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Testicular tumors represent the most common malignancy among young men. Nevertheless, the pathogenesis and molecular underpinning of testicular tumors remain largely elusive. We aimed to delineate the intricate intra‐tumoral heterogeneity and the network of intercellular communication within the tumor microenvironment. A total of 40,760 single‐cell transcriptomes were analyzed, encompassing samples from six individuals with seminomas, two patients with mixed germ cell tumors, one patient with a Leydig cell tumor, and three healthy donors. Five distinct malignant subclusters were identified in the constructed landscape. Among them, malignant 1 and 3 subclusters were associated with a more immunosuppressive state and displayed worse disease‐free survival. Further analysis identified that APP–CD74 interactions were significantly strengthened between malignant 1 and 3 subclusters and 14 types of immune subpopulations. In addition, we established an aberrant spermatogenesis trajectory and delineated the global gene alterations of somatic cells in seminoma testes. Sertoli cells were identified as the somatic cell type that differed the most from healthy donors to seminoma testes. Cellular communication between spermatogonial stem cells and Sertoli cells is disturbed in seminoma testes. Our study delineates the intra‐tumoral heterogeneity and the tumor immune microenvironment in testicular tumors, offering novel insights for targeted therapy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Testicular tumors are extremely rare, representing 1–1.5% of all neoplasms in men, and sex cord-stromal tumors account for about 5% of them. Histopathological diagnosis of such entities poses several challenges, mainly related to the fact that they can present in mixed forms and that immunohistochemical analyses can only be of partial help. We herein report a unique case of a collision sex cord-stromal tumor and discuss all the challenges faced in the diagnosis of such an entity. An accurate morphological examination of the entire lesion and a suitable immunohistochemical panel are essential for a correct diagnosis. [ABSTRACT FROM AUTHOR]

Central precocious puberty secondary to Leydig cell tumors is rare in children. We retrospectively analyzed the mid- to long-term follow-up data of patients with Leydig cell tumors. The clinical data of 12 consecutive patients who were treated at Beijing Children’s Hospital, Capital Medical University (Beijing, China), between January 2016 and October 2023 were retrospectively reviewed. Clinical evaluations, including physical examination, hormone examination, serum tumor marker analysis, abdominal and scrotal ultrasound, chest X-ray, and bone age measurement, were conducted before surgery and at follow-up time points. Surgical approaches were selected according to the individual conditions. Patients with an abnormal hormonal status and suspected of having central precocious puberty were referred to endocrinologists to confirm the diagnosis. Subsequently, gonadotropin-releasing hormone analog therapy was proposed. The mean patient age was 81.3 (range: 40–140) months at the time of the operation. Ten patients had peripheral precocious puberty at admission. All patients had elevated preoperative testosterone levels, whereas tumor marker levels were normal. Testis-sparing surgery was performed in eleven patients, and radical orchiectomy was performed in one patient. The follow-up duration (mean ± standard deviation) was 36.2 ± 25.3 months. Five patients had central precocious puberty, with a mean duration of 3.4 (range: 1–6) months postoperatively. Three patients were receiving gonadotropin-releasing hormone analog therapy, and good suppression of puberty was observed. No risk factors were found for secondary central precocious puberty. There was a high prevalence of central precocious puberty secondary to Leydig cell tumors in our study. Gonadotropin-releasing hormone analog therapy has satisfactory treatment effects. Larger sample sizes and long-term follow-up are needed in future studies.

