Histidine decarboxylase inhibitors: a novel therapeutic option for the treatment of leydigioma.

Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (α-methyl-dl-histidine dihydrochloride (α-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, representing two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with α-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment.

Is testis sparing surgery safe in patients with incidental small testicular lesions referring to a fertility center? A retrospective analysis reporting factors correlated to malignancy and long-term oncological outcomes.

PURPOSE: To define predictors of malignancy after Testis sparing surgery (TSS) in patients referring to a fertility center with incidental small testicular lesions. Sub analyses were performed to assess predictors of Leydig cell hyperplasia and Leydig cell tumor. MATERIALS AND METHODS: We performed a retrospective analysis of a single institutional database including patients treated with TSS between 2002 and 2020. All patients who underwent TSS as a first line surgical approach for incidentally detected lesions found during fertility evaluation were included. RESULTS: Data of 64 patients were collected. The median follow up was 58 months and no recurrences were observed. At univariable logistic regression multifocal lesions, hypervascularization, microlithiasis, age and lesion size were significantly associated with malignancy. At multivariable logistic regression lesion dimension, hypervascularization and multifocal lesions were predictors of malignancy. Lesions smaller than 5 mm proved to be benign in 96.6% of the cases (32/33). Intraoperative color of the lesion and US pattern of vascularization were predictors at multivariable logistic regression for Leydig cell hyperplasia and Leydig cell tumor. CONCLUSION: Ultrasonographic characteristics and intraoperative appearance of the lesion can predict the malignant nature of small testicular lesions, guiding their surgical management in patients referring to a fertility center. Based on our experience, clinicians may safely perform TSS in carefully selected patients.

Multiparametric ultrasound for the diagnosis of Leydig cell tumours in non-palpable testicular lesions.

BACKGROUND: The widespread use of ultrasonography has led to an increased number of incidentally detected small non-palpable lesions, with Leydig cell tumours representing the majority of them. OBJECTIVES: The ultrasonography, real-time elastography and contrast-enhanced ultrasonography features of a large series of non-palpable testicular lesions were evaluated, focusing on the differences between Leydig cell tumours and other testicular masses. MATERIALS AND METHODS: Of the 4679 testicular ultrasonography examinations performed at the Authors' Institution between January 2009 and December 2018, 78 patients (1.7%) were incidentally diagnosed with at least one non-palpable lesion and were enrolled. Thirteen patients (16.6%) declined surgery and were thus excluded. The remaining 65 underwent surgical resection with frozen section analysis. The conventional ultrasonography, colour Doppler, real-time elastography and contrast-enhanced ultrasonography were performed by a radiologist having more than 10 years of experience. Demographic and clinical data were collected. RESULTS: Leydig cell tumours were detected in 32 patients, being the most frequent benign tumours (49.2%); of the non-Leydig cell tumours, 25 patients had malignant tumours, five non-neoplastic lesions and three other benign tumours. The Leydig cell tumour group had mostly infertility problems whereas the non-Leydig cell tumour group frequently experienced pain (p < 0.001). Leydig cell tumours were all hypoechoic (32/32, 100%; p = 0.002), more frequently presented with well-defined margins compared to non-Leydig cell tumours (30/32, 93.8% vs. 19/33, 57.6%; p = 0.001) and tended to be smaller than non-Leydig cell tumours (5.3 mm [standard deviation 2.7 mm] vs. 10.6 mm [standard deviation 3.8 mm], respectively; p < 0.001). The vascular pattern characterised by the rapid wash-in followed by the delayed wash-out observed during contrast-enhanced ultrasonography was significantly associated with the Leydig cell tumour histological diagnosis, even at multivariate analysis (odds ratio 480.5, p < 0.001), and yielded a high diagnostic accuracy (area under the receiver operating characteristic curve 0.954, 95% confidence interval 0.903-1). DISCUSSION: Contrast-enhanced ultrasonography demonstrated high diagnostic accuracy in identifying benign testicular lesions, such as Leydig cell tumours; they are the most common non-palpable tumours detected in infertile men and may benefit from enucleation.

Precocious puberty related to Leydig cell testicular tumor: the diagnostic imaging keys.

