Stesura Seveso Archivio Italiano di Urologia e Andrologia 2021; 93, 3296 ORIGINAL PAPER No conflict of interest declared. per 100000 men (1). The traditional treatment for sus- pected tumors is radical orchidectomy and organ-sparing surgery is considered primarily in cases of bilateral tumors or monorchid patients (2). In recent years the widespread use of ultrasound for non- cancerous indications has resulted in an increase in inci- dental, small testicular masses (STMs) of questionable sig- nificance (3, 4). STMs are most efficiently characterized as non-palpable testicular lesions measuring < 25 mm in diameter. However, a specific size cutoff is difficult to define and the exact dimensions are still debated in the literature (5, 6). In this size though, the probability of benign pathology is regarded as significantly high, and thus, a stepwise approach of inguinal surgical explo- ration, delivery of the organ and frozen section examina- tion is recommended. Organ-preserving surgery is pre- ferred if the diagnosis is benign while radical orchidecto- my is usually preserved if there is evidence of malignan- cy (5, 7, 8). The most common scenario on routine ultrasound is the finding of a non-palpable lesion during workup for infer- tility or scrotal pain, where the majority of these patients have benign lesions and a conservative approach is strongly indicated (9). Nevertheless, the management of incidental STMs warrants a critical review of the literature as there are no patient selection criteria for an organ-spar- ing approach, and a strict diagnostic algorithm is lacking. In this review we discuss the significance of STMs and the role of organ-sparing approach in the management of the condition. MATERIAL AND METHODS We performed a non-systematic search in PubMed with the terms ‘small testicular masses’, ‘incidental testicular masses’, ‘testicular sparing approach’ and ‘partial orchidecto- my’. Only studies in English were included. Case reports were excluded and literature reviews were used to identify additional articles. After screening the abstracts, full-text articles were evaluated in an attempt to identify studies engaging with relevant clinical topics. Objectives: The widespread use of ultra- sonography for the investigation of common urological conditions, such as infertility or pain, has resulted in an increased incidence of incidental non-palpable testicular masses. The majority of these are expected to be benign there- fore a conservative approach, either active monitoring or organ- sparing approach, is recommended. However, there are no clini- cal or radiological parameters which define the exact nature of such lesions and optimal patient selection criteria are lacking. In this comprehensive review we discuss the significance of inciden- tal, small testicular masses (STMs) and the role of organ-spar- ing approach in the management of these lesions. Materials and methods: A non-systematic search was performed using PubMed to identify articles that covered the following top- ics; clinical implications at diagnosis, role of imaging in identify- ing the malignant capabilities of a lesion, role of surgery and the final pathology. Results: Incidental STMs are routinely identified following ultra- sound examination of infertile men. STMs usually measure a few millimeters in size and the majority of these are benign. Therefore, strict follow up or an organ-sparing approach, with utilisation of frozen section analysis (FSA), is favored for STMs. FSA has a high correlation with final pathology and prevents unnecessary orchidectomies. Advances in imaging, namely ultra- sound and magnetic resonance imaging may provide enhanced assessment of STMs and guidance intraoperatively. Conclusions: The optimal approach is not well defined and there is no specific clinical parameter that can predict the nature of STMs. The increasing incidence of small, benign testicular mass- es has resulted in the development of organ-sparing surgery to investigate and manage these lesions. Organ-sparing surgery has been shown to be practical and carries excellent oncological outcomes. KEY WORDS: Incidental testicular masses; Non-palpable; Testis- sparing surgery; Surveillance; ultrasound. Submitted 25 February 2021; Accepted 5 July 2021 INTRODUCTION Testicular germ-cell tumors (GCT) are the most common solid neoplasms in young men with an incidence of 10 Incidental testicular masses and the role of organ-sparing approach Yash Narayan 1, Dominic Brown 1, Stella Ivaz 1, Krishanu Das 2, 3, Mohamad Moussa 4, Georgios Tsampoukas 1, 2, Athanasios Papatsoris 2, 3, Noor Bucholz 2 1 Department of Urology, Princess Alexandra Hospital, Harlow, UK; 2 U-merge Ltd.* (Urology for emerging countries), London, UK; 3 Consultant Urologist, Bahrain Specialist Hospital, Bahrain; 4 Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon. * U-merge Ltd. (Urology for Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.U-merge.com DOI: 10.4081/aiua.2021.3.296 Summary 297Archivio Italiano di Urologia e Andrologia 2021; 93, 3 Incidental testicular masses RESULTS Clinical implications at time of discovery of incidental mass STMs can be found at any age, ranging from childhood to adolescence and up to middle aged men (10-12). Male infertility presenting as dyspermia or the more severe azoospermia, are amongst the most frequently reported indications for ultrasound examination which results in the diagnosis of an incidental STM (13-19). Unspecified testicular or epididymal pain, an acute inflammation in the genital area, scrotal swelling, a history of trauma, varicocele, abdominal pain, hydrocele, suspicion of nephrolithiasis, gynecomastia, and follow up of cryp- torchidism are also reported as indications (8, 11, 12, 20- 25). Of note small masses might be discovered during the follow up of patients with previous treatment of GCT or other testicular tumors (26-28), and a prior history of cryptorchidism might unmask an undetected testicular mass during follow up (12, 15, 23, 29). In the same vein, extra attention should be given to patients with suspect- ed retroperitoneal, extragonadal GCT as STMs might indicate a burned out primary testicular tumor (30). Role of imaging in the assessment of the malignant potential of the lesion The size of STMs on ultrasound usually ranges from 3 mm up to 25 mm (4, 31), and the majority of these lesions will be found to be benign however malignancy cannot be excluded even in the smallest lesions (7, 17). In spite of this, size and risk of malignancy are strongly correlated (5, 32); large lesions seem to carry a greater risk of malignancy and the smaller the nodule, the less likely it is to be malignant (5, 8, 33). Using a cutoff of 5 mm in infertile patients with STMs, Bieniek et al. reported that the majority of these masses did not show significant growth during follow up and could be safely surveilled (19). In such cases Toren et al. observed that initial larger size and vascular flow, as identified on ultrasound, were factors associated with intervention during follow up (14). Similarly Scandura et al. reported that lesions small- er than 5 mm are always benign whereas malignancy can be found in one third of cases in lesions measuring 5-10 mm (29). In another study, Gentile and colleagues stated that the malignant probability of STMs, measuring less than 10mm, is smaller than 10% whilst the risk increases sevenfold with each millimeter (5). However other authors have advised that inguinal exploration and frozen section analysis (FSA) are essential even in small masses, less than 5 mm, as malignancy cannot be excluded defi- nitely (11). This is because the most common ultrasono- graphic appearance is of an hypoechoic lesion, a finding which should be regarded as non-specific (33, 34). However Dell’Atti et al. reported that malignant and benign lesions differ significantly as cancerous lesions were strongly hypoechoic, in appearance, in comparison to benign lesions (89.8% vs 39.3%, p > 0.001) and calci- fied lesions were strongly associated with benign tumors (25). Others have suggested that extra attention should be given to echogenic foci as these might represent burned out tumors and in such cases, the retroperitoneal space should be evaluated (30, 35). The presence of vas- cularization on Color Doppler Ultrasound is also strongly associated with malignancy whereas small, inflammatory lesions usually do not exhibit any flow (28). Contrast- enhanced testicular ultrasound, if available, is a cost- effective imaging method for the characterization of non- palpable testicular lesions (36). With the enhancement of diagnostic performance, some authors have reported that the combination of different ultrasonographic techniques in a multiparametric fashion offers excellent sensitivity and specificity in the assessment of STMs. The combina- tion of elastography with contrast-enhanced scrotal ultra- sound demonstrated a sensitivity of 100%, a specificity of 93%, and a positive likelihood ratio of 14.3 for malig- nancy (37). Magnetic Resonance Imaging (MRI) might also increase the diagnostic accuracy in its ability to distin- guish between fat, fluid, fibrosis, cystic and solid lesions; gadolinium contrast enhancement technique may also be able to differentiate between benign and malignant lesions (6, 20). Thus, MRI can assist the decision making in cases of diagnostic uncertainty favoring a testicular sparing approach in patients with low suspicion of malig- nancy (6, 38, 39). The operative technique If an intervention is scheduled, the procedure follows the same principles as for radical orchidectomy. The testis is exposed, mobilized and exteriorized through an inguinal incision. The clamping of the spermatic cord is contro- versial as seeding of malignant cells is mostly related to the nature of the tumor and not with the manipulation alone (40). If cross-clamping is performed before deliv- ery, the testis should be protected from warm ischemia, with an iced pack, as warm ischemia may cause irre- versible damage of the testicular parenchyma thus impairing both the endocrine and exocrine functions of the organ (15). There are two possible approaches; one in an avascular plane on the anterior aspect of the organ exposing the whole parenchyma or alternatively a small- er incision directly onto the tumor (40). Intraoperatively the use of a linear ultrasound transducer (7.5-15 MHz) can guide the excision and also ensure adequate preser- vation of testicular parenchyma. Some authors perform real-time ultrasonography to facilitate the placement of a stereotaxic hook-shaped needle which can guide the resection (15, 20). Either way the tumor is excised and sent for FSA leaving 2-3 mm safe surgical margins (15, 41). Frozen-section biopsies should be taken from the borders of the lesion to ensure adequate resection and as a rule, if there is not enough parenchyma for frozen-sec- tion biopsies then preservation of the organ is not rec- ommended (40). If