Ultrasound is the most used interdisciplinary non-ionizing imaging technique in clinical pathologies of the testis. The testis may be affected by a plethora of different disorders such as vasculopathies, trauma, infections and manifestations of primary and secondary malignant masses. Conventional ultrasound represents the basic imaging modality of choice to assess scrotal disorders. Contrast-enhanced ultrasound (CEUS) can provide further information to distinguish between benign and malignant testicular mass lesions. The recent introduction of Super Resolution CEUS Micro-Vascular Imaging (MVI SR) and Time of Arrival (TOA SR) parametric mapping compliments the information provided by conventional CEUS, since these two new post-processing techniques improve the visualization of microvascular structures with slow blood flow and provide high-resolution images of the peak contrast enhancement and temporal perfusion patterns. This paper gives a comprehensive overview of differential diagnoses of the testicular disorder and their corresponding sono-morphologic correlates based on representative cases of the Interdisciplinary Ultrasound Center of the University Hospital Munich. [ABSTRACT FROM AUTHOR]

Leydig cell tumors (LCT) are usually unilateral and can seldom show malignant behavior. Testicular adrenal rest tumors (TART), which typically present bilaterally, are always benign and associated with congenital adrenal hyperplasia (CAH). Herein, along with a literature review, we aim to present a rare case of CAH associated with bilateral testicular masses, which led to difficulty in differential diagnosis between LCT and TART. An 8-year-old boy with 11ß-hydroxylase deficiency was referred to an outpatient clinic because of bilateral testicular masses. From his medical history, it was ascertained that he was under hydrocortisone treatment for 4 years after his first surgical examination, followed by serial ultrasounds with a preliminary diagnosis of TART. However, testicular masses gradually enlarged during follow-up, and magnetic resonance imaging showed characteristic findings for LCT. The patient underwent bilateral testis-sparing surgery, and histopathological examination was reported as benign LCT. The patient has been doing well postoperatively for 6 months. Although emerging bilateral testicular masses in patients with CAH may suggest TART, they may rarely originate from LCT and cause delay in diagnosis or difficulties in differential diagnosis in cases that do not respond to hormonal replacement. [ABSTRACT FROM AUTHOR]

Aim: Leydig cell tumors (LCT) are rare neoplasms that represent less than 0.1% of all ovarian tumors. This tumor usually presents with signs and symptoms of excess androgen levels. Diagnosis is made based on a combination of history, laboratory findings, imaging techniques and histopathological findings.Case: We present the case of a 35-year-old gravida five para 3+1 pregnant woman with a unilateral ovarian cystic mass that was discovered incidentally during a cesarean section. The cyst measured 9 cm in its maximum dimension. A left oophorectomy was performed after the delivery of an alive male baby. Morphological and immunophenotypic findings were consistent with those of a pure Leydig cell tumor.Conclusion: Leydig cell tumors are uncommon and usually present with hyperandrogenism. The presentation could be polymorphic, ranging from the rapid onset of virilization to being asymptomatic.

Leydig cell tumor (LCT) is a rare testicular tumor. We report a case of an elderly male patient who discovered a left testicular mass during a regular health examination four years ago. The patient did not experience any significant discomfort and opted for regular follow‐up visits. During the most recent visit, we performed routine ultrasound and contrast‐enhanced ultrasound (CEUS) examinations. By observing the lesion's location, echogenicity, margins, vascular distribution, as well as the rapid enhancement and slow washout characteristics on contrast‐enhanced ultrasound, we arrived at a diagnosis of LCT. Subsequently, the patient underwent left inguinal orchiectomy. Postoperative pathology and immunohistochemistry confirmed the diagnosis of LCT. Additionally, we conducted a comprehensive review of LCT‐related literature from PubMed and SCOPUS, summarizing the clinical features, follow‐up duration, prognosis, and ultrasound characteristics associated with LCT. [ABSTRACT FROM AUTHOR]

Testicular adrenal rest tumors (TART) are common in males suffering from congenital adrenal hyperplasia (CAH). Correct and timely diagnosis is important for differential diagnosis with malignant testis tumors, related infertility and as TART may worsen in time, especially in the absence of adequate and continuous hormonal control. The rarity of the disease, predominance of small cohorts and case reports and research heterogeneity (concerning type of CAH, patients' age and specific focus of the paper) complicate the understanding of this condition. To review epidemiological and clinical aspects of TART, including treatment and prognosis. Non-systematic review of CAH-related TART research. TART's prevalence grows progressively over time, predominating after puberty, affecting a mean of 20–40 % of CAH males. There is no proof of more frequent proportional affection of specific CAH phenotypes or types of enzyme deficiency, but cases of TART among non-classic CAH patients have been rarely reported. Chronic undertreated are more frequently affected and present larger tumors. Systematic ultrasound screening of CAH males is the state-of–the art for diagnosis, but TART are still often diagnosed in CAH adults seeking infertility treatment. TART are usually asymptomatic and present normal testicular volume. Biopsies are not recommended, except when the differential diagnosis between TART and testicular tumors cannot be guaranteed. Abnormal semen analysis is common. Leydig cell tumors are the main differential diagnosis, due to histological similarities to TART. Misdiagnosis may lead to unnecessary orchiectomies. Preservation of gonadal functions is inversely proportional to the total tumor volume. Tumors tend to regress under adequate adrenal suppression with steroids. Surgery in not indicated to treat TART. The reported prevalence of TART depends on age, usage of systematic follow-up ultrasound, and adequate CAH control. Timely detection of the disease is important to avoid irreversible gonadal dysfunction (not clinically apparent, due to high serum levels of androgen) and infertility. The relationship between TART and specific CAH phenotypes/genotypes has not been proved, and some cases do not present abnormal serum ACTH levels. Knowledge about TART should be disseminated among non-experts, to avoid unnecessary orchiectomies and false diagnosis of malignant testis tumors. Infertility is frequent, but has not been not satisfactorily addressed by physicians, even among experts. Sperm cryopreservation should be early offered to CAH adult males, but there are offer problems related to high cost. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Objective: Leydig cell tumors are a rare androgen-secreting ovarian tumor. We present a patient with virilization symptoms secondary to a Leydig cell tumor, with nonrevealing imaging studies, that was localized using ovarian vein sampling (OVS). Case Report: A 56-year-old postmenopausal woman was referred by her gynecologist to the endocrinology clinic for voice-deepening, clitoral enlargement, scalp hair loss, and excessive body hair growth. Her total testosterone was 11.5 (0.3-1.3 nmol/L), bioavailable testosterone was 7.19 (0.1-0.6 nmol/L), and dehydroepiandrosterone sulfate was 4.0 (0.8-4.9 μmol/L). Transvaginal ultrasound and abdominal magnetic resonance imaging showed no adrenal or ovarian masses bilaterally. On adrenal vein sampling (AVS) and OVS, total testosterone from the left gonadal vein was 780.0 (0.3-1.3 nmol/L) and right gonadal vein was 18.6 (0.3-1.3 nmol/L), with a left-to-right ovarian testosterone ratio of 41.94. A bilateral salpingo-oophorectomy was performed, and a 1.0 cm Leydig cell tumor in the left ovary was noted on histopathology. One month after surgery, her total and bioavailable testosterone were

We report a case of a 19-year-old male referred to the Endocrine Unit because of gynecomastia. Initial investigation revealed elevated levels of estradiol (E2) along with secondary hypogonadism (hypotestosteronemia and severe oligoasthenoteratozoospermia (OAT)) despite normal testicular volume (12 mL) and secondary sexual characteristics. Surprisingly, an ultrasound examination revealed a small hypoechoic mass (1.1 cm) with intense intralesional vascularization within the right testicle, even though tumor markers were normal. Surgical removal of testicular mass led to the identification of Leydigioma, and the patient showed regression of gynecomastia during the nine-month follow-up. Unexpectedly, hypergonadotropinemia manifested along with normal testosterone (T) levels and significant improvement in OAT. Magnetic resonance imaging (MRI) showed pituitary hyperplasia (PH). Gynecomastia represents an atypical manifestation of Leydig cell tumors and typically resolves after surgical removal. However, unilateral orchiectomy may determine compensatory PH. Currently, it is uncertain whether the shift from hypogonadotropic to permanent hypergonadotropinemia was the only factor responsible for the high sperm count occurring in our patient. Further research is needed to elucidate the underlying mechanisms.

