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Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise. Methods and results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3mm; malignant LCTs, mean 44mm) (P&nbsp

BACKGROUND AND OBJECTIVES To evaluate the pathological features and recurrence of incidental testis tumours treated by partial orchiectomy in a population of infertile men. METHODS We retrospectively pooled, from four andrology referral centres, 32 patients diagnosed with testis mass during regular infertility workup. Patients included had an impaired sperm analysis and testis sparing surgery was performed to prevent secondary azoospermia or androgen therapy. RESULTS Mean age was 36 (IQR, 32 to 37). The mean largest tumoral diameter was 8.5 mm (IQR, 5 to 10). A total of 25% (8 of 32) of patients had a malignant tumour (seminoma, 7 of 32, 22%; teratoma, 1 of 32, 3%) and 75% (24 of 32) had a benign lesion (Leydig cell tumour, 23 of 32, 72%; scar tissue, 1 of 32, 3%). Malignant tumours were then managed by total orchiectomy (six of eight) or by radiotherapy (two of eight). With a mean follow up of 26 months (IQR, 8 to 32), one patient (3%) had an homolateral recurrence, which was a Leydig cell tumour. Not a single patient developed metastasis. CONCLUSION Seventy-five per cent of the tumours discovered during infertility management were of a benign pathology. A conservative approach could be proposed initially to avoid unnecessary orchiectomies. Orchiectomy and radiotherapy could be discussed as salvage therapies for malignant lesions.

Leydig cell tumours of the testis are uncommon. They typically present in a bimodal age distribution between either 5 and 10 years of age, or 20 to 60 years of age. Affected prepubertal boys usually present with a palpable lump or precocious puberty. With improvements in imaging technology, diagnosis can be incidental and precede clinical symptoms. This report describes the incidental finding of a Leydig cell tumour of the testis in an eight-year-old boy with a history of scrotal trauma and haematuria.

A 14-year-old American Staffordshire cross was presented with a history of enlargement of the right testicle of two months duration. Findings included hormonally active testicular tumour, epididymitis, unilateral hydrocele of the right testicle and bilateral testicular atrophy; furthermore, benign prostate gland hypertrophy or prostatitis and balanoposthitis was also present; this variety hampered diagnosis. Radiographs of the lungs and abdominal ultrasound did not reveal any metastatic disease. After two weeks of antibiotics and NSAIDs, bilateral castration and radical excision of the testicular cords were performed. During surgery, an infiltrative growing mass of the testicular cord was observed and hindered complete removal. Histological examination of the excised tissue revealed mesothelioma of the right and left tunica vaginalis testis and a presumably oestrogen-secreting Leydig cell tumour of the left testicle with secondary bilateral testicular atrophy. The dog9s condition deteriorated within the following two months. Diagnostic work-up and treatments are discussed.

Oparka R, Cassidy A, Reilly S, Stenhouse A, McCluggage W G & Herrington C S (2012) Histopathology 60, 838–842 The C134W (402 C>G) FOXL2 mutation is absent in ovarian gynandroblastoma: insights into the genesis of an unusual tumour Aims: Ovarian gynandroblastomas are rare tumours that, by definition, comprise a combination of components resembling both female, typically granulosa cell tumour (GCT), and male, typically Sertoli or Sertoli/Leydig cell tumour (ST/SLT), sex cord/stromal differentiation. The histogenesis of these tumours is unknown and, in view of the very strong association between the C134W (402 C>G) FOXL2 mutation and adult-type GCT, we analysed a series of gynandroblastomas for this mutation. Methods and results: Both components of each lesion were isolated by laser capture microdissection and the C134W (402 C>G) FOXL2 mutation was analysed by polymerase chain reaction sequencing. No mutation was identified in either the GCT or ST/SLT component of six cases, three of which contained adult-type GCT. Conclusions: This suggests that, despite their similar morphological appearances, the GCT-like component of gynandroblastoma has a different molecular basis from conventional adult-type GCT. This finding underscores a more general principle that morphological similarity does not necessarily indicate molecular identity.

