Stesura Seveso 47Archivio Italiano di Urologia e Andrologia 2016; 88, 1 REVIEW Primary adenocarcinoma of the seminal vesicles. A review of the literature Ioannis Katafigiotis 1, Stavros Sfoungaristos 2, Mordechai Duvdevani 2, Panagiotis Mitsos 1, Eleni Roumelioti 1, Konstantinos Stravodimos 1, Ioannis Anastasiou 1, Constantinos A. Constantinides 1 1 1st University Urology Clinic Laiko Hospital, Athens, Greece; 2 Hebrew Hadassah University Medical Center, Jerusalem, Israel. Primary adenocarcinoma of the seminal vesicles (SV) are extremely rare and approximately only 60 cases have been reported in the litera- ture. Due to the lack of specific symptoms the patients often present in an advanced stage of their disease. The only clini- cal examination that can indicate the presence of a neoplasm in the SVs is the digital rectal examination (DRE). Serum prostatic specific antigen (PSA) and prostate specific acid phosphatase (PAP) are usually normal in patients with pri- mary adenocarcinoma of the SV and only CA-125 can be proved a useful blood biomarker contributing to the diagnosis and the follow up of the SV adenocarcinoma. Computed tomography (CT) and magnetic resonance imaging (MRI) and FDG-PET/CT have been used for the diagnosis and the staging of the SV adenocarcinoma. Various combinations of radical surgery, radiotherapy androgen deprivation therapy and chemotherapy have been proposed for the management of the disease but the prognosis is poor and the mean survival is two years after the diagnosis. KEY WORDS: Primary adenocarcinoma of the seminal vesicles; Seminal vesicle cancer; Primary neoplasm of the seminal vesicle. Submitted 27 October 2015; Accepted 5 December 2015 Summary No conflict of interest declared. able. Also papers that were referring to primary cancer of the seminal vesicle but to histology types other than ade- nocarcinoma were excluded from the main text but were used to the formation of Table I in the classification of the histology types. An additional search was made with “Primary seminal vesicle carcinoma” being the key words; 185 papers was the result and only 2 were chosen. The majority of the papers excluded were either the same papers as in the first search either irrelevant to the sub- ject. After the final selection 23 papers were chosen on which the review was based. One additional reference (reference 3) was not present in the Pubmed search but was traced from another paper and was used only for the historical aspect of the subject since it was the first paper published referring to the subject. DISCUSSION 1. Epidemiology Primary carcinomas of the SVs are extremely rare and the first case presented in the literature was by Lyons in 1925 (1, 3). Although primary adenocarcinomas of the SVs are rare it isn’t very easy to record with precision the exact number of the cases recorded in the literature. Following the papers published year by year in the liter- ature, in 2000 only 48 cases were recorded (4), in 2006 49 cases (5), 50-51 cases in 2011 (6, 7), and 5 more since then rising the total number of cases to 55-56 (1, 8-11).The mean patient age at diagnosis is 62 years old (range: 13-90 years) (9). 2. Histology types Primary adenocarcinoma is the most common neoplasm of the SVs. Other histology types of the primary neo- plasms of the SVs that have been recorded in the literature are sarcomas, squamous cell carcinoma, yolk salk tumor, neuroendocrine carcinoma, paraganglioma, epithelial stromal tumors, lymphoma (Burkitt, B-Cell), extragastroin- testinal stromal tumor (EGIST), myxoid solitary fibrous tumor, and seminoma peripheral primitive neuroectoder- mal tumor (PPNET) (Table 1). Benign tumors of the SVs are even rarer (5) and the reported histology types in the literature are cystic dysplasia, fibroepithelial tumor, leiomyoma, cystadenoma and Schwannoma (Table I). DOI: 10.4081/aiua.2016.1.47 INTRODUCTION Primary adenocarcinoma of the seminal vesicles (SV) are extremely rare and approximately only 60 cases have been reported in the literature (1). Due to the lack of specific symptoms the diagnosis and differentiation of a SV adenocarcinoma from neoplasms of the anatomic vicinity like the