Archivio Italiano di Urologia e Andrologia 2016; 88, 4320 ORIGINAL PAPER Testicular sparing surgery in small testis masses: A multinstitutional experience Andrea B. Galosi 1, Paola Fulvi 1, Andrea Fabiani 2, Lucilla Servi 2, Alessandra Filosa 3, Luca Leone 1, Angelo Marronaro 4, Enrico Caraceni 4, Rodolfo Montironi 5 1 Clinica Urologica, Dipartimento Scienze Cliniche e Odontostomatologiche, Università Politecnica delle Marche, AO Ospedale Riuniti, Ancona, Italy; 2 UOC Urologia Macerata, Area Vasta 3, ASUR Marche, Italy; 3 UOC Anatomia Patologica, Area Vasta 3, ASUR Marche, Italy; 4 UOC Urologia, Civitanova Marche, Area Vasta 3, ASUR Marche, Italy; 5 UOC Anatomia Patologica, Università Politecnica delle Marche, Ancona, Italy. Introduction: The incidence of benign testicular tumors is increasing in particular in small lesion incidentally found at scrotal ultrasonography. Primary aim of this study was to perform radical surgery in malignant tumor. Secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery in benign lesions. Materials and methods: In this multicenter study, we reviewed all patients with single testis lesion less than 15 mm at ultra- sound as main diameter. We applied the diagnostic-therapeu- tic pathway described by Sbrollini et al. (Arch Ital Urol Androl 2014; 86:397) which comprises: 1) testicular tumor markers, 2) repeated scrotal ultrasound at the tertiary center, 3) surgi- cal exploration with inguinal approach, intraoperative ultra- sound, and intraoperative pathological examination. Definitive histology was reviewed by a dedicated uro-pathologist. Results: Twenty-eight patients completed this clinical flow- chart. The mean lesion size was 9.3 mm (range 2.5-15). Testicular tumor markers were normal except in a case. Intraoperative ultrasound was necessary in 8/28 cases. We treated 11/28 (39.3%) with immediate radical orchiectomy and 17/28 (60.7%) with testis-sparing surgery. Definitive pathological results were: malignant tumor in 6 cases (semino- ma), benign tumor in 10 cases (5 Leydig tumors, 2 Sertoli tumors, 1 epidermoid cyst, 1 adenomatoid tumor, 1 angiofibro- ma), benign disease in 11 (8 inflammation with haemorragic infiltration, 2 tubular atrophy, 1 fibrosis), and normal parenchyma in 1 case. We observed a good concordance between frozen section examination and definitive histology. Any malignant tumor was treated conservatively. Any delayed orchiectomy was necessary based on definitive histology. Conclusions: The incidence of benign lesions in 60% of small testis lesions with normal tumor markers makes orchiectomy an overtreatment. Testicular sparing surgery of single testicu- lar nodules below 15 mm is a safe option, but requires a standardized pathway in diagnosis. Our pathway has shown good reliability and security profile to be applied in a multicen- ter management for small scrotal masses. Our study has shown the reliability of the diagnostic-therapeutic pathway in the management of single testicular masses. The higher incidence of benign lesions in 60% of patients makes often orchiectomy an overtreatment. KEY WORDS: Testis neoplasms; Ultrasound; Surgery; Small testis masses. Submitted 15 November 2016; Accepted 15 December 2016 Summary No conflict of interest declared. INTRODUCTION Scrotal ultrasound increased detection of small and not palpable testicular lesions. The incidence of benign tumors is clinically relevant in lesions smaller than 15 mm (1, 2). This suggest organ-sparing surgery rather than radical orchiectomy (3, 4). The first step to diagnose testicular cancer is the clinical examination, principally with scrotal palpation, that can give to the physician the first suspect of tumor. But it is possible only for masses which have a large volume. Consequently patients must undergo scrotal ultrasound, that confirms the presence of the neoplasia. The defini- tive histologic diagnosis of testicular cancer can only be achieved through exploration and inguinal orchiectomy and subsequent histological examination (5). In fact, the gold standard for the treatment of palpable testicular lesions is inguinal exploration and orchiectomy. Meanwhile, the diagnostic-therapeutic pathway for small and not palpable small testicular lesions exclusively identified by ultrasonography is still under debate. According to