2003;169(1):82–85. doi:10.1097/01.ju.0000040589.56827.4a. 13. Deligne E, Colombel M, Badet L, et al. Conservative management of upper urinary tract tumors. Eur Urol 2002;42(1):43–48. 14. Lam JS, Gupta M. Ureteroscopic management of upper tract transitional cell carcinoma. Urol Clin North Am 2004;31(1):115–128. doi:10.1016/S00940143(03)00099-5. 15. Childs MA, Umbreit EC, Krambeck AE, et al. Fibroepithelial polyps of the ureter: a single-institutional experience. J Endourol Endourol Soc 2009;23(9):1415–1419. doi:10.1089/end.2009.0403. 10
ACCEPTED MANUSCRIPT 16. Sun Y, Xu C, Wen X, et al. Is endoscopic management suitable for long ureteral fibroepithelial polyps? J Endourol Endourol Soc 2008;22(7):1459–1462. doi:10.1089/end.2008.0060. 17. El-Hakim A, Weiss GH, Lee BR, et al. Correlation of ureteroscopic appearance with histologic grade of upper tract transitional cell carcinoma. Urology 2004;63(4):647–650; discussion 650. doi:10.1016/j.urology.2003.10.076.
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18. Shiraishi K, Eguchi S, Mohri J, et al. Role of ureteroscopic biopsy in the management of upper urinary tract malignancy. Int J Urol Off J Jpn Urol Assoc 2003;10(12):627–630.
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19. Multescu R, Geavlete B, Geavlete P. A new era: performance and limitations of the latest models of flexible ureteroscopes. Urology 2013;82(6):1236–1239. doi:10.1016/j.urology.2013.07.022.
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20. Fujii Y, Kawakami S, Koga F, et al. Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential. BJU Int 2003;92(6):559–562.
Figure 1: Left: Papillary neoplasm lined with non-fused multilayered uretelial epithelium (H&Ex40). Right: Uretelial cells have no cytological atypia, only a few
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cells stained with Ki-67. (immunohistochemistryX100).
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64 53 43 62 48 57
7
64
M
L
8
1
8
56
M
L
8
1
9 10
69 72
F M
L R
6 4
1 1
11
55
M
L
5
1
Recurrence?
Tumor Site
Patient History
Negative Negative Negative Negative Negative Negative
Follow-up length (months) 72 15 13 31 53 34
15 months None None 9 months None None
Distal Distal Distal Proximal Mid Distal
Negative
7
None
Distal
None None Ureterolithiasis None None Bladder Tumor, Ureterolithiasis Diabetes Mellitus
Negative
50
None
Mid
Hypertension
Negative Negative
30 25
17 months None
Distal Distal
Negative
17
None
Distal
Bladder Tumor Renal Pelvis Tumor Ureterovesical Junction Obstruction
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1 2 3 4 5 6
Urinary Cytology
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Number of lesions 1 2 1 2 1 1
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M M M F M M
Side Lesion Length (mm) R 8 L 8&4 L 5 L 7&5 R 5 R 7
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Sex
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Patient Age (Years)
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Table 1: Patient demographics and follow-up data
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