Ovarian torsion is an uncommon cause for acute abdominal pain in children while the possibility of malignancy presenting as ovarian torsion is even rarer. We report here an atypical case of ovarian neoplasm presenting as ovarian torsion in a 5‑year‑old child. The highlight of this case is the epithelial component staining positive for both CK 7 and CK 20 in addition to Sertoli–Leydig cell component indicating it as mixed Sertoli–Leydig cell tumor of retiform variant with focal heterologous elements. The heterologous element is the CK7 and 20 being positive epithelium. The ovarian torsion should make one suspect malignancy in and around the ovary and subject it for detailed histopathologic study and manage accordingly; lest, one’s failure to suspect the same may compromise patient management and prognosis. [ABSTRACT FROM AUTHOR]

We report a case of a 19-year-old male referred to the Endocrine Unit because of gynecomastia. Initial investigation revealed elevated levels of estradiol (E2) along with secondary hypogonadism (hypotestosteronemia and severe oligoasthenoteratozoospermia (OAT)) despite normal testicular volume (12 mL) and secondary sexual characteristics. Surprisingly, an ultrasound examination revealed a small hypoechoic mass (1.1 cm) with intense intralesional vascularization within the right testicle, even though tumor markers were normal. Surgical removal of testicular mass led to the identification of Leydigioma, and the patient showed regression of gynecomastia during the nine-month follow-up. Unexpectedly, hypergonadotropinemia manifested along with normal testosterone (T) levels and significant improvement in OAT. Magnetic resonance imaging (MRI) showed pituitary hyperplasia (PH). Gynecomastia represents an atypical manifestation of Leydig cell tumors and typically resolves after surgical removal. However, unilateral orchiectomy may determine compensatory PH. Currently, it is uncertain whether the shift from hypogonadotropic to permanent hypergonadotropinemia was the only factor responsible for the high sperm count occurring in our patient. Further research is needed to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Testicular cancers comprise 1–1.5% of entire cancers in men, and sex cord-stromal tumors include 5% of testicular cancers. This study aims to report a simultaneous Sertoli cell-only syndrome and Leydig cell tumor in the same patient. A 32-year-old man presented with a history of primary infertility for 3 years. Physical examination revealed normal secondary sexual characteristics. Two successive seminal fluid analyses revealed azoospermia. A scrotal ultrasound scan showed a 28 × 27 mm hypoechoic and hypervascular right testicular mass. Right radical orchiectomy and simultaneous left testicular biopsy were conducted. The histopathological examination revealed Sertoli cell-only syndrome and Leydig cell tumor with focal Leydig cell hyperplasia. Reversing fertility following the management of Leydig cell tumor is rarely mentioned in the literature. A study revealed that fertility recovered following 4 months of management in a primary infertile male. However, infertile men with nonobstructive azoospermia due to SCOS can only have a child by testicular sperm extraction technique. Despite the rare occurrence of Leydig cell tumor, it could be seen in association with Sertoli cell-only syndrome in infertile men with azoospermia. Clinical examination and imaging studies are important in these patients as the possibility of having a testicular mass is high among them.

Leydig cell tumors can cause precocious puberty in prepubertal males. Radical orchiectomy is the standard therapy for Leydig cell tumors, with a good overall prognosis. Here, we present a rare case of secondary central precocious puberty caused by a Leydig cell tumor in a 5 year-old boy. He had an isosexual precocity and advanced bone age. Laboratory investigations showed high testosterone and low gonadotropin levels, presenting as precocious pseudo-puberty. Seven months after surgical removal of the tumor, the patient was diagnosed with central precocious puberty by GnRH stimulation test. He was initiated on GnRH agonist therapy, which has been administered every 13 weeks to date. Post-surgery surveillance of Leydig cell tumors should include evaluation for progression to secondary central precocious puberty as well as recurrence of Leydig cell tumor or metachronous tumors in prepubertal children.