BACKGROUND: We report the challenging case of a 6-year-old boy with precocious puberty related to histologically proven Leydig cell tumor. CASE PRESENTATION: Multiparametric ultrasound and magnetic resonance imaging (MRI) was performed. Interesting findings were scarcely or never reported in children and differed from adults Leydig cell tumors s such as the hyperechogenic halo surrounding the lesion and the dominant central vascularization using ultrasensitive Doppler. MRI revealed an enlarged testicle with strong enhancement of a tumor, a tumor apparent diffusion coefficient (ADC) of 600 × 10-3 mm2/s and a lower ADC value of the non-tumor parenchyma compared to the contralateral testis (ADC = 800 × 10-3 mm2/s vs 1100 × 10-3 mm2/s), attributed to the spermatogenesis induced by hormonal impregnation. CONCLUSION: We illustrate multiparametric US and MRI findings of a pediatric Leydig cell tumor, including the imaging changes attributed to local hormone secretion, which may be helpful in similar cases.

Testicular Lesions in Infertile Men.

OBJECTIVES: An increasing number of incidental testicular tumors are diagnosed in patients during infertility workup. The aim of this study was to evaluate the accuracy of frozen section examination (FSE) for the management of these tumors. METHODS: We retrospectively studied a series of 46 testicular tumors diagnosed during exploration for infertility from 2000 to 2019 and submitted for FSE. RESULTS: A diagnosis of malignancy was made in 23 cases on both gross examination (yellow-white or cream-colored nodules for seminomas) and FSE, then confirmed on final diagnosis in 22 of the cases. One seminoma reported on FSE was revised as being a Leydig cell tumor. The 23 other lesions were diagnosed as benign on FSE, including 11 Leydig cell tumors (yellow-brown nodules), 2 Leydig cell hyperplasias, and 10 whitish fibrous lesions. All Leydig cell lesions were confirmed except 1, which was reclassified as a Sertoli cell tumor. Of the 10 cases of fibrous lesions, 6 were associated with malignancy. CONCLUSIONS: The high incidence of Leydig cell tumors and the accuracy of FSE for these lesions demonstrate the interest in FSE. In contrast, FSE is not reliable for fibrous lesions, and surgeons should be aware that a fibrosis result often corresponds with regressed tumors.

New-onset hirsutism.

This postmenopausal patient developed hirsutism following a surgical procedure. Thorough lab work directed us to the unusual cause.

Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.

Comparative molecular analysis of testicular Leydig cell tumors demonstrates distinct subsets of neoplasms with aggressive histopathologic features.

Testicular Leydig cell tumor (LCT), the most common sex-cord stromal tumor in men, represents a small fraction of all testicular tumors (~1 to 3%). Although most testicular LCTs are indolent and cured by radical orchiectomy, 5-10% have aggressive biology and metastatic potential. In primary LCTs, large size, cytologic atypia, necrosis, increased mitotic activity, and vascular invasion have been associated with clinically aggressive tumors. From a molecular perspective, the characteristics of aggressive LCTs and the differences between aggressive and nonaggressive LCTs remain largely unexplored. This study compares the genomic landscape of aggressive and nonaggressive testicular LCTs. Twenty-six cases were analyzed using next-generation DNA sequencing (NGS) and immunohistochemistry. Cases were classified as aggressive LCT if they met published criteria for malignancy in primary (i.e., testicular) tumors or if they had pathology-proven metastatic disease; otherwise, cases were considered nonaggressive. This multi-institutional series included 18 aggressive LCTs (14 primary/testicular, 4 metastatic) and 8 nonaggressive LCTs. Two cases (2/26, 8%; both aggressive LCTs) failed sequencing and had negative (i.e., uninformative) FH immunohistochemistry results. One additional primary aggressive LCT failed sequencing but had informative FH immunohistochemistry results. Combined NGS and immunohistochemical analysis demonstrated FH inactivation in 5/26 cases (19%). In addition, NGS demonstrated CTNNB1 mutations or biallelic APC inactivation in 9/23 cases (39%), copy number changes without recurrent mutations in 6/23 (26%) cases, and no alterations in 4/23 cases (17%). CTNNB1 mutations were present in both aggressive and nonaggressive LCTs. In contrast, FH inactivation and multiple copy number changes were only identified in aggressive LCTs. In conclusion, three distinct subgroups of aggressive LCTs were characterized by FH inactivation, Wnt pathway activation, and copy number changes without recurrent mutations, respectively. Nuclear translocation of ß-catenin and Wnt pathway activation appear to be early driver events that provide an environment conducive for progression to aggressive biology in a subset of LCTs.

Testis-sparing surgery for testicular tumors in children: a 20 year single center experience and systematic review of the literature.