Donato D P, Johnson M T, Yang X J & Zynger D L (2011) Histopathology 59, 1229–1239 Expression of carbonic anhydrase IX in genitourinary and adrenal tumours Aims: High expression of carbonic anhydrase IX (CAIX) is reported for clear cell renal cell carcinoma (RCC), with a paucity of data for non-renal genitourinary or adrenal tumours. This study investigated the immunohistochemical expression of CAIX throughout the genitourinary tract and adrenal gland. Methods and results: High expression in the renal cortex was restricted to clear cell, papillary and clear cell papillary RCC and carcinoid. Core biopsies of clear cell RCC were consistently positive. Positivity within the urothelial tract was seen in urothelial carcinoma including squamous, small-cell, sarcomatoid and adenomatous differentiation and clear cell adenocarcinoma. Signet ring and plasmacytoid variants of urothelial carcinoma were negative. Phaeochromocytoma, adrenal cortical adenoma, seminoma, yolk sac tumour, choriocarcinoma, Leydig cell tumour and prostatic adenocarcinoma were predominately negative, with variable reactivity in adrenal cortical carcinoma, embryonal carcinoma, teratoma and Sertoli cell tumour. Conclusions: Carbonic anhydrase IX is a sensitive marker for clear cell RCC in core biopsies. However, other genitourinary or adrenal tumours that can have a clear cell appearance including urothelial, squamous cell, clear cell adeno and adrenal cortical carcinoma and Sertoli cell tumour express CAIX. Knowledge of expression overlap between these entities may prevent incorrect interpretation of immunohistochemical results, particularly if limited tissue is available.

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Leydig cell tumours (LCTs) of the testis are rare tumours, accounting for 1–3% of all testicular neoplasms. Our data indicate that using scrotal ultrasound with high resolution imaging in routine checkups leads to an earlier detection of LCTs. Most patients underwent an organ-sparing surgery and no androgen deprivation was observed. OBJECTIVE • To report an observed high frequency of Leydig cell tumours (LCTs) diagnosed at our centre. PATIENTS AND METHODS • Charts of all patients who underwent surgery for a testicular tumour between 1999 and 2008 at our department were searched and data from patients with LCT were collected. • Before surgery all patients underwent ultrasound and complete staging. In all but two patients with LCT an organ-sparing surgery was performed. Surgery was performed under ultrasound or palpation guidance. • All patients underwent postoperative follow-up. We retrospectively reviewed surgical technique, histology, epidemiology and outcome in all LCT patients. RESULTS • In the study period, 197 testicular tumours were surgically removed of which 29 were diagnosed as LCT (14.7% of 197; further study group) in 25 patients. Mean age of patients with LCT was 45 years (range 21–68 years). • Tumour size ranged from 1.2 to 80 mm (mean 10.23 mm). In two patients (8%) the lesion was palpable whereas incidental diagnosis was made in seven patients (28%). • In the remaining patients diagnosis was made by ultrasound performed for testicular pain (six patients, 24%) or during infertility or erectile dysfunction evaluation (10 patients, 40%). • Definitive histology reported no malignant histopathological features in all but one patient; this particular patient experienced tumour progression after 2 months and died from advanced disease 1 year later. All other patients are free of disease after a mean follow up of 56 months (range 7–93 months). • During this period one patient developed a second LCT on the contralateral side; another patient had a recurrence within the same testicle, but on the opposite pole. Both underwent a subsequent organ-sparing tumour resection. CONCLUSION • The percentage of LCT (14.7% of all testicular tumours removed) was significantly higher than expected from the literature. One possible explanation for this phenomenon is the increasing use of better ultrasound technology and the subsequent increased detection of small nodules that have not been found in historical series. Use of ‘observation-only’ for very small lesions detected at infertility clinics is under debate.