prostate, bladder and rectum that infil- trate secondarily the SVs is usually difficult (2). We pres- ent a comprehensive review of the literature. MATERIAL AND METHODS-AEARCH ATRATEGY Two different Pubmed-based search strategies were fol- lowed in order to acquire the necessary data for a com- plete review. The first search was “Primary adenocarcino- ma of the seminal vesicles” and 87 papers was the original result. From these 87 papers 21 papers-references were chosen and constituted the main base of the review; 66 papers were excluded either because they were irrele- vant to the subject, either because no abstract was avail- Katafigiotis_Stesura Seveso 08/04/16 11:29 Pagina 47 Archivio Italiano di Urologia e Andrologia 2016; 88, 1 I. Katafigiotis, S. Sfoungaristos, M. Duvdevani, P. Mitsos, Eleni Roumelioti, K. Stravodimos, I. Anastasiou, C.A. Constantinides 48 3. Diagnosis From 1956 already Dalgaard and Giertson described the following criteria for the diagnosis of a primary adeono- carcinoma of a SVs: the tumor should be a macro- and microscopically verified carcinoma, localized exclusively or mainly to the seminal vesicle; there must be no other primary carcinoma in the body; and the tumor should preferably be a papillary adenocarcinoma that resembles the architecture of the non-neoplastic seminal vesicle (4, 12). Nevertheless these criteria are referring mainly to the final specimen of the surgical resection4 and the pre- surgical diagnosis is a difficult task and the differential diagnosis from the primary adenocarcinomas of the prostate, bladder and colon that infiltrate the SVs is even more difficult (6, 9, 11). a) Symptoms Due to the lack of specific symptoms the patients often present in an advanced stage of their disease (13). All the data in the literature refer to non-specific symptoms from the genitourinary and the gastrointestinal tract (1, 5). The main symptoms from the genitourinary system can be dysuria, frequency, hematuria, hematospermia and blad- der outlet obstruction (1, 5, 9). From the gastrointestinal tract the main symptoms can be constipation and intestin- al bleeding (8, 11). Other symptoms that have been reported are painful sensation in the pelvis and perineum and general symptoms like appetite loss (1, 8). b) Clinical examination-Digital rectal examination (DRE) The only clinical examination that can indicate the pres- ence of a neoplasm in the SVs is the DRE. Although there is no unanimous description of the findings of a DRE in SV neoplasm the majority of the cases in the literature refer to a large irregular mass above the prostate (13). Usually the mass is non ten- der and immobile with a hard elastic composition (5, 9, 8, 13). Even though an abnormal DRE constitutes an integral part of the diagnosis, up to 30% of patients have no abnormal findings during DRE (9). c) Blood biomarkers -Table 2 Serum prostatic specific antigen (PSA) and prostate specific acid phosphatase (PAP) are usually normal in patients with primary adenocarcinoma of the SVs (1, 9, 6, 13). Also in our case the patient had a normal PSA of 1.5 ng/ml. Apart from the PSA also CA-19.9 has been reported to be normal in patients with primary adenocarcinoma of the SVs (1, 9). Special consideration must be taken for the other two biomark- ers CEA and CA-125. Normal serum CEA can be interpreted as absence of invasion of a colon carcinoma (9). Although usually CEA is normal in primary adenocarcinoma of the SVs, increased serum CEA levels are seen in rare cases (1, 9, 13). CA-125 is a useful biomarker in SV adenocarcinoma since there are reports of tumors producing CA-125 ele- vating the levels of the marker in serum (9, 14). CA-125 is a useful biomarker not only for the diagnosis but also for the follow-up of the patient since it can be decreased even to normal value after the treatment or rise again up to 6 months before the occurrence of clinical metastases (8, 14). Finally there is a reference of an elevated CA15-3 in a patient with primary SV adenocarcinoma (9). d) Imaging-biopsy Computed tomography (CT) and magnetic resonance imaging (MRI) have been widely used for the depiction of a SV neoplasm (1, 9, 13). Various descriptions