PURPOSE: Although surgical therapy for testicular tumors (TT) is often radical orchidectomy, tumor resection with preservation of healthy testicular parenchyma has been proposed. This study herein reports a 20 year single center experience applying testicular sparing surgery (TSS) as a primary operative strategy in pediatric patients. A systematic literature review summarizes the utility and outcomes of TSS in appropriately selected patients. METHODS: Pediatric patients with TT who underwent TSS between 1997 and 2018 were studied. TSS was indicated if patients presented evidence of adequately spared healthy testicular parenchyma on preoperative ultrasound and negative serum tumor markers. A systematic review of the literature was also performed. RESULTS: 12 cases met full inclusion criteria with 10 of 12 subjects in the prepubertal age group. Follow-up was 73 months (range 18-278 months). Only a single male patient (GSCCT) presented with early recurrence and orchidectomy was then performed. No cases of postoperative testicular atrophy were identified. Sexual maturation (Tanner stage) expected for age in each patient was documented. Review of the literature identified 34 published studies including 269 patients (94% prepubertal). Pathologic lesions here were mainly mature teratoma(s)-(62%) with a follow-up period of 4 years. Recurrent tumors were observed in only three patients (1.1%) notably two Leydig Cell Tumors and one Teratoma. Testicular atrophy reportedly occurred in only one single case (0.37%). DISCUSSION: TSS is a feasible alternative to radical orchidectomy in pediatric male patients with localized TT and negative tumor markers. Long term follow-up is essential to monitor testicular growth, puberty with sexual development and psychological male health.

The Leydig cell tumour Scaled Score (LeSS): a method to distinguish benign from malignant cases, with additional correlation with MDM2 and CDK4 amplification.

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 13.3 mm; malignant LCTs, mean 44 mm) (P < 0.001) and five other parameters (infiltrative margins, necrosis, vascular invasion, mitotic count, and nuclear atypia) showed significant differences (Wilcoxon's test, P < 0.001). Eight metastatic LCTs and one benign LCT had infiltrative margins. Foci of coagulative necrosis occurred in 10 metastatic LCTs, whereas vascular invasion was identified in nine of 14 metastatic LCTs and none of 37 benign LCTs. Benign LCTs showed <2 mitoses/10 high-power fields (HPFs), whereas a high mitotic count (range, 3-50 mitoses/10 HPFs) was a feature of malignant LCTs. These parameters were selected by use of an inferential analysis based on univariate logistic regression models to develop a score. A LeSS of <4 correctly identified all histologically and clinically benign LCTs. A LeSS of ≥4 correctly identified all malignant LCTs. MDM2 and CDK4 immunostains were applied in all 51 cases: benign LCTs were negative; three of 11 malignant LCTs (27%) showed strong and diffuse immunopositivity and high levels of MDM2 and CDK4 amplification as determined with fluorescence in-situ hybridisation analysis and next-generation sequencing. CONCLUSION: We provide a new tool, the LeSS, for the prediction of malignant behaviour in LCTs.

Hyperandrogenism caused by ovarian Leydig cell tumour: finding the needle in a haystack.

Leydig cell tumours (LCTs) of the ovary are rare ovarian tumours that usually present with hyperandrogenism. Conventional radiological imagings are helpful in localising these tumours. However, some tumours may be too small to be localised before curative surgical removal. It is important to identify these androgen-secreting neoplasms which originate mostly from adrenals or ovaries because they are potentially malignant and require specific treatment. When conventional imagings are unrevealing, selective ovarian and adrenal venous sampling (SOAVS) is the next option. We report a case of LCT that was localised by SOAVS after results from other imaging modalities remained inconclusive.

SRY-Positive 46, XX Testicular Disorder of Sexual Development With Leydig Cell Tumor.

The risk of a gonadal tumor is high in testicular disorder of sexual development (DSD) with the Y chromosome, but cases of DSD without the Y chromosome are extremely rare. We reported a gonadal tumor in a phenotypically male individual with 46, XX testicular DSD. A testicular tumor was incidentally found in a 32-year-old phenotypic male who was presented to the hospital with male infertility. A diagnosis of 46, XX testicular DSD was made by the presentation of karyotype analysis of 46, XX with the sex-determining region of the Y chromosome (SRY) positive and gonadal tissue without female gonads. Surgery was performed due to a gradually growing tumor. The partial orchidectomy was performed with the diagnosis of a benign Leydig cell tumor in frozen biopsy.

Leydig cell tumor of a testis with azoospermia: A case report and literature review.