Ovarian torsion is an uncommon cause for acute abdominal pain in children while the possibility of malignancy presenting as ovarian torsion is even rarer. We report here an atypical case of ovarian neoplasm presenting as ovarian torsion in a 5-year-old child. The highlight of this case is the epithelial component staining positive for both CK 7 and CK 20 in addition to Sertoli–Leydig cell component indicating it as mixed Sertoli–Leydig cell tumor of retiform variant with focal heterologous elements. The heterologous element is the CK7 and 20 being positive epithelium. The ovarian torsion should make one suspect malignancy in and around the ovary and subject it for detailed histopathologic study and manage accordingly; lest, one’s failure to suspect the same may compromise patient management and prognosis.

Sexual precocity in boys is defined as any sign of secondary sexual characteristics present before the age of 9. Leydig cell tumors of the testes are a rare cause of peripheral precocious puberty in boys. Here, we report 8 years and 4-month-old boys with signs of peripheral precocious puberty because of a testicular Leydig cell tumor that developed true precocious puberty after surgical removal. Examination of genitalia showed Tanner 4 hair growth. The penis length was 14.5 cm with a 2.5 cm width. The right testis was enlarged but the left testis was measured at 2cm in length and 1 cm in width. Laboratory results showed low serum gonadotropin levels and increased androgen levels. Testicular sonography reported one solid mass measured 31×28×15 millimeters. With a presumptive diagnosis of Leydig cell tumor, the patient underwent radical orchiectomy. Pathologic evaluation confirmed it. Two months after surgery, the diagnosis of central precocious puberty was confirmed according to physical examination and rising of serum gonadotropins. We started treatment with a Gonadotropin-releasing hormone (GnRH) agonist. Leydig cell tumor in children is an uncommon cause of precocious puberty. In every boy with the sign of peripheral precocious puberty and asymmetrical testicular enlargement, the testicular tumor should be considered. It may induce central precocious puberty after surgical resection and this diagnosis should be considered in the patient’s follow-up in the next visits.

Sexual precocity in boys is defined as any sign of secondary sexual characteristics present before the age of 9. Leydig cell tumors of the testes are a rare cause of peripheral precocious puberty in boys. Here, we report 8 years and 4-month-old boys with signs of peripheral precocious puberty because of a testicular Leydig cell tumor that developed true precocious puberty after surgical removal. Examination of genitalia showed Tanner 4 hair growth. The penis length was 14.5 cm with a 2.5 cm width. The right testis was enlarged but the left testis was measured at 2cm in length and 1 cm in width. Laboratory results showed low serum gonadotropin levels and increased androgen levels. Testicular sonography reported one solid mass measured 31×28×15 millimeters. With a presumptive diagnosis of Leydig cell tumor, the patient underwent radical orchiectomy. Pathologic evaluation confirmed it. Two months after surgery, the diagnosis of central precocious puberty was confirmed according to physical examination and rising of serum gonadotropins. We started treatment with a Gonadotropin-releasing hormone (GnRH) agonist. Leydig cell tumor in children is an uncommon cause of precocious puberty. In every boy with the sign of peripheral precocious puberty and asymmetrical testicular enlargement, the testicular tumor should be considered. It may induce central precocious puberty after surgical resection and this diagnosis should be considered in the patient's follow-up in the next visits. [ABSTRACT FROM AUTHOR]

A 71-year-old woman, gravida 4 para 3, presented with abnormal genital bleeding. Transvaginal ultrasonography showed a thickened endometrium of 11.5 mm, but no bilateral adnexal enlargement. Cervical cytology was negative for intraepithelial lesion or malignancy, and endometrial curettage was performed, and no malignant findings were found histologically. Pelvic MRI showed only 9 mm endometrial thickening and no ovarian tumor. Serum estradiol was elevated (55 pg/mL), and CA125, CA19-9, and CEA were not elevated. A hormone-producing ovarian tumor was suspected, and total laparoscopic hysterectomy and bilateral salpingo-oophorectomy were performed. Although no tumor was found macroscopically in the bilateral ovaries, histopathology revealed a 1.5 × 1.5 mm Leydig cell tumor in the right ovary. Serum E2 decreased after surgery. Thus, in cases with postmenopausal irregular bleeding and endometrial thickening, it is essential to consider Leydig cell tumor, even in the absence of ovarian tumors on imaging. [ABSTRACT FROM AUTHOR]

