Risk Factors and Treatment Outcomes of 1,375 Patients with Testicular Leydig Cell Tumors: Analysis of Published Case Series Data.

PURPOSE: Leydig cell tumors are rare but they are the most common nongerm cell testicular tumors. Only limited evidence exists for reliably differentiating between benign and malignant Leydig cell tumors and for optimally managing the different types and stages of this rare disease. In this review we synthesize the available evidence on the clinical presentation and clinicopathological characteristics associated with Leydig cell tumor malignancy and management. MATERIALS AND METHODS: We analyzed published case series data on Leydig cell tumors. The association between clinicopathological variables and the presence of metastatic disease was assessed using regression analyses. RESULTS: We included 357 reports, reviewing available data from 1,375 patients (median age 34 years). Testis sparing surgery was performed in 463 patients. Local recurrence after testis sparing surgery occurred in 8 of 121 (7%) patients with available followup information. Metastases were found in 101 patients and were most often located in the retroperitoneal lymph nodes (60%), lungs (38%) and/or liver (29%). The multivariable models with or without multiple imputation predicting metastatic disease included older age, larger tumor size, presence of any adverse factor (larger tumor diameter, necrosis, angiolymphatic invasion, pleomorphism, high mitotic index, atypia) and any protective factor (Reinke crystals, lipofuscin pigments, gynecomastia) with model AUCs of 0.93. Durable remission after resection of metastases or use of platinum based chemotherapy was rarely seen. CONCLUSIONS: Our risk tables using clinicopathological parameters can help identify patients with malignant tumors. These patients should undergo disease staging and be followed or receive further treatment. In some patients with metastatic disease surgical and systemic treatment might result in disease control.

Testicular and testicular adnexa tumors in the elderly.

Neoplasms in the testis and in the testicular adnexa of elderly patients are completely different from those observed in younger patients. Indeed, although conventional seminomas and nonseminomas are mainly observed in the age range of 20-45 years, spermatocytic seminoma, malignant Leydig tumors, and lymphomas in the testis and sarcomas in the paratesticular region are encountered in individuals older than 60 years of age. Here, we discuss the testis and paratesticular region neoplasm more commonly diagnosed in elderly men.

Increased incidence of Leydig cell tumours of the testis in the era of improved imaging techniques.

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

A five-year cohort study on testicular tumors from a population-based canine cancer registry in central Italy (Umbria).

Canine testicular tumors account for about 90 % of tumors affecting the male genitalia. Seminomas (SEM), Sertoli cell tumors (SCT), and interstitial cell tumors (ICT) are the most common histological diagnoses, but their incidence shows high variability among studies. Our aim is to report the results on the analysis of testicular tumors recorded by the population-based Umbria Canine Cancer Registry (CCR) for a 5-year time period and to assess the value of tumor major diameter, measured during trimming, in discriminating neoplastic from non-neoplastic lesions. The study was conducted on 388 testicular tumors (on 1969 total male tumors) diagnosed in 355 dogs from 2014 to 2018. The median incidence was 35 cases/100,000 dogs, with a proportion equal to 19,7 % of all tumors. The incidence on neutered male dogs was 352/100,000. Most tumors were ICTs (50 %), with fewer SEMs and SCTs (29 % and 17 %, respectively). Only 3 % of tumors were mixed germ cell-sex cord-stromal tumors (MGC-SCST). Ten percent of cases had multiple tumors in the same testicle, with SEM-ICT being prevalent (69.2 %). Tumors in cryptorchid testes were 5.9 % of the total, mostly SCT (60.9 %). Mean age at diagnosis was 10.7 ± 2.7, with similar values for different tumor types. Significant incidence ratios (IRR) were found in Golden retriever (IRR 7.18, CI95 % 4.72-10.92) and in English cocker spaniel (IRR 2.30, CI95 % 1.28-4.13) when compared with mixed breed dogs. A value of 0.3 cm (major diameter) of lesions at the moment of trimming was helpful in discriminating a final tumor histological diagnosis from a non-tumor lesion. Since the number of tumors included in this evaluation was limited, further studies to confirm the diagnostic value of this measure are recommended. Our results provided information on the incidence of canine testicular tumors in Umbria region that can be compared with future results and incidence from other geographical areas if provided with reliable data on the total population, can offer solid information on the incidence and proportion of different tumor types in specific territories, contributing also to the supervision of its inhabitants' health. Moreover, pathological data such as the major diameter of tumors can be obtained and contribute to diagnostic routine and standardization.

Canine testicular tumours: a study on 232 dogs.

The aim of this study was to provide an up-to-date estimate of the prevalence of canine testicular tumours, an earlier study (reported in 1962) having found a prevalence of 16%. Histological examination of both testes collected at necropsy from 232 dogs revealed that 62 (27%) had one or more testicular tumours, the total number of tumours identified being 110. Of these, 55 were interstitial cell tumours, 46 were seminomas, and nine were Sertoli cell tumours. The results suggest that, as reported in man, testicular tumours in dogs have increased during the past 40 years. Further studies should investigate the possible causative role of environmental pollutants.