RATIONALE: Testicular tumors represent 1% to 1.5% of all tumors in men. Those derived from Leydig cells are rare and account for 1% of testicular tumors. Leydig tumor cells can produce steroid hormones such as estrogen, progesterone and testosterone. The amount and type of hormones secreted by these tumors may produce complicated clinical characteristics in these patients. PATIENT CONCERNS: Here, we report a patient with azoospermia, a testicular Leydig cell tumor (LCT), and elevated plasma testosterone levels. We describe the diagnostic and therapeutic experience of this case, and our follow-up of the patient's clinical indicators and fertility status. DIAGNOSIS: The patient was diagnosed with azoospermia and a testicular LCT. INTERVENTIONS: The patient underwent testicular tumor removal and long-term follow-up. OUTCOMES: After 4 months of follow-up, the patient's semen examination index significantly improved and his wife became naturally pregnant. At 4 months of gestation, the fetus was delivered because of a ruptured amniotic cavity. Twenty-six months after tumor removal, the patient's sex hormone levels had completely returned to normal and spermatogenic function had partially recovered, but there was no natural pregnancy with his partner. CONCLUSION: For LCTs, testis sparing surgery may provide a safe and feasible option to restore spermatogenic function, although longer-term follow-up is required. Drug assistance may be required to maintain spermatogenic function and achieve fertility, and further research is required.

Evaluation of cytotoxic T lymphocyte-mediated anticancer response against tumor interstitium-simulating physical barriers.

Tumor antigen-specific cytotoxic T lymphocyte (CTL) is a promising agent for cancer therapy. Most solid tumors are characterized by increased interstitial fluid pressure (IFP) and dense collagen capsule, which form physical barriers to impede cancer treatment. However, it remains unclear how CTL-mediated anticancer response is affected at the presence of these obstacles. Using a microfluidic-based platform mimicking these obstacles, we investigated the migration characteristics and performance of anticancer response of CTLs targeting hepatic cancer cells via antigen-specific and allogeneic recognition. The device consisted of slit channels mimicking the narrow interstitial paths constrained by the fibrous capsule and increased IFP was simulated by applying hydrostatic pressure to the tumor center. We found that antigen-specificity of CTLs against the targeted cancer cells determined the cytotoxic efficacy of the CTLs but did not significantly affect the success rate in CTLs that attempted to infiltrate into the tumor center. When increased IFP was present in the tumor center, CTL recruitment to tumor peripheries was promoted but success of infiltration was hindered. Our results highlight the importance of incorporating the physical characteristics of tumor interstitum into the development of CTL-based cancer immunotherapy.

Ginecomastia e hipogonadismo hipogonadotropo por tumor de células de Leydig: una causa poco frecuente de tumor testicular / Gynecomastia and hypogonadotropic hypogonadism caused by Leydig cell tumor: a rare cause of testicular tumor

Los tumores de células de Leydig son raros y suponen una pequeña proporción de neoplasias testiculares (1-3 %). La forma más frecuente de presentación es una masa indolora testicular o un hallazgo ecográfico incidental acompañado en más del 80 % de los casos de desórdenes hormonales. Los marcadores tumorales séricos son negativos y aproximadamente el 30 % de los casos presentan ginecomastia. El tratamiento de elección es la cirugía (orquiectomía ingui-nal) y el seguimiento postoperatorio será prolongado. El diagnóstico definitivo es histológico y se realizará durante o tras la cirugía. Entre los marcadores inmunohistológicos de tumores de células de Leydig se incluyen alfa inhibina, calretinina y melan A. La presencia de la subunidad alfa de inhibina mediante técnica de inmunohistoquímica, destaca la intensa positividad de las células tumorales en comparación con la del tejido sano circundante. La calretinina es más sensible pero menos específica que la inhibina. Melan A es un marcador moderadamente sensible y específico en la diferenciación de tumores del estroma del cordón sexual y como tal es un valor complementario a otros marcadores inmunohistoquímicos en la valoración de tumores de difícil diagnóstico. El interés de este caso es mostrar la complejidad de alteraciones clínicas asociadas a estos tumores, así como establecer un diagnóstico diferencial con otros tumores histológicos