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 (a-methyl-dl-histidine dihydrochloride (a-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, re presenting two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with a-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context Autosomal dominant and rarely de novo gain-of-function variants in the LHCGR gene are associated with precocious male puberty, while somatic LHCGR variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the LHCGR gene. Digital droplet polymerase chain reaction of the LHCGR variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in LHCGR. The gain-of-function nature of the LHCGR variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys. [ABSTRACT FROM AUTHOR]

Aim: Leydig cell tumors (LCT) are rare neoplasms that represent less than 0.1% of all ovarian tumors. This tumor usually presents with signs and symptoms of excess androgen levels. Diagnosis is made based on a combination of history, laboratory findings, imaging techniques and histopathological findings. Case: We present the case of a 35-year-old gravida five para 3 +1 pregnant woman with a unilateral ovarian cystic mass that was discovered incidentally during a cesarean section. The cyst measured 9 cm in its maximum dimension. A left oophorectomy was performed after the delivery of an alive male baby. Morphological and immunophenotypic findings were consistent with those of a pure Leydig cell tumor. Conclusion: Leydig cell tumors are uncommon and usually present with hyperandrogenism. The presentation could be polymorphic, ranging from the rapid onset of virilization to being asymptomatic.

Testicular adrenal rest tumors are a rare development of patients with congenital adrenal hyperplasia. It is difficult to diagnose due to similarities with Leydig cell tumors. Treatment can be conservative or surgical. We describe the case of a 56 year old male presenting with bilateral testicular pain and irregular growth that was managed with a unilateral orchiectomy. We analyzed the distinguishing factors of testicular adrenal rest tumors compared to Leydig cell tumors, as well as the diagnostic and treatment methods.

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.

Prothymosin α (PTMA) is a phylogenetically conserved polypeptide in male gonads of Vertebrates. In Mammals, it is a ubiquitous protein, and, possessing a random-coil structure, it interacts with many other partners, in both cytoplasmic and nuclear compartments. PTMA has been widely studied during cell progression in different types of cancer because of its anti-apoptotic and proliferative properties. Here, we provided the first evidence of PTMA expression and localization in human testis and in two testicular cancers (TC): classic seminoma (CS) and Leydig cell tumor (LCT). Data showed that its protein level, together with that of proliferating cell nuclear antigen (PCNA), a cell cycle progression marker, increased in both CS and LCT samples, as compared to non-pathological (NP) tissue. Moreover, in the two-cancer tissue, a decreased apoptotic rate and an increased autophagic flux was also evidenced. Results confirmed the anti-apoptotic action of PTMA, also suggesting that it can act as a switcher from apoptosis to autophagy, to favor the survival of testicular cancer cells when they develop in adverse environments. Finally, the combined data, even if they need to be further validated, add new insight into the role of PTMA in human normal and pathological testicular tissue. [ABSTRACT FROM AUTHOR]