of a SV mass during a CT have been reported in the literature from a solid mass originating from the SVs mildly enhancing to a lesion with an hypodense central area presenting peripheral contrast enhancement (1, 8, 13). MRI imaging can depict a high signal-intensity fluid in the SV (T1-weighted), a papillary mass (T2-weighted), or Primary neoplasms Histology type References of the SVs Malignant 1. Squamous cell Wang J, et al. 2013 Tabata K, et al. 2001 2. Yolk salk Dong Yao, et al. 2012 3. Neuroendocrine Kreiner B, et al. 2010 4. Paraganglioma AlvarengaI CA, et al. 2012 5. Epithelial stromal tumor Hoshi A, et al. 2006 6. Extragastrointestinal stromal tumor Song W, et al, 2012 7. Myxoid solitary fibrous tumor Wei YC, et al. 2006 8. Seminoma Adachi Y, et al. 1991 9. Lymphoma - Burkitt - Ouyang J, et al. 2009 - B Cell - Jiang Zhu, et al. 2011 10. Sarcomas -- Leiomyosarcoma -- Angiosarcoma -- Extraskeletal osteosarcoma -- Cauvin C,et al. 2011 -- Chang K, et al. 2014 -- Choi JD, et al. 2011 11. Peripheral primitive neuroectodermal tumor (PPNET) Lawrentschuk N, et al. 2008 Benign 1. Cystic dysplasia Domínguez DM, et al. 1999 2. Fibroepithelial tumor Zanetti GR, et al. 2003 3. Leiomyoma Gentile AT, et al. 1994 4. Cystadenoma Lee CB, et al. 2006 5. Schwannoma Arun G, et al. 2014 PSA Normal CA-19.9 Normal CA-125 Usually elevated but could be normal CA 15-3 Normal rarely elevated Table 1. Histology types. Table 2. Profile of blood biomarkers in primary adenocarcinoma of the seminal vesicles. Katafigiotis_Stesura Seveso 08/04/16 11:29 Pagina 48 49Archivio Italiano di Urologia e Andrologia 2016; 88, 1 Primary adenocarcinoma of the seminal vesicles. A review of the literature even a malignant cystic-necrotic lesion with irregular solid components (9, 13). Nevertheless MRI can also depict the anatomy and the extent of the SV neoplasm contributing to the preoperative evaluation of the case (7, 15). FDG-PET/CT has also been used for the diagno- sis the staging and the assessment of the treatment response (1, 8). FDG-PET/CT usually confirms radio- pharmaceutical uptake in the primary SV lesion (1, 8). Transrectal ultrasonography has been recommended as the first imaging method because can contribute both to the depiction of the mass and a simultaneous biopsy that will set the diagnosis (1, 9). A solid mass or a cystic lesion with the inclusion of a solid mass is the usual depiction at transrectal ultrasonography (13, 16). Cystoscopy is usual negative and has been reported to be normal up to 20% of patients and it isn’t the standard method used for the depiction and the diagnosis of a SV (1, 9). Colonoscopy has been proposed for the exclusion of a primary rectal tumor (8, 17). e) Immunohistochemical analysis and differential diagnosis (Table 3) Immumohistochemical analysis can play a vital role both for the diagnosis and the differentiation of a SV adeno- carcinoma from prostate, bladder and the colorectal car- cinomas (1, 4, 6, 9). All the data in the literature report an absence of staining both for prostate specific antigen (PSA) and prostate-specific acid phosphatase (PAP) of the SV adenocarcinoma contributing in the differentiation from a prostatic adenocarcinoma (1, 4). CA-125 a large, highly glycosylated glycoprotein, though is used as a marker of mullerian differentiation, can even show a par- adoxical immunoreactivity to a well-differentiated papil- lary SV adenocarcinoma that is of a wolffian duct origin (4, 6). CA-125 can help in the differentiation of a SV ade- nocarcinoma from prostatic, bladder and rectal tumors, since these carcinomas are usually negative (4). CA-125 immunoreactivity alone may be not sufficient for the diagnosis of a SV adenocarcinoma, since other tumors that can express CA-125, although less frequently, like breast, pancreatic, lung, colon carcinomas, primary serous carcinoma of the peritoneum, clear cell adenocar- cinoma of the bladder and metastases especially from a pancreatic-biliary carcinoma and clear cell adenocarcino- ma of the bladder must be ruled out (4, 6). At the same time there are cases in the literature of SV adenocarcino- mas especially with a poor differentiation that are CA-125 negative (1, 4). Simultaneously, poorly differentiated pro- static adenocarcinomas can be negative to PSA and PAP although only in 1% to 2% of cases, constituting the use of additional markers necessary (4). The profile of cytok- eratins 7 and 20 can help further in the differential diag- nosis of a SV adenocarcinoma since CK7 is usually posi- tive and CK20 negative (1, 4, 6). The combination of PSA, PAP, CA-125, CK7, and CK20 markers can help in the discrimination of a SV adenocarcinoma from a blad- der, prostatic and colon adenocarcinoma, since the PSA- negative, PAP-negative, CK20-negative and CK7 and CA- 125 positive profile of a SV adenocarcinoma is unique (4). Also the negative immunoreactivity of the CDX-2 of a SV adenocarcinoma can contribute to the discrimina- tion form a colon cancer (1, 6). CEA should be negative in a primary SV adenocarcinoma but there are many cases of CEA positive or focally positive SV adenocarcinomas reported in the literature (1, 4, 9, 17). 4. Metastases Primary adenocarcinoma of the SVs can invade both the adjacent organs and give distant metastases. Invasion to the rectum leads to rectal bleeding (8, 11). Due to the anatomic vicinity. primary adenocarcinoma can invade both the prostate and the bladder (18, 19). Lymph node metastases to the pelvis, to the infrarenal para-aortic nodes, to the cervical chain and the mediastinal lymph nodes have been reported (6, 9, 10). Apart from the lymph nodes, metastases to the lungs and the liver are common (2, 6, 8, 9, 11). Skeletal metastases with severe pain have also been reported to one case in the literature (20). There is also a rare case of an isolated penile metas- tasis from seminal vesicle adenocarcinoma (2). Finally a case of a disseminated carcinoma with metastases to lymph nodes, pleura, pericardium, liver, heart, and lung revealed to an autopsy of a patient died from a primary adenocarcinoma of the seminal vesicles (6). 5. Treatment Although local excision of the mass-SVs has been pro- posed the majority of the data in the literature propose a radical surgery as a part of a multimodal approach com- bined with hormone therapy, radiation therapy and chemotherapy. Local excision, whenever possible due to the adhesions with the surrounding tissues, has been proposed as a conservative surgical approach again as a part of a multimodal approach (9, 20). In one case the local excision couldn’t achieve a complete removal of the tumor leaving residual mass to the bladder and the rec- tum9. Radical surgery and the extent of the necessary limits are not well defined and various operations have been performed in order to achieve a complete resection of the tumor (10, 11, 21, 22). Radical prostatectomy, radical cystoprostatectomy, partial cystectomy and total pelvic exenteration with ileal conduit for urinary diver- sion and a sigmoid colostomy, combined with pelvic lymphadenectomy are the various radical operations suggested in the literature (1, 0, 11, 13, 21). The best chance of extended survival seems to be the combination of a radical surgery with clear margins com- bined with adjuvant hormone therapy, or radiotherapy or both (10, 21-23). Hormone therapy has been pro- posed as an adjunct therapy to surgery or to radiothera- py both for the local control of the tumor and the man- agement of the metastases (2, 8, 20, 22, 23). In the hormone manipulation and the achievement of androgen deprivation, estrogens and bilateral orchiecto- PSA Negative PAP Negative CA-125 Positive CK 7 Positive CK20 Negative Table 3. Profile of Immunohistochemical markers in primary adenocarcinoma of the seminal vesicles. Katafigiotis_Stesura Seveso 08/04/16 11:29 Pagina 49 Archivio Italiano di Urologia e Andrologia 2016; 88, 1 I. Katafigiotis, S. Sfoungaristos, M. Duvdevani, P. Mitsos, Eleni Roumelioti, K. Stravodimos, I. Anastasiou, C.A. Constantinides 50 my and have also been used (2, 20, 24). Radiotherapy to the whole pelvis combined with antiandrogen blockade without surgery has been proposed as a sole therapy but the patient developed liver metastases 19 months later receiving two cycles of docetaxel and cisplatin chemotherapy and finally dying of his disease 22 months after the diagnosis (8). Radiotherapy has also been pro- posed also for the management of local lymph node metastases, with pelvic irradiation combined with chemotherapy and for the management of residual mass after the operation (1, 9, 10). As an adjuvant therapy for the management of residual mass a total dose of 50 Gy in 2 Gy fractions has been proposed (9). Hormone therapy or chemotherapy or the combination of both modalities have been used for the management of distal metastases (1, 2, 8, 9, 20). Various combinations of chemotherapy regimens have been used, like docetaxel and cisplatin (2 cycles) for the management of liver metastases, cisplatin and 5-FU (6 cycles) for pulmonary lesions, and taxol with caroplat- inum (6 Cycles) for a left transverse perineal muscle lesion (1, 8, 9). In one case with skeletal metastases an one year estrogen therapy resulted the disappearance of the metastases and the survival of the patient for at least for two years (20). Finally the combination of six cycles of 5-fluorouracil, leucovorin, and oxaliplatin chemother- apy with bilateral orchiectomy to a patient with an iso- lated metastasis to penis, resulted the clinical improve- ment of the patient and the regression of penile swelling and seminal vesicle mass, but the patient developed later lung metastases and died (2). 6. Prognosis Prognosis of a primary vesicle adenocarcinoma of the SVs is general considered poor due to delayed diagnosis and approximately the 95% of the patients die in less than three years (9, 11, 22, 23). Although there is a case of a patient dying three months postoperatively and two cases of a prolonged survival of 3 years and 4 months in one case and 5 years in the other, the majority of the cases in the literature refer to an approximately 2 years survival after the diagnosis (8, 10, 11, 13, 18, 20). 7. Follow-up The main goal of the follow up of the patient with a pri- mary vesicle adenocarcinoma is the detection of metas- tases. A combination of clinical examination, serum tumor markers, CT (chest and abdomen) MRI and [18F]FDG-PET/CT has been proposed for the follow up (1, 8, 9, 22). CA-125 can be used for the detection of the recurrence and the clinical course of the disease (8, 15, 22). CA-125 elevation in some cases precede up to 6 months before the emergence of the metastases (8). Suspicious lesions to the surgical bed to patients with possible residual mass or positive surgical margins can be detected with the use of MRI (9). CT scan of the chest and the abdomen combined with clinical examination and serum markers every 3 months for the first year and every 6 months thereafter have been proposed as a fol- low up scheme (1). [18F]FDG-PET/CT can help in the clarification of suspicious lesions depicted in the CT (1, 9). Lesions to soft tissues depicted to [18F]FDG-PET/CT can be further clarified with the use of an MRI1. Finally ultrasound guided cytology has been used during the fol- low up for the confirmation of a metastasis (1). 8. Risk factors and bilateral primary SV adenocarcinomas Although may not be easy to locate the SV from the can- cer originates, due to the volume of the mass, there are cases that clearly declare the bilateral origin of the pri- mary vesicle adenocarcinoma (10, 18). The bilateral pri- mary SV adenocarcinoma is considered even more rare (18). Considering the risk factors or predisposition for the occurrence of a primary SV adenocarcinoma the presence of a renal agenesis or dysgenesis has been reported to be a possible aggravating factor (10, 13). The renal agenesis or dysgenesis seems to contribute either to a ipsilateral or a bilateral SV adenocarcinoma (10, 13). The proposed pathway for the development of a SV adenocarcinoma is the chronic stimulation of the ectopic ureter’s secretion (13) REFERENCES 1. Sollini M, Silvotti M, Casali M, et al. The role of imaging in the diagnosis of recurrence of primary seminal vesicle adenocarcinoma. World J Mens Health. 2014; 32:61-5. 2. Thyavihally YB, Tongaonkar HB, Gupta S, Gujral S. Primary seminal vesicle adenocarcinoma presenting as isolated metastasis to penis responding to chemotherapy and hormonal therapy. Urology. 2007; 69:778.e1-3. 