international guidelines testis-sparing sur- gery can be performed only in special and selected cases: bilateral testicular tumors (synchronous bilateral testicu- lar tumors or metachronous contralateral tumors) or monorchid patient with normal pre-operative testos- terone levels when tumor volume is less than 30% of tes- ticular volume (2-4). For some years the testis sparing surgery is being practiced with success, with good onco- logic out-comes, but there is not currently international- ly agreed protocol for management and treatment of small non-palpable testicular masses. Our team pub- lished a flow chart including ultrasound diagnosis and surgical management of lesion with maximum diameter of 15 mm (6). This protocol was established with agree- ment of pathology, radiology, urology and oncology units. However application of this clinical protocol is not yet published. Primary aim of this study was to perform radical surgery in all malignant tumor. Secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in management of small masses with testis spar- ing surgery only in benign lesions. DOI: 10.4081/aiua.2016.4.320 Presented at 20th National Congress SIEUN, Sciacca 2016 Galosi3_Stesura Seveso 09/01/17 10:43 Pagina 320 321Archivio Italiano di Urologia e Andrologia 2016; 88, 4 Testicular sparing surgery MATERIALS AND METHODS In this multicenter study, we recruited patients with single testicular lesion of 15 mm as main diameter, based on scro- tal ultrasound. We applied the diagnos- tic-therapeutic pathway described by Sbrollini et al. (6) which comprises: 1) normal testicular tumor markers, 2) repeated scrotal ultrasound at the terti- ary center to confirm size, localization and ultrasound characteristics, 3) surgi- cal exploration with inguinal approach using intraoperative ultrasound, and intraoperative pathological examination. The diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery is summarized in Figure 1. Definitive histology was reviewed by a dedicated uro-pathologist. After their identification, the nodule was removed and 3 additional biopsies were perfomed in surround normal-looking parenchyma. If the pathologist considered the nodule size with enough amount of tissue, the intraoperative frozen was done, otherwise if not the specimen was sent for definitive histology. In case of benign or doubtful histology on frozen section, the specimen were submitted to definitive exam. Delayed orchiectomy was suggested only if malignant neoplasia was confirmed. In case of testicular intraepithelial neoplasia, patients were addressed to radiotherapy or orchyfuniculectomy. The protocol suggests that small masses (< 8 mm) are sent to the pathologist for histologi- cal definitive examination, avoiding the extemporaneous examination, which due to the small volume of the tumor, might subtract material necessary for definitive histological diagnosis. The masses of diameter between 8 and 15 mm are sent to the pathologist for the extemporaneous histo- logical examination of frozen sections, which determines: histological nature, size and relationship with the sur- rounding pa renchyma. All testicular masses were submit- ted to definitive histological examination including im - munohistochemistry. RESULTS We recruited 28 patients, mean age was 38 years (18-68) and mean lesion size was 9.3 mm (range 2.5-15). Baseline clinical features are summarized in Table 1 and 2. Oncological testicular markers were normal except in a case who had small increase beta-HCG (9.0). Intraoperative ultrasound was necessary in 8/28 cases to identify the exact cancer location. In particular, 10/28 (36%) patients had testicular nodules smaller than 8 mm and 18/28 (64%) between 8 and 15 mm (Figure 3-6). Concerning nodules smaller than 8 mm, 2/10 underwent definitive histological examination (because of low volume of the sample). Primary aim of this study was to perform radical surgery in malignant tumor. We performed 11 Table 1. Overall baseline clinical and pathological characteristics of all patients (TSS = Testis Sparing Surgery, IRO = Intraoperative Orchiectomy). Case AGE Size (mm)/ Tumor Definitive Intraoper. Tipe of side markers histology histology surgery 1 25 6/left Normal Sertoli tumor Not done TSS 2 33 8/right Normal Seminoma Malignant IO 3 25 5/right Normal Leydig tumor Benign TSS 4 41 15/right Normal Haemorrhagic infiltration No tumor IO 5 37 10/left Normal Haemorrhagic infiltration No tumor TSS 6 53 12/left Normal Fibrosis and normal parenchyma No tumor TSS 7 53 11/left Normal Haemorrhagic infiltration No tumor TSS 8 57 10/right HCG 9 Haemorrhagic infiltration No tumor TSS 9 47 11/right Normal Angiofibroma Benign TSS 10 34 15/right Normal Epidermoid cyst Benign TSS 11 39 15/right Normal Normal parenchyma No tumor IO 12 34 10/left Normal Fibrosis with tubular atrophy No tumor TSS 13 68 10/left Normal Leydig tumor Benign TSS 14 20 8/left Normal Haemorrhagic infiltration No tumor TSS 15 38 7/left Normal Haemorrhagic infiltration No tumor IO 16 18 5/left Normal Haemorrhagic infiltration No tumor IO 17 36 4/left Normal Seminoma and Intratubular neoplasia Malignant IO 18 42 6/right Normal Seminoma and Intratubular neoplasia Malignant IO 19 23 6,5/left Normal Leydig tumor Benign TSS 20 27 6/right Normal Leydig tumor Benign TSS 21 38 2.5/right Normal Sertoli tumor Benign TSS 22 30 2.7/right Normal Seminoma and intratubular neoplasia Malignant IO 23 60 8.8/right Normal Adenomatoid tumor Not done TSS 24 45 13/left Normal Haemorrhagic infiltration No tumor TSS 25 30 14/right Normal Leydig tumor Benign TSS 26 19 10/left Normal Seminoma Malignant IO 27 46 15/right Normal Fibrosis with tubular atrophy No tumor IO 28 43 15/right Normal Seminoma Malignant IO Table 2. Summary of results. Total patients 28 Mean age 38 (18-68) Mean lesion size (mm) 9.3 (2.5-15) High alfa feto protein 0 High lattic dehidrogenasi 0 High beta-human corionic gonadot. 1 (3.6%) Intraoperative ultrasound 8 (28.6%) Intraoperative orchiectomy 11 (39.3%) Delayed orchiectomy 0 Testis sparing surgery 17 (60.7%) Malignant tumor 6 (21.4%) Benign tumor 10 (35.7%) Benign disease 11 (39.3%) Normal parenchyma 1 (3.6%) (39.3%) radical orchiectomy and 17 (60.7%) testis-sparing procedures. Secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in man- agement of small masses with testis sparing surgery in benign lesions: any delayed orchiectomy was necessary and any radical surgery was performed in benign lesions (Figure 2). Eight of 10 nodules smaller than 8 mm underwent frozen section examination. All the 18 nodules between 8 and 15 have been subjected to frozen section histological examina- Galosi3_Stesura Seveso 09/01/17 10:43 Pagina 321 Archivio Italiano di Urologia e Andrologia 2016; 88, 4 A.B. Galosi, P. Fulvi, A. Fabiani, L. Servi, A. Filosa, L. Leone, A. Marronaro, E. Caraceni, R. Montironi 322 tion. 19/26 masses subjected to frozen section examination resulted benign tumors: 14/19 of them have been treated conservatively, while 5/19 underwent intraoperative radi- cal orchiectomy. We observed a good concordance between frozen section examination and definitive histology, without any false positive results at frozen section. One of 26 mass resulted as healthy parenchyma. Six of 26 masses resulted as malignant tumors and underwent radical orchiectomy. We have had no cases of benign tumor associated with Testicular Intraepithelial Neoplasia. Definitive pathological results were: malignant tumor in 6 cases (semino- ma), benign tumor in 10 cases (5 Leydig tumors, 2 Sertoli tumors, 1 epidermoid cyst, 1 adenomatoid tumor, 1 angiofibroma), benign dis- ease in 11 (8 inflammation with hemorragic infiltration, 2 tubular atrophy, 1 fibrosis), and normal parenchyma in 1 case (Table 2). DISCUSSION Our study has shown the reliability of the diagnostic-therapeutic path- way suggested by Sbrollini et al. in the management of single testicular masses below 15 mm. The higher incidence of benign lesions in this group of tumors (60%) makes often orchiectomy an overtreatment. We observed a complete concordance between frozen section examination and definitive histology regarding malignant cell. Previous experience in high volume centers had same results with dedicated pathologist (7, 8), pointing out that in our cen- ter there was always a dedicated uro-pathologist too. In our experi- ence the definitive intraoperative diagnosis of non-palpable testicular lesions was always reliable even in very small lesions (< 8 mm). However in case of uncertain diag- nosis or small tissue, the definitive histology is recommended. This protocol is useful also for centres were the frozen section is not avail- able: very small lesions could be managed with definitive histology and any subsequent decision can be delayed. In our experience, intraop- erative histology on frozen section was possible in 8 of 10 small nod- ules with diameter less than 8 mm, Figure 1. Diagnostic and surgical flow chart for management of not-palpable testis masses modified from Sbrollini et al.