Distribution of testicular tumors in Lebanon: a single institution overview.

BACKGROUND: Testicular tumors constitute a rare type of cancer affecting adolescents and young adults with recent reports confirming an increase in incidence worldwide. The purpose of this study was to estimate the epidemiological characteristics and histological subtypes of testicular tumors in the Lebanese population according to the WHO classification of testicular and paratesticular tumors. MATERIALS AND METHODS: In this single institutional retrospective study, all patients diagnosed with a testicular tumor in Hotel-Dieu de France Hospital University in Beirut between 1992 and 2014 were enrolled. The age, subtype based on the 2004 WHO classification and body side of tumor were analyzed. RESULTS: A total of two hundred and forty-four (244) patients diagnosed with a testicular tumor in our institution were included in the study. Two hundred and one patients (82.4% of all testicular tumors) had germ cell tumors (TGCT). Among TGCT, 50% were seminomatous tumors, 48% non-seminomatous tumors (NST) and 2% were spermatocytic seminomas. The NST were further divided into mixed germ cell tumors (63.9%), embryonic carcinomas (18.6%), teratomas (15.4%) and yolk sac tumors (2.1%). The mean age for testicular tumors was 32 years. The mean age for germ cell tumors was 31 years and further subtypes such as seminomatous tumors had a mean age of 34 years, 28 years in non-seminomatous tumors and 56 years in spermatocytic seminoma. Patients with right testicular tumor were the predominant group with 55% of patients. Three patients (1.2%) presented with bilateral tumors. CONCLUSIONS: The distribution of different subgroups and the mean age for testicular tumors proved comparable to most countries of the world except for some Asian countries. Germ cell tumors are the most common subtype of testicular tumors with seminomatous tumors being slightly more prevalent than non-seminomatous tumors in Lebanese patients.

On the occurrence of Leydig cell tumors in the F344 rat.

Dunning began inbreeding, what is now the Fischer F344 rat, in 1931. Because of her publications showing a low incidence of spontaneous tumors to 35 months of age, we selected the F344 rat for most of the studies in the National Cancer Institute (NCI) Bioassay Program, beginning in 1964. We were surprised by the finding that untreated male F344 rats displayed a high incidence of Leydig cell tumors of the testes beginning at about 17 months of age. The key difference between the results of Dunning and the NCI Bioassay Program was that her animals were retired breeders, whereas the NCI studies utilized virgin rats. The question of breeding was, therefore, examined as a possible protective factor. Groups of male F344 CDF/Crl rats were kept as virgin animals, or permitted access to bilaterally tube ligated female F344/Crl rats that were replaced twice over a 52-week period. At that time, all males from both groups were housed three per cage to 85 weeks when they were killed in a CO(2) atmosphere and necropsied. Sections were prepared from the fixed tissues, stained and studied by histopathology. The results were evaluated by appropriate statistical methods. Virgin and sexually active F344 rats displayed monolateral or bilateral Leydig cell tumors. There was no statistical difference between the two groups. Despite the early difference between breeding and virgin F344 rats, a control experiment failed to disclose an effect of sexual activity on the occurrence of Leydig cell cancers. This disease displays some difference in incidence in various parts of the world, with the higher socioeconomic groups having a greater incidence. Etiological factors on the occurrence of this disease in animals and in humans remain to be discovered.

Effect of individual versus group caging on the incidence of pituitary and Leydig cell tumors in F344 rats: proposed mechanism.

Recently, an increase in pituitary tumor (pars distalis adenoma) incidence, and decrease in testicular interstitial cell tumor incidence, has been noted in F344 rats, in 2 year National Toxicology Program dermal and inhalation studies. One of the factors that may have contributed to this correlation is the difference in housing protocols. Rats in inhalation and dermal toxicity studies are singly caged, in contrast to other types of studies in which rats are group-caged, such as dosed-feed, dosed-water, or gavage studies. We propose that stress, related to individual caging, particularly among males, directly impairs testosterone synthesis and produces Leydig cell atrophy which leads to a feedback increase in the synthesis of luteinizing hormone by the anterior pituitary. This is followed by anterior pituitary cell functional hypertrophy, hyperplasia, and eventually neoplasia. It is known that individual caging of male rats produces a stress response associated with increased serum corticosteroids. The testicular interstitial cells (Leydig cells) have specific receptors for the glucocorticoid hormones. The Leydig cell enzyme 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) inactivates gluococorticoids; however, prolonged stress depletes this enzyme, enabling the gluococorticoids to impair steroidogenesis and eventually to lead to compensatory pituitary proliferations, including neoplasms.

Spontaneous neoplastic lesions in aged Sprague-Dawley rats.

Neoplastic lesions were observed in untreated aged Sprague Dawley (SD) rats throughout their lifespