Suspected renal interstitial cell tumor causing polycythemia in two dogs.

Here we report a case series of two dogs diagnosed as renal interstitial cell tumor (RICT) accompanied by elevated serum erythropoietin level and marked polycythemia. RICT is a rare tumor in dogs, originating from renal interstitial cells. While several renal tumors such as renal lymphoma, adenocarcinoma, carcinoma, sarcoma, fibrosarcoma and nephroblastoma may cause polycythemia, polycythemia caused by RICT has never been reported in dogs. The tumors in both dogs were solitary and lied within cortex or cortico-medullary junction. Histopathology revealed spindle-shaped cells suggesting mesenchymal origin, with no mitotic figures suggesting that the tumors in both dogs were benign. Following surgical removal of the affected kidney, serum erythropoietin level and polycythemia normalized in both dogs.

Ovarian Leydig Cell Tumor Associated with Recurrent Torsion and Virilization in an Adolescent Patient.

Ovarian tumors are rare in children; however, their incidence increases with age. Of these ovarian tumors, Leydig cell tumors are some of the rarest, accounting for less than 0.1% of all ovarian tumors across all ages. Leydig cell tumors predominantly occur in postmenopausal women and are characterized by nodular proliferation of Leydig cells in the ovarian hilum with intracytoplasmic Reinke crystals. These tumors secrete androgens, which can disrupt ovarian function, clinically presenting with abnormal uterine bleeding and virilization. Although they are generally benign, current recommendations are for treatment with a unilateral salpingo-oophorectomy. In adolescents, hyperandrogenism is most commonly caused by polycystic ovarian syndrome (PCOS); however, the differential for hyperandrogenism is broad. We present a case of a 15-year-old girl with a history of primary amenorrhea who presented with a Leydig cell tumor associated with recurrent ovarian torsion and virilization. This case reviews the challenges with diagnosis, management, and future implications of a rare androgen-secreting tumor in young patients.

Two Rare Cases of Paratubal Leydig Cell Nodules: Clinical Relevance and Debated Terminology of a Noteworthy Incidentaloma.

Cells with cytologic and immunohistochemical features of Leydig cells are normally present in the ovary and the ovarian hilum, are testosterone-producing, and have been referred to as ovarian hilus cells. Rarely these cells form nests or nodules in extraovarian sites such as the mesovarium or mesosalpinx. Because they are so rare, these nodules can present a diagnostic challenge when first encountered. This report describes 2 such incidental nodules in the mesosalpinx associated with a small paratubal cyst and suggests that the term Leydig cell nodule be preferred over the nonspecific and confusing historical term ovarian hilus cell nest.

Ovarian Leydig Cell Tumor and Ovarian Hyperthecosis in a Postmenopausal Woman: A Case Report and Literature Review.

Ovarian Leydig cell tumor is a rare type of ovarian steroid cell neoplasms, presenting in only 0.1% of all ovarian tumor cases, and is generally androgen-secreting and unilateral. Although they are often malignant non-spreading tumors, which have excellent prognosis, benign ovarian Leydig cell tumors with low-risk malignancy can be also detected. Ovarian hyperthecosis is a rare non-neoplastic disorder, in most cases bilateral. Ovarian tumors and ovarian hyperthecosis are one of the main causes of hyperandrogenism in postmenopausal women, a condition strongly associated with both hormonal and metabolic changes. Here, we report a 65-year-old patient with complaints of excessive body hairiness and alopecia. The laboratory investigation showed increased levels of serum testosterone and dehydroepiandrosterone sulfate (DHEA-S). Imaging, including transvaginal ultrasound and pelvic MRI revealed the presence of two masses in the ovaries. The patient underwent a laparoscopic bilateral salpingo-oophorectomy due to the ovarian tumors unknown etiology, and histopathological examination revealed a unilateral benign left ovarian Leydig cell tumor with bilateral ovarian stromal hyperplasia and ovarian hyperthecosis. Making differential diagnosis between ovarian tumors and ovarian hyperthecosis is difficult. Bilateral salpingo-oophorectomy is the treatment of choice in postmenopausal women with benign Leydig cell ovarian tumor, as well as ovarian hyperthecosis, as it offers both a cure and diagnostic confirmation.

Leydig cell tumor of the testis with characteristic contrast patterns of tumor and non-tumorous testicular parenchyma on MRI: a case report.

PURPOSE: Testicular Leydig cell tumor (LCT) is a rare subtype of testicular neoplasms that occurs in the interstitial tissue of testes, accounting for 1-3% of total testicular masses removed annually. We report a case of 70-year-old man diagnosed as testicular LCT. This report demonstrates a testicular LCT with intratumoral and non-tumorous testicular parenchymal enhancement in the affected testis, which should be considered characteristic findings of LCT. METHODS: Ultrasonography showed a hypoechoic mass. On magnetic resonance imaging, the tumor showed low signal intensity comparable to the surrounding testicular tissue on T1-weighted images (T1WI) and low signal intensity on T2-weighted images (T2WI). On gadolinium contrast-enhanced T1WI (CE-T1WI), the tumor showed a rapid and marked wash-in and subsequent prolonged washout. The spared, non-tumorous testicular parenchyma showed slow and progressive enhancement in the early phase, which was as strong as or stronger than that of the mass in the delayed phase. The patient underwent right orchiectomy. RESULTS: Pathologically, the tumor was diagnosed as a testicular Leydig cell tumor (LCT). Leydig cell proliferation was observed with well-developed microvessels, atrophy of the seminiferous tubules, and stromal edema in the non-tumorous testicular parenchyma. Leydig cells in the non-tumorous parenchyma were positive for estrogen receptors. CONCLUSION: Since the contrast findings in the non-tumorous testicular parenchymal region on CE-T1WI likely match the histopathological features of LCT, our case suggests that the presence of non-tumorous testicular parenchymal enhancement on imaging might indicate a diagnosis of LCT.

Utilization of NKX3.1, P501S, Prostate-Specific Antigen, and Steroidogenic Factor 1 to Distinguish Malignant Leydig Cell Tumor From Metastatic Prostatic Adenocarcinoma to the Testis.

CONTEXT.­: A recent study demonstrated that NKX3.1-positive staining can uncommonly be seen in testicular Sertoli cell tumors (1 of 4 cases). Also, it was reported that 2 of 3 Leydig cell tumors of the testis showed diffuse cytoplasmic staining for P501S, although it was unclear whether it was specific granular staining that defines true positivity. However, Sertoli cell tumors do not typically pose a diagnostic dilemma with metastatic prostate carcinoma to the testis. In contrast, malignant Leydig cell tumors, which are exceedingly rare, can closely resemble Gleason score 5 + 5 = 10 prostatic adenocarcinoma metastatic to the testis. OBJECTIVE.­: To evaluate the expression of prostate markers in malignant Leydig cell tumors and steroidogenic factor 1 (SF-1) in high-grade prostate adenocarcinoma, as no data are currently published on these topics. DESIGN.­: Fifteen cases of malignant Leydig cell tumor were collected from 2 large genitourinary pathology consult services in the United States from 1991 to 2019. RESULTS.­: All 15 cases were negative immunohistochemically for NKX3.1, and all 9 with available additional material were negative for prostate-specific antigen and P501S and positive for SF-1. SF-1 was negative immunohistochemically in a tissue microarray with cases of high-grade prostatic adenocarcinoma. CONCLUSIONS.­: The diagnosis of malignant Leydig cell tumor and its distinction from metastatic adenocarcinoma to the testis can be made immunohistochemically on the basis of SF-1 positivity and negativity for NKX3.1.

cAMP-specific phosphodiesterase 8A and 8B isoforms are differentially expressed in human testis and Leydig cell tumor.

Cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) signaling pathway is the master regulator of endocrine tissue function. The level, compartmentalization and amplitude of cAMP response are finely regulated by phosphodiesterases (PDEs). PDE8 is responsible of cAMP hydrolysis and its expression has been characterized in all steroidogenic cell types in rodents including adrenal and Leydig cells in rodents however scarce data are currently available in humans. Here we demonstrate that human Leydig cells express both PDE8A and PDE8B isoforms. Interestingly, we found that the expression of PDE8B but not of PDE8A is increased in transformed Leydig cells (Leydig cell tumors-LCTs) compared to non-tumoral cells. Immunofluorescence analyses further reveals that PDE8A is also highly expressed in specific spermatogenic stages. While the protein is not detected in spermatogonia it accumulates nearby the forming acrosome, in the trans-Golgi apparatus of spermatocytes and spermatids and it follows the fate of this organelle in the later stages translocating to the caudal part of the cell. Taken together our findings suggest that 1) a specific pool(s) of cAMP is/are regulated by PDE8A during spermiogenesis pointing out a possible new role of this PDE8 isoform in key events governing the differentiation and maturation of human sperm and 2) PDE8B can be involved in Leydig cell transformation.

Chlorinated organophosphorus flame retardants-induced mitochondrial abnormalities and the correlation with progesterone production in mLTC-1 cells.

Environmental monitoring data have indicated that three chlorinated organophosphorus flame retardants (Cl-OPFRs), including tris(2-chloroethyl)-phosphate (TCEP), tris(2-chloropropyl)-phosphate (TCPP), and tris(1,3-dichloro-2-propyl)-phosphate (TDCPP) are the predominant chemicals in various environmental matrices and exhibit reproductive endocrine disrupting activities. Currently, mitochondrial abnormality is a new paradigm for evaluating chemical-mediated cell dysfunction. However, a comprehensive correlation between these two aspects of Cl-OPFRs remains unclear. In this research, the effects of TCEP, TCPP, and TDCPP on progesterone production and mitochondrial impairment were investigated by using mouse Leydig tumor cells (mLTC-1). The half maximal inhibitory concentration (IC50) values at 48 h exposure indicated that the rank order of anti-androgenic activity was TDCPP > TCPP. Whereas, TCEP exhibited elevation of progesterone production. At concentrations close to IC50 of progesterone production by TCPP and TDCPP, the elevation of intracellular reactive oxygen species (ROS), depletion of mitochondrial membrane potential (MMP), reduction of cellular adenosine triphosphate (ATP) content, and alteration of mitochondrial structures was observed. In addition, the expression of main genes related to progesterone synthesis was dramatically down-regulated by TCPP and TDCPP treatments. These results imply that the inhibition effect of TCPP and TDCPP on progesterone production might be related to mitochondrial damage and down-regulated steroidogenic genes.

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.

Hyperandrogenism due to ovarian Leydig cell tumour presenting with polycythaemia.

A postmenopausal woman in her 60s was referred due to an elevated haemoglobin value found during her annual check-up. On physical examination, characteristic features of hyperandrogenism were observed which were not earlier mentioned. Laboratory investigations revealed polycythaemia accompanied by a normal erythropoietin and a negative analysis for JAK2-V617F mutation. A disproportionally and markedly elevated testosterone in combination with normal levels of adrenal androgens raised the suspicion of an ovarian source. CT scan showed nodular hyperdense lesions in both ovaries. A bilateral oophorectomy was performed and histological evaluation unfolded a Leydig cell ovarian tumour. Testosterone levels and haematological parameters normalised after surgery. Polycythaemia secondary to hyperandrogenism in postmenopausal women is an extremely rare condition and patients should be carefully analysed for the presence of androgen-secreting neoplasms. Diagnosis of the underlying pathology requires careful history, physical examination and comprehensive investigation. Treatment for this condition is surgery and resolves polycythaemia.

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.

Ultrasound examination assisted clinical diagnosis of Leydig cell tumor of ovary: An extremely rare case report.

INTRODUCTION: Leydig cell tumor (LCT) is a sex cord-stromal tumor, which is a clinically rare ovarian tumor. It is characterized by endocrine hormonal changes and usually occurs in postmenopausal women. PATIENT CONCERNS: We report the clinical case of a 38-year-old female of childbearing age with LCT of the right ovary who presented with significantly decreased menstrual flow and elevated androgen levels, with persistent hypoechoic areas in the ovary as demonstrated by transvaginal ultrasound. DIAGNOSIS: The transvaginal ultrasound suggested the presence of a hypoechoic area in the right ovary with elevated androgens, interstitial tumor of the ovarian sex cord may be considered. INTERVENTIONS: The patient underwent laparoscopic right adnexectomy. OUTCOMES: Postoperative pathology confirmed the morphology and immunohistochemistry of the right adnexa consistent with LCT, and no areas of malignant transformation were found on multiple sections of the surgical specimen. The patient had normal androgen levels at postoperative day 2, day 45 and month 3. There was no sign of recurrence. CONCLUSION: This case suggests that when women of childbearing age have abruptly decreased menstrual flow with increased testosterone, clinicians should pay attention to intra-ovarian occupying lesions and consider the possibility of LCT. In such cases, ultrasound examination can determine the presence, location, shape and size of occupying ovarian lesions and play an important role in the diagnosis of condition.

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.

Testicular Sertoli cell tumour and potentially testicular Leydig cell tumour are features of DICER1 syndrome.

DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.

Transcriptome analysis of human Leydig cell tumours reveals potential mechanisms underlying its development.

Leydig cell tumours are the most common sex cord-stromal tumours. In the last years, apparent increased incidence is noted while aetiology of the tumour is still unknown. Therefore, here, we focused on the genetics of Leydig cell tumours using the next-generation sequencing. Leydig cell micronodules were revealed in patients with azoospermia who were qualified for testicular biopsy. Complete gene set of Leydig cell tumours was compared with transcriptome of healthy Leydig cells obtained from donors. Bioinformatic analysis of the obtained sequencing data revealed alterations in expression of 219 transcripts. We showed, for the first time, that a significant proportion of differentially expressed genes is directly involved in regulation of apoptotic process, which downregulation might be important to Leydig cell tumour development. Additionally, we found a significant upregulation of heat shock protein genes that might be a unique feature of Leydig cell tumours when compared to other tumour types. Our study offers fundamental transcriptomic data for future studies on human Leydig cell tumour that are crucial to determine its causes. Moreover, presented here the in-depth analysis and discussion of alterations observed in tumour transcriptome may be important for the diagnosis and therapy of this pathology.