(6). Figure 2. Oncological results in 28 patients submitted to surgery according to flow chart. Galosi3_Stesura Seveso 09/01/17 10:43 Pagina 322 323Archivio Italiano di Urologia e Andrologia 2016; 88, 4 Testicular sparing surgery without any false positive results and without wasting tis- sue for the final histology and ancillary immunohisto- chemistry. Only 20% of the specimens were considered unsuitable for frozen section analysis. Unusual malignant tumor has been observed also arising from stromal cells tumors (e.g. malignant Leydig cells tumors, malignant Sertoli cells tumors). The differential diagnosis may be not easy among malignant and benign testis tumor such as Sertoli tumor, Leydig cells tumors, epidermoid cyst, Brenner tumor, adenomas of the ducts. Testis sparing sur- gery is adopted also in selected cases in children (9). During surgery the surgeon should use loop for optical magnification and use palpation to detect the nodule. In case of soft nodule, were the palpation is not helpful, the intraoperative ultrasound is mandatory. This protocol should be shared in the first instance by the involved spe- cialists, such as the urologist, as an active operator in the operating room, the pathologist, the oncologist and the radiologist. High resolution and high frequency ultrasound (12 MHz) with adequate focusing, fine-tunig and gray- scale regulation should be ready available in operating room. Machine with low resolution and frequency (8 MHz) with inadequate tuning are not enough to have a good imaging and could be misleading (10). The patient, before being subjected to this type of approach has to be informed in detail about the various benefits, risks and implications, first of all the possibility of being subjected to a second sur- gery as soon as the urologist is in possession of the defini- tive histological result. CONCLUSION Testicular sparing surgery of single testicular nodules below 15 mm is a safe option, but requires a standardized Figure 6. Leydig tumor with irregular bordered and irregular content with very small anechoic lacunas. Figure 5. Epidermoid cyst with circular calcifications (A longitudinal view; B axial). The follow-up ultrasound: 8 years later after testis sparing surgery (C, arrows show surgical scar). Figure 4. Cyst of the testis (A) that was only observed, compared to irregular solid hypoecoic (B, arrowhead) confirmed at the referral center before surgey, that contained a Sertoli tumor. Figure 3. Small solid hypoechoic lesion (5 x 3 mm) well defined compared to normal parenchyma: Leydig cell tumor. Galosi3_Stesura Seveso 09/01/17 10:43 Pagina 323 Archivio Italiano di Urologia e Andrologia 2016; 88, 4 A.B. Galosi, P. Fulvi, A. Fabiani, L. Servi, A. Filosa, L. Leone, A. Marronaro, E. Caraceni, R. Montironi 324 pathway in diagnosis. Our pathway has shown good reli- ability and security profile to be applied in a multicenter management for small scrotal masses. 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Arch Ital Urol Androl. 2014; 86:56-78. Correspondence Andrea B Galosi, MD galosiab@yahoo.it Paola Fulvi, MD, Resident in Urology paola.fulvi19@gmail.com Luca Leone, Resident in Urology lucaleone85@virgilio.it Clinica Urologica, Dipartimento Science Cliniche e Odontostomatologiche,Università Politecnica delle Marche, AO Ospedale Riuniti, Ancona, Italy Andrea Fabiani, MD Urologist andreadoc1@libero.it Lucilla Servi, MD Urologist UOC Urologia Macerata, Area Vasta 3, ASUR Marche, Macerata, Italy Alessandra Filosa, MD Pathologist UOC Anatomia Patologica, Area Vasta 3, ASUR Marche, Italy Angelo Marronaro, MD Urologist Enrico Caraceni, MD Urologist ecarace@libero.it UOC Urologia, Civitanova Marche, Area Vasta 3, ASUR Marche, Civitanova Marche, Italy Rodolfo Montironi, MD, Pathologist r.montironi@univpm.it UOC Anatomia Patologica, Università Politecnica delle Marche, Ancona, Italy Galosi3_Stesura Seveso 09/01/17 10:43 Pagina 324