Background: Reinke crystals are structures pathognomonic for Leydig cells, which have the important function of testosterone production and are vital for male reproductive health. These crystalline inclusions are thought to be of protein origin; however, the molecular composition has not yet been resolved. Objectives: This review summarizes all available information regarding Reinke crystal's characteristics and aims to produce a comprehensive guide for research on this topic as well as to determine and discuss potential Reinke‐protein candidates. Methods: Pubmed was thoroughly searched for all publications regarding Reinke crystals and 137 publications were identified. All publications were surveyed and all relevant information was included in the review. Results: Along with the cytoplasm, structures that resemble Reinke crystals were also observed in the nucleus, suggesting that their formation depends only on protein concentration. Variations in tissue processing protocols could impact Reinke crystal microscopic visualization, which is an important factor in diagnosing Leydig cell disorders such as Leydig cell tumors. Reinke crystals appear to be hallmarks of normally differentiated, adult, Leydig or Leydig‐like cells in humans, while some abnormal and nonhuman Leydig cells contain Reinke‐like paracrystalline inclusions or crystalloids. Conclusions: These characteristics point to some differentially expressed proteins, which could be involved in Reinke crystal formation. Differential Reinke crystal and paracrystalline inclusion presence could also be due to small changes in protein structure or the cell environment. Further research is needed to solve the ongoing mystery of the Reinke crystal, which would enhance our knowledge of Leydig cell contribution in the pathogenesis of various male reproductive disorders and improve their diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Testicular cancers comprise 1–1.5% of entire cancers in men, and sex cord-stromal tumors include 5% of testicular cancers. This study aims to report a simultaneous Sertoli cell-only syndrome and Leydig cell tumor in the same patient. A 32-year-old man presented with a history of primary infertility for 3 years. Physical examination revealed normal secondary sexual characteristics. Two successive seminal fluid analyses revealed azoospermia. A scrotal ultrasound scan showed a 28 × 27 mm hypoechoic and hypervascular right testicular mass. Right radical orchiectomy and simultaneous left testicular biopsy were conducted. The histopathological examination revealed Sertoli cell-only syndrome and Leydig cell tumor with focal Leydig cell hyperplasia. Reversing fertility following the management of Leydig cell tumor is rarely mentioned in the literature. A study revealed that fertility recovered following 4 months of management in a primary infertile male. However, infertile men with nonobstructive azoospermia due to SCOS can only have a child by testicular sperm extraction technique. Despite the rare occurrence of Leydig cell tumor, it could be seen in association with Sertoli cell-only syndrome in infertile men with azoospermia. Clinical examination and imaging studies are important in these patients as the possibility of having a testicular mass is high among them. [ABSTRACT FROM AUTHOR]

Abstract Objective To perform a systematic review on the effects of testicular sparing surgery (TSS) on the oncological, functional, and hormonal outcomes of adults with testicular tumors. Methods A literature search was performed after PROSPERO registration (CRD42020200842) and reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) methods. We conducted a systematic search of Medline (Ovid), Embase, Cochrane CENTRAL, CINAHL, Scopus, Web of Science, ClinicalTrials.gov, and the WHO/ICTRP from inception to November 20, 2020. Manuscripts and published abstracts were included if they involved testis‐sparing surgery (TSS) and contained data on any outcomes related to fertility, hormonal parameters, or oncological control, or if they evaluated surgical technique. Results Our initial search yielded 3,370 manuscripts, with 269 of these screened for full‐text eligibility. After our exclusion criteria were applied, 32 studies were included in the final analysis. Oncological outcomes were obtained from 12 studies (average follow‐up 57.8 months), functional data from 26 studies (average follow‐up 49.6 months), fertility information from 10 studies (average follow‐up 55.8 months), and data on nonpalpable tumors from 11 studies (average follow‐up 32.1 months). Oncological control appears to be excellent in studies that reported these outcomes. Presence of germ cell neoplasia in situ was controlled with adjuvant radiation in nearly all cases. Functional outcomes are also promising, as development of primary and compensated hypogonadism was rare. Semen parameters are poor preoperatively among men with benign and malignant testis tumors, with occasional decline after TSS. Frozen section analysis at the time of surgery appears to be very reliable, and the majority of nonpalpable tumors appear to be benign. Conclusions TSS is a safe and efficacious technique with regards to oncological control and postoperative hormonal function based on retrospective, noncontrolled studies. TSS avoids unnecessary removal of benign testicular tissue, and should be given serious consideration in cases of nonpalpable, small tumors under 2 cm. In cases of malignancy, TSS can safely avoid anorchia in men with bilateral tumors and in men with solitary testicles. The use of the operating microscope, while theoretically promising, does not necessarily lead to better outcomes, however data are limited.