Wang Z, Yang S, Shi H, Du H, Xue L, Wang L, Dong Y & Han A (2011) Histopathology 58, 1013–1018 Histopathological and immunophenotypic features of testicular tumour of the adrenogenital syndrome Aims: Testicular tumour of the adrenogenital syndrome (TTAGS) is a rare neoplasm histologically resembling Leydig cell tumour (LCT). We report six cases of TTAGS and analyse histopathological and immunophenotypical features that distinguish TTAGS from LCT. Methods and results: Six cases of congenital adrenal hyperplasia with bilateral TTAGS were examined histologically and immunohistochemically and compared to seven cases of testicular LCT. TTAGS was characterized histologically by sheets of polygonal cells separated by dense fibrous tissue with focal lymphocyte infiltration. All cases of TTAGS lacked cytological atypia except for one, which displayed scattered large pleomorphic, nuclei with one or two prominent nucleoli and sporadic mitotic figures. Immunohistochemically, all cases of TTAGS showed diffuse and strong positivity for CD56 and negative reactivity for androgen receptor. Reactivity for synaptophysin varied from focal (five cases) or diffuse (one case). In contrast, LCT displayed focal weak to moderate or negative reactivity for CD56 and focal weak or negative reactivity for synaptophysin, but positive reactivity for androgen receptor in six of seven cases. Conclusions: In addition to clinical information, biochemical profile and histopathological findings, our results suggest that immunohistochemistry using a panel of antibodies including CD56, synaptophysin and androgen receptor is helpful in differentiating TTAGS from LCT.

OBJECTIVE To review all non-germ-cell testicular lesions presenting at our institution and to determine the feasibility of testis-sparing surgery for these patients. PATIENTS AND METHODS All surgery for testicular masses between June 1995 and June 2005 were reviewed retrospectively. Patients with atrophy, germ cell tumours, infection or torsion were excluded. The study comprised men who had radical orchidectomy for suspected germ-cell tumour but had other final pathology, and those where testis-sparing surgery was attempted for a presumed benign lesion. RESULTS Thirteen patients with lesions appropriate for the study were identified; all but one had a palpable lesion. The lesions could be categorized as inflammatory (three hyalinized fibrosis, two sarcoidosis, one chronic inflammation), cystic (one epidermoid cyst, one unilocular cyst), benign neoplasms (two adenomatoid tumours, one Leydig cell tumour, one capillary haemangioma) or malignant neoplasms (one lymphoma). Based on the preoperative impression, testis-sparing surgery was attempted in eight of the lesions and was successful in six where it was attempted. In the other five, testis-sparing surgery was not attempted because the preoperative impression was that of a germ cell tumour. Testis-sparing surgery was successful in only six of the 13 patients with these lesions. CONCLUSION Testis-sparing surgery might be possible if there is significant suspicion of a benign lesion. If frozen-section analysis is equivocal, a radical orchidectomy is required. Testis-sparing surgery was feasible in highly selected cases.

Aim: To analyse the urinary steroid metabolome in a boy who had true precocious puberty after a Leydig cell tumour. Method: Case report and detailed description of clinical and metabolic findings in a 7-year-old-boy with a Leydig cell tumour. Results: Before surgery, the urinary steroid metabolome showed an activation of an alternative route to gonadal androgens independent of dehydroepiandrosterone (DHEA). After surgery, the boy entered true precocious puberty. Under leuprolide acetate treatment, clinical and laboratory findings normalized. Conclusion: Central precocious puberty after precocious pseudopuberty may be more common than expected and should be considered in children with persistent or recurrent symptoms after initial treatment of precocious pseudopuberty. Patients with a Leydig cell tumour seem to reactivate the so-called ‘back door pathway’ of androgen production, which is independent of the classical route via DHEA.

Simultaneous occurrence of a well-demarcated interstitial cell tumour and an intratubular seminoma-like tumour, which was beginning to invade peritubular areas, in the contralateral testes of a 3-year-old Dutch-Belted rabbit is described. Morphological hallmarks of carcinoma in situ, which have not been reported previously for the rabbit, were observed in association with the seminoma. These observations indicate that carcinoma in situ, preceding a seminoma-like tumour, occurs in the rabbit and that the rabbit may serve as a practically useful animal model for studying testicular germ cell neoplasia.

AIMS Testicular Leydig cell tumours are rare. Although most behave benignly approximately 10% are malignant. Clinicopathological features have been described which have some value in predicting malignant behaviour, although as with other endocrine tumours uncertainties remain in many individual cases. Our aim was to determine the clinicopathological features of 20 testicular Leydig cell tumours. We wished to investigate whether, in addition to established clinicopathological features, the MIB1 index and/or flow cytometric analysis of nuclear DNA content are of value in predicting malignancy. We also wished to investigate the frequency of p53 protein accumulation in these neoplasms. METHODS AND RESULTS Twenty testicular Leydig cell tumours were studied and the clinical case notes examined. Histological sections were assessed by pathologists involved in the study. Pathological features evaluated included: tumour size, extratesticular extension, nuclear pleomorphism, mitotic activity, necrosis and vascular invasion. Immunohistochemical staining was performed with the anti-p53 monoclonal antibody DO-7 and the cell proliferation marker MIB1. A flow cytometric analysis of nuclear DNA content was also performed. Three tumours behaved in a malignant fashion with the development of metastases. Another had morphological features of malignancy but the patient died a short time after diagnosis from unrelated causes. These four neoplasms were larger than benign tumours, often contained areas of necrosis and sometimes exhibited vascular invasion. They generally exhibited greater nuclear pleomorphism and a higher mitotic rate than benign tumours. Three of the four malignant tumours had a high MIB1 index (20-50%) and the fourth exhibited DNA aneuploidy by flow cytometry. Two malignant tumours showed increased expression of p53 protein, with approximately 50% of nuclei staining with DO-7. All benign tumours had a low MIB1 index (0-2%) and a diploid DNA profile, except for one case where there was DNA aneuploidy. There was little or no staining of benign tumours with DO-7. CONCLUSIONS The study confirms that large size, marked nuclear pleomorphism, high mitotic rate, necrosis and vascular invasion are important factors in predicting malignant behaviour in testicular Leydig cell tumours. Additional prognostic value may be derived from the MIB1 index and flow cytometry. Accumulation of p53 protein, through mutational or other events, may be important in malignant progression in these tumours.

Objective The purposes of our study concerning two patients with oestrogen secreting Leydig cell tumour were to determine whether endogenous LH levels are involved in testicular tumour steroidogenesis and whether aromatase activity of oestrogen secreting Leydig cell tumours is directly or indirectly dependent on LH levels. Measurements E2 and T were evaluated after hCG injection (5000 IU) during 96 hours. Bio and immuno LH, T, E2, were determined at the basal state and after administration of D-Trp-6-GnRH agonist (3.75 mg) every 3 weeks. The abnormal testis was removed after the third injection and testicular venous blood was collected during the operation. Testicular tumour was incubated with 4-14C-T. Results Oestradiol (E2) response to hCG injection (5000 IU) was prolonged and exaggerated while that of testosterone (T) was similar to that of the controls. The aromatase index (E2/T) remained elevated even 96 hours after hCG. Intramuscular injection of the GnRH agonist, D-Trp-6-GnRH (3.75 mg) resulted in a reduction of immunoreactive and bioactive LH. T was decreased to about 10% of baseline levels and E2 fell from 240 to 36 pmol/l. In the blood of the spermatic veins collected in the course of surgery, E2 levels were found to be lower in comparison with the controls. E2 was found to be twofold higher in the spermatic vein draining the tumoral side than in that of the contralateral testis. Incubation of the testicular tumours with 4-14C-T, displayed a reduced aromatase activity (conversion of T to E2: 0.3 and 0.1% in patients 1 and 2 respectively). Conclusions The kinetics of E2 response to hCG administration would suggest a modification of the regulation of the aromatase activity in this type of oestrogen secreting tumour. A certain endogenous LH level may be necessary to supply a sufficient quantity of T substrate, and to maintain aromatase activity of such Leydig cell tumours secreting oestrogens. These tumours seem to be responsive to endogenous LH levels.

Testicular biopsies from normal men and from men with testicular disorders were examined by immunohistochemistry for the presence of the inhibin-alpha subunit using two different antisera. Immunoreactive inhibin-alpha (irI-alpha) was found in Leydig cells in normal, oligospermic, and azoospermic men and in men with Klinefelter's syndrome, and it was also found in a Leydig cell tumour. hCG-treatment apparently increased the amount of immunoreactive inhibin-alpha, particularly in Leydig cells. Sertoli cells also contained irI-alpha but the staining intensity was considerably stronger in testes with impaired spermatogenesis or Sertoli-cell-only syndrome than in normal testes. It is suggested that the serum concentration of irI-alpha and inhibin in humans may, in a complex way, be related to both Leydig and Sertoli cell function, and that the relative contribution from these cells may change in cases of testicular malfunction.

An ossifying malignant Leydig cell tumour of the testis in a patient with associated gynaecomastia is presented. The criteria for diagnosing malignancy in these tumours are briefly discussed. After left orchidectomy he received cyclical chemotherapy consisting of bleomycin, etoposide and cis-platinum. At three months the gynaecomastia and pulmonary lesions have regressed and serum oestrogen has gradually fallen to 228 i.u./l.

SUMMARY A 44-year-old lady presenting with hirsutism was found to have a testosterone-secreting Leydig cell tumour of the right ovary. Serum testosterone levels were adequately suppressed for 8 years by combined oestrogen/progestogen preparation (Microgynon 30, Schering, West Sussex). The fall in gonadotrophin and testosterone levels during therapy and their rise after stopping therapy suggests that the tumour was gonadotrophin dependent.

In adult men referred with gynaecomastia, the prolonged plasma oestradiol (E2) response to hCG appears to be a useful tool in the diagnosis of feminizing Leydig cell tumour (LCT) of the testis. However, its specificity is uncertain. The hormonal status was therefore studied in 85 men with gynaecomastia including 17 with LCT, 52 with clinically isolated gynaecomastia and 16 hypogonadal men (13 with Klinefelter's syndrome and three with hypogonadotrophic hypogonadism). The data obtained after hCG (5000 IU i.m., n = 85) or GnRH (100 micrograms i.v., n = 70) administration were compared to those of a group of control men. Means of basal gonadotrophin and of gonadotrophin responses to GnRH were similar in LCT and controls but were significantly (P less than 0.001) higher than controls in patients with either Klinefelter's syndrome or isolated gynaecomastia. Half the patients with isolated gynaecomastia had normal gonadotrophin parameters (NGG) while half had significantly (P less than 0.001) higher levels (EGG) than controls, suggesting either primary testicular failure or androgen resistance. The T responses to hCG did not differentiate patients with LCT from either isolated gynaecomastia or controls. A prolonged E2 response (greater than 300 pmol/l on day 3 following hCG) was observed in all patients with LCT, in 10/21 EGG patients and in 3/13 patients with Klinefelter's syndrome. Such a response was observed in only one NGG patient. We conclude that a prolonged E2 response to hCG does not appear to be specific to LCT but that specificity is greatly improved (from 80 to 98%) when the gonadotrophin pattern (basal and/or responses to GnRH) is also taken into account.

Summary A case of Leydig cell tumour in a 6 ½ year-old boy is presented. The need for more elaborate methods for the biochemical separation of Leydig cell tumour from aberrant adreno-cortical tissue is stressed. Normal urinary output of Preganetriol and a lack of increase of the 17-beta-ketosteroids in the urine in a patient with a tumour in one of the testes serve to exclude the possibility of an adreno-cortical disorder.