the benign nature of a lesion is con- firmed or the removal of a malignant tumor is complet- ed, the testicle is placed back into the scrotum otherwise a radical orchidectomy is performed for all other indica- tions (42). Significance of frozen section analysis, testis-sparing surgery and random biopsies FSA is regarded as indispensable during organ-sparing surgery in patients with indeterminate STMs or if the diagnosis of malignancy is in doubt, regardless of size (8, 43). The correlation of FSA with the final pathology is high, the procedure is dependable, and FSA is not limit- Archivio Italiano di Urologia e Andrologia 2021; 93, 3 Y. Narayan, D. Brown, S. Ivaz, K. Das, M. Moussa, G. Tsampoukas, A. Papatsoris, N. Bucholz 298 ed by size (5, 31, 44, 45). It could be stated that FSA pre- vents unnecessary orchidectomies and enables preserva- tion of the testicular parenchyma (5, 46). Therefore, the optimal treatment of STMs should include FSA to guide management of the extricated tumour, in the form of testis-sparing surgery (TSS) or radical orchidectomy. If a GCT is identified on FSA, TSS should be considered if imperative indications are met (synchronous bilateral tumours, metachronous tumours in solitary testicle) in order to attempt preservation of fertility and hormonal function (5, 8). In that scenario, field biopsies in a sys- tematic and random manner are also mandatory as in situ germ cell neoplasia may be present elsewhere, even a long distance from the initial tumor. This finding reflects the malignant spread of the tumor and warrants treatment with adjuvant radiotherapy (12, 33). The final pathology In the final specimen, benign lesions are found in most patients and in some studies the incidence is as high as 80% (5, 21, 34, 47). Leydig cell tumor is the most fre- quently reported pathology in non-malignant cases (5, 11, 15, 21, 27, 48). Other diagnoses include fibrosis, epi- dermoid cysts, granulomatous orchitis (25), ectopic nod- ule of adrenal cortex, adenomatous tumour and fibrous pseudotumor (29). Sertoli tumor and hemorrhagic infil- tration with no evidence of tumor have also been report- ed (49). Of the malignant lesions, pure seminoma along with the presence of distant carcinoma in situ is the most commonly reported finding (11, 23, 28, 49). Leiomyoma, mixed germ cell tumours including embryonal carcino- ma, mature teratoma, and liposarcoma have also been reported in the final specimen (27, 50, 51). DISCUSSION Although there is no specific clinical parameter that can predict the exact nature of STMs, those that are non-pal- pable are usually benign (24). Palpability, raised testicu- lar markers, hypoechoicity on ultrasound images, and larger size are considered risk factors for malignancy (52). Specific patient groups such as infertile patients seem to enjoy a favorable prognosis thus justifying the avoidance of unnecessary surgery. Eifler et al. and Lagabrielle et al. found that patients with small, incidental masses identi- fied during work-up for infertility, can usually be moni- tored with repeat ultrasound and additionally surgical intervention can be performed safely should the clinical need arise (13, 16). In such cases, where intervention is required, the simultaneous performance of TSS and microscopic testicular tissue extraction has been pro- posed by some authors, without causing any significant complication or compromising the remaining testicular volume (15). With regards to the development of sec- ondary hypogonadism, no significant change in plasma testosterone has been reported and secondary hypogo- nadism should not be expected in patients with bilateral testis undergoing TSS for STMs (11, 51). However it seems that patients undergoing TSS for malignant lesions are at higher risk of secondary hypogonadism as this may be found in up to 15% of cases (42). Similarly the effect on endocrine function is comparative even when a radi- cal approach is performed and it increases significantly as the treatment is escalated (53). In this regard, it seems that the approach alone is not entirely responsible, rather it is the relative risk of malignancy that affects the out- come. Importantly the oncological prognosis in patients with malignancy is regarded to be excellent (54). Therefore, it seems apparent that an organ sparing approach or a surveillance protocol is optimal for patients with incidental testicular masses. Some authors have attempted to provide specific recommendations regard- ing the management of STMs such as the diagnostic algo- rithm proposed by Scandura et al. in patients with STMs less that 10 mm. They state that if tumor markers are neg- ative an ultrasound should be repeated in 3 months, and if there is no change then the patient can be discharged from further follow up with the recommendation of self- examination. 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Correspondence Yash Narayan, MD y.narayan@nhs.net Dominic Brown, MD dominic.brown5@nhs.net Stella Ivaz, MD stellaivaz@hotmail.com Georgios Tsampoukas, MD tsampoukasg@gmail.com Department of Urology, Princess Alexandra Hospital, Harlow (UK) Hamstel Road, Harlow, United Kingdom, CM20 1QX Krishanu Das, MD Consultant Urologist, Bahrain Specialist Hospital, Bahrain Mohamad Moussa, MD mohamad.moussa@zhumc.org.lb Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut (Lebanon) Athanasios Papatsoris, MD agpapatsoris@yahoo.gr U-merge Ltd., London (UK) Noor Bucholz, MD noor.buchholz@gmail.com U-merge Ltd., London (UK)