Background: Congenital adrenal hyperplasia (CAH) refers to group of congenital diseases resulting from impaired adrenal steroidogenesis, and its most common cause is 21-hydroxylase deficiency. Testicular adrenal residual tumor (TART) is one of the major complications of CAH, possibly resulting from ectopic remnants of intra-testicular adrenal tissue which is stimulated by excessive secretion of adrenocorticotropic hormone (ACTH). This tumor can be misdiagnosed as Leydig cell tumor (LCT) in these people. Case Presentation: The patient we are presenting is a 20-year-old man with a history of precocious puberty and a height below 3% of the population who underwent radical left testicular orchiectomy with a complaint of bilateral testicular mass, which is reported LCT in the pathology report. In preoperative imaging examinations, bilateral adrenal hyperplasia is observed. In hormonal examinations, the patient is diagnosed with CAH and has been treated with corticosteroids for one year. Conclusion: In patients who present with bilateral testicular mass, it is the best image by abdominopelvic CT scan before surgery to detect CAH.

A 10-year-old intact female Chinese Crested dog was presented for evaluation and further diagnostics due to persistent symptoms of vulvar swelling, vaginal discharge, and an 8-year history of acyclicity. At presentation, generalized hyperpigmentation and truncal alopecia were identified, with no aberrations of the female phenotype. Vaginal cytology confirmed the influence of estrogen at multiple veterinary visits, and hormonal screening of progesterone and anti-Mullerian hormone indicated gonadal presence. Based on findings from abdominal laparotomy and gonadectomy, the tissue was submitted for histopathology. Histopathologic evaluation identified the gonads to be abnormal testes containing multiple Sertoli and interstitial (Leydig) cell tumors. The histopathologic diagnosis of testes and concurrent normal external female phenotype in the patient lead to a diagnosis of a disorder of sexual development (DSD). Karyotype evaluation by conventional and molecular analysis revealed a two cell line chimeric pattern of 78,XX (80%) and 78,XY (20%) among blood leukocytes, as well as a positive PCR test for the Y-linked SRY gene. Cytogenetic analysis of skin fibroblasts revealed the presence of 78,XX cells exclusively, and PCR tests for the Y-linked SRY gene were negative in the hair and skin samples. These results are consistent with an XX/XY blood chimerism. This is one of the few case reports of a canine with the diagnosis of leukocyte chimerism with normal female phenotypic external genitalia. This case illustrates a distinct presentation for hormonally active Sertoli cell tumorigenesis and demonstrates surgery as a curative treatment option for clinically affected patients.

Objective: identification and description of clinical and morphological characteristics of rare forms of stromal cell tumors of the ovaries.Materials and methods. Retrospectively processed over 10 thousand case histories of patients with various ovarian tumors who were examined and treated at the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia and the National Center for Oncology and Hematology of the Ministry of Health of Kyrgyz Republic. In 473 patients were diagnosed stromal cell tumors, among them 3 cases of rare forms of tumors of the stroma of the sex cord were identified: stromal tumor from Sertoli cells, malignant luteoma of the ovary, lipid‑cell tumor from Leydig cells. All patients underwent a planned morphological study of surgical material and immune-histochemical study.Results. The detailed data of clinical observations of rare types of tumors, which was presented in the literature by isolated cases, are presented, the description of which in the literature is presented by isolated cases. The possible effect of clinical and morphological characteristics on the survival of patients with rare forms of stromal cell tumors of the ovaries were analyzed.Conclusions. The necrobiotic changes in the tumor, the degree of malignancy, and the stage of the disease are potential predictors of poor prognosis in patients with rare forms stromal cell tumors of the ovaries which require confirmation in a larger sample of patients.