Leydig cell tumors are rare and account for a small proportion of testicular neoplasms (1-3%). They most frequently present as a painless testicular mass or as an incidental ultrasound finding, accompanied by hormonal disorders in more than 80% of cases. Serum tumor markers are negative and approximately 30% of cases present gynecomastia. The treatment of choice is surgery (inguinal orchiectomy) with a long post-operative follow-up. The definitive diagnosis is histological, which will be carried out during or after surgery. The immunohistochemical markers of Leydig cell tumors include inhibin alpha, calretinin, and melan-A. The presence of the inhibin alpha subunit in immunohistochemical analysis shows intense positivity of tumor cells compared with the surrounding healthy tissue. Calretinin is more sensitive but less specific than inhibin. Melan-A is a moderately sensitive and specific marker of sex cord-stromal tumors, and, as such, complements other immunohistochemical markers in the assessment of tumors which are difficult to diagnose. The interest of this case is to show the complex pattern of clinical presentation of these tumors, and to establish a differential diagnosis with other testicular tumors

Renal interstitial cell tumor in a dog: clinicopathologic, imaging, and histologic features.

Renal interstitial cell tumors are benign tumors of renomedullary origin; however, malignant features have not been reported in dogs, to our knowledge. A 17-y-old spayed female Maltese dog was presented to a local animal hospital with a mass in the right abdomen. Clinicopathologic findings prior to surgery revealed renal insufficiency and anemia. Imaging revealed that the right kidney was enlarged by an amorphous mass with opaque areas, indicative of mineralization. Upon histologic examination, the mass was comprised of malignant mesenchymal cells that produced mucinous matrix. The tumor cells were positive for vimentin and COX-2, but negative for pancytokeratin; the matrix stained positively with alcian blue. Therefore, the mass was diagnosed as a renal interstitial cell tumor, with malignant features. COX-2 may be useful in the diagnosis of canine renal interstitial cell tumors, similar to its diagnostic role in humans.

Malignant leydig cell tumor in a 91-year-old man: Case report.

Testicle tumors are a rare entity among men population, accounting for only 1-1.5% of all can-cers among men. The stromal tumors of the sexual cord correspond just 4% of all testicular cancers. Only 10% of them are malignant. The major representative of the sex cord-stromal tumors is the Leydig cell tumor, corresponding to 75 to 80% of the total. It has bimodal age incidence, involving children and adults between 30 and 60 years. We report the caso of a 91-year-old man with malignant Leydig cell tumor, presenting increase of the volume of scrotum, local pain and hyperemia. The are few cases in the literature, only 1 with pacient above 85 years old.

Malignant leydig cell tumor in a 91-year-old man: Case report

ABSTRACT Testicle tumors are a rare entity among men population, accounting for only 1-1.5% of all cancers among men. The stromal tumors of the sexual cord correspond just 4% of all testicular cancers. Only 10% of them are malignant. The major representative of the sex cord-stromal tumors is the Leydig cell tumor, corresponding to 75 to 80% of the total. It has bimodal age incidence, involving children and adults between 30 and 60 years. We report the caso of a 91-year-old man with malignant Leydig cell tumor, presenting increase of the volume of scrotum, local pain and hyperemia. The are few cases in the literature, only 1 with pacient above 85 years old.

Testis-sparing Surgery for Pediatric Leydig Cell Tumors: Evidence of Favorable Outcomes Irrespective of Surgical Margins.

OBJECTIVE: To review our single institution experience, exploring the role of testis-sparing surgical resection in a cohort of children with Testicular Leydig cell tumors (LCTs). MATERIALS AND METHODS: We reviewed all consecutive children presenting with testicular tumors between 2003 and 2017 (n = 66), excluding patients with alternative pathologies (n = 57). Subsequently data were collected on age at surgery, laterality, type of surgery, operative time, presenting symptoms, serum markers, imaging findings, frozen section, final pathology, and follow-up. RESULTS: During the study period, a total of 9 (9/66; 14%) children were treated for LCT of the testis. Age at surgery was 8.4 ± 1.7 years and the majority (7/9; 77%) had unilateral disease. Most presented with a testicular mass, and 3 (33%) complained of testicular pain. None of the patients had elevated tumor markers. The primary method of management was ultrasound-guided testis-sparing surgery, with an operative time of 98.5 ± 58.7 minutes. Mean tumor size was 15 ± 10.8 mm (range 5-40 mm). In 2 of 6 patients with positive margins radical orchidectomy was performed without residual disease encountered. At a mean follow-up of 31.8 ± 26.3 months (range 2-87) none of the patients demonstrated disease recurrence. CONCLUSION: Our data suggest that LCT in children is associated with a good prognosis, and that TSS is a reasonable surgical approach without detrimental perioperative morbidity or negative long-term outcomes. Moreover, positive margins should not prompt a reflex decision for completion of orchidectomy.