3. Lyons O Primary carcinoma of the left seminal vesicle. J Urol. 1925; 13:477. 4. Ormsby AH, Haskell R, Jones D, Goldblum JR. Primary seminal vesicle carcinoma: an immunohistochemical analysis of four cases. Mod Pathol. 2000; 13:46-51 5. Hoshi A, Nakamura E, Higashi S, et al. Epithelial stromal tumor of the seminal vesicle. Intern J Urol. 2006; 13:640-642 6. Stenzel P, Wettach G, Leroy X. Primary seminal vesicle carcino- ma. Intern J Surg Path. 19(3)401-404. 7. Angulo JC, Romero I, Cabrera P, et al. Vesiculectomy with laparoscopic partial prostatectomy in the treatment of primary ade- nocarcinoma of the seminal vesicle with carcinomatous transforma- tion of the ejaculatory duct. Actas Urol Esp. 2011; 35:304-9. 8. Mizuno N, Fujikawa N, Hayashi N, et al. A case of primary sem- inal vesicle cancer detected by FDG-PET/CT. Nihon Hinyokika Gakkai Zasshi. 2012; 103:704-7. 9. Eken A, Izol V, Aridogan IA, et al. An unusual cause of hematospermia: Primary adenocarcinoma of the seminal vesicle. Can Urol Assoc J. 2012;6:E259-E262. 10. Campobasso D, Fornia S, Ferretti S, et al. Primary bilateral seminal vesicle carcinoma: description of a case and literature review. Int J Surg Pathol. 2012; 20:633-5. 11. Kinjo T, Nonomura D, Yamamoto Y, et al. Primary adenocar- cinoma of the seminal vesicle difficult to differentiate from rectal carcinoma : a case report. Hinyokika Kiyo. 2013; 59:597-601. 12. Dalgaard JB, Giertson JC. Primary carcinoma of the seminal vesicle: case and survey. Acta Pathol Microbiol Scand. 1956; 39:255-67. Katafigiotis_Stesura Seveso 08/04/16 11:29 Pagina 50 51Archivio Italiano di Urologia e Andrologia 2016; 88, 1 Primary adenocarcinoma of the seminal vesicles. A review of the literature 13. Lee BH, Seo JW, Han YH, et al. Primary mucinous adenocarcino- ma of a seminal vesicle cyst associated with ectopic ureter and ipsilat- eral renal agenesis: a case report. Korean J Radiol. 2007; 8:258-61. 14. Ohmori T, Okada K, Tabei R, et al. CA125-producing adeno- carcinoma of the seminal vesicle. Pathol Int. 1994; 44:333-7. 15. Navallas M, Vargas HA, Akin O, et al. Primary seminal vesicle adenocarcinoma. Clin Imaging. 2011; 35:480-2. 16. Al-Saeed O, Sheikh M, Kehinde EO, Makar R. Seminal vesicle masses detected incidentally during transrectal sonographic exami- nation of the prostate. J Clin Ultrasound. 2003; 31:201-6. 17. M. Tarján, I. Ottlecz, T. Tot. Primary adenocarcinoma of the seminal vesicle. Indian J Urol. 2009; 25:143-145. 18. Ormsby AH, Haskell R, Ruthven SE, Mylne GE. Bilateral pri- mary seminal vesicle carcinoma. Pathology. 1996; 28:196-200. 19. Tanaka T, Takeuchi T, Oguchi K, et al. Primary adenocarcino- ma of the seminal vesicle. Hum Pathol. 1987; 18:200-2. 20. Kindblom LG, Pettersson G. Primary carcinoma of the seminal vesicle. Case report. Acta Pathol Microbiol Scand A. 1976; 84:301-5. 21. Möhring C, Bach P, Kosciesza S, Goepel M. A primary adeno- carcinoma of the seminal vesicles. Case report of a rare malignan- cy. Urologe A. 2008; 47:616-9. 22. Thiel R, Effert P. Primary adenocarcinoma of the seminal vesi- cles. J Urol. 2002; 168:1891-6. 23. Benson RC Jr, Clark WR, Farrow GM. Carcinoma of the semi- nal vesicle. J Urol. 1984; 132:483-5. 24. RODRIGUEZKEES OS. Clinical improvement following estro- genic therapy in a case of primary adenocarcinoma of the seminal vesicle. J Urol. 1964; 91:665-70. Correspondence Ioannis Katafigiotis, MD, MLS, PhD, Resident in Urology (Corresponding Author) katafigiotis@yahoo.com Panagiotis Mitsos, MD Resident In Urology mitsospanagiotis@yahoo.com Eleni Roumelioti, Finance and Statistics eleniroum81@gmail.com Konstantinos Stravodimos, MD, PhD, FEBU Associate Professor in Urology kgstravod@yahoo.com Ioannis Anastasiou, MD, PhD, FEBU Assistant Professor in Urology ekati2@otenet.gr Constantinos A. Constantinides, MD, PhD, FEBU Professor in Urology ckonstan@med.uoa.gr 1st University Urology Clinic Laiko Hospital Agiou Thoma 17 - 11527 Athens, Greece Stavros Sfoungaristos, MD, PhD sfoungaristosst@gmail.com Mordechai Duvdevani, MD, Associate Professor in Urology moti_duv@yahoo.com Hebrew Hadassah University Medical Center Jerusalem, Israel Katafigiotis_Stesura Seveso 08/04/16 11:29 Pagina 51