Clinical presentation, management and follow-up of 83 patients with Leydig cell tumors of the testis: a prospective case-cohort study

Abstract

STUDY QUESTION When should ‘not so rare’ Leydig cell tumors (LCTs) of the testis be suspected, diagnosed, and treated? SUMMARY ANSWER LCTs are more frequent than generally believed, are associated with male infertility, cryptorchidism and gynecomastia, and should be treated conservatively (in compliant patients) with active surveillance, which appears to be a safe alternative to surgical enucleation. WHAT IS KNOWN ALREADY Increasing referrals for testicular imaging have led to an increase in findings of LCTs. The features and natural history of these tumors remain largely unknown, as the available studies are small and heterogeneous. LCTs were previously treated aggressively and follow-up data are lacking. STUDY DESIGN, SIZE, DURATION A case-cohort study of consecutive patients diagnosed with LCTs over a 10-year period was prospectively enrolled from 2009 to 2018 and compared to matched cohorts of patients with seminomas or no testicular lesions screened in the same timeframe. PARTICIPANTS/MATERIALS, SETTING, METHODS Of the 9949 inpatients and outpatients referred for scrotal ultrasound, a total of 83 men with LCTs were included. Enrolled subjects underwent medical history and clinical examination and were asked to undergo routine blood tests, hormone investigations (FSH, LH, total testosterone, estradiol, inhibin B, sex hormone-binding globulin (SHBG), prolactin), and semen analysis. Patients who consented also underwent contrast-enhanced ultrasound, elastography, gadolinium-enhanced scrotal magnetic resonance imaging, and hCG stimulation test (5000 IU i.m.) with serum total testosterone and estradiol measured at 0, 24, 48, and 72 hours. MAIN RESULTS AND THE ROLE OF CHANCE In total, 83 patients diagnosed with LCTs were compared against 90 patients diagnosed with seminoma and 2683 patients without testicular lesions (NoL). LCTs were diagnosed by enucleation (48.2%), orchiectomy (13.3%), or clinical surveillance (38.5%). Testicular volume, sperm concentration, and morphology were lower (P = 0.001, P = 0.001, and P < 0.001, respectively) in patients with LCTs than in the NoL group. FSH, LH, and SHBG were higher and the testosterone/LH ratio was lower in LCTs than in the NoL group (P < 0.001). The LCT group showed higher SHBG (P = 0.018), lower sperm concentration (P = 0.029), and lower motility (P = 0.049) than the seminoma group. Risk factors for LCTs were cryptorchidism (χ2 = 28.27, P < 0.001), gynecomastia (χ2 = 54.22, P < 0.001), and low testicular volume (χ2 = 11.13, P = 0.001). Five cases were recurrences or bilateral lesions; none developed metastases during follow-up (median, 66 months). LIMITATIONS, REASONS FOR CAUTION This study has some limitations. First, hCG and second-line diagnostic investigations were not available for all tumor patients. Second, ours is a referral center for infertility, thus a selection bias may have altered the baseline features of the LCT population. However, given that the comparison cohorts were also from the same center and had been managed with a similar protocol, we do not expect a significant effect. WIDER IMPLICATIONS OF THE FINDINGS LCTs are strongly associated with male infertility, cryptorchidism, and gynecomastia, supporting the hypothesis that testicular dysgenesis syndrome plays a role in their development. Patients with LCTs are at a greater risk of endocrine and spermatogenesis abnormalities even when the tumor is resected, and thus require long-term follow-up and prompt efforts to preserve fertility after diagnosis. LCTs have a good oncological prognosis when recognized early, as tissue-sparing enucleation is curative and should replace orchiectomy. Conservative surgery and, in compliant patients, active surveillance through clinical and radiological follow-up are safe options, but require monitoring of testicular failure and recurrence. STUDY FUNDING/COMPETING INTEREST(S) The project was funded by the Ministry of University and Research Grant MIUR 2015ZTT5KB. There are no conflicts of interest. TRIAL REGISTRATION NUMBER ALCeP trial (ClinicalTrials.gov Identifier: NCT01206270).

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

“…The incidence of benign Leydig cell tumours in patients with KS has been reported higher than in the general population, although this may simply reflect a higher prevalence of Leydig cell hyperplasia rather than tumours. In a recent series, the frequency of Leydig cell tumours in KS does not seem higher than that found in infertile men 183,184 …”

Testicular ultrasound score: A new proposal for a scoring system to predict testicular function

“…The volumetric predominance of one testis over the other, termed testicular asymmetry, has been proposed for the assessment of the functional ability of small testes, especially in patients with a history of cryptorchidism, and as a prognostic factor for varicocoele (VC) repair, with a cutoff for significance of ≥20% 22 . On US examination, non‐palpable testicular solid lesions are usually associated with benign conditions such as focal Leydig cell hyperplasia or Leydig cell tumors, 23‐25 whereas palpable solid lesions show a high probability of malignancy. Both types appear to be associated with cryptorchidism and Leydig cell tumors also with impaired spermatogenesis 23 .…”

“…On US examination, non‐palpable testicular solid lesions are usually associated with benign conditions such as focal Leydig cell hyperplasia or Leydig cell tumors, 23‐25 whereas palpable solid lesions show a high probability of malignancy. Both types appear to be associated with cryptorchidism and Leydig cell tumors also with impaired spermatogenesis 23 . Lastly, color‐Doppler imaging has been extensively employed in the detection and evaluation of testicular VC, which has been associated with ipsilateral hypotrophy and infertility, although this association is still under debate 26,27 …”

Bilateral testicular masses and adrenal insufficiency: is congenital adrenal hyperplasia the only possible diagnosis? First two cases of TARTS described in Addison-only X-linked adrenoleukodystrophy and a brief review of literature

“…Currently available glucocorticoid replacement therapy (GRT) are unable to provide a physiological substitution, which leads to persistently elevated ACTH levels in PAI patients, a chronic stimulus to pluripotent testicular cells which may evolve into growing lesions. Differential diagnosis between TARTs and Leydig cell tumors (LCTs) relies on clinical, radiological [12][13][14] and histological features [4], and it is of utmost importance, since the therapeutic approach can be different (surgery or active surveillance in LCTs and medical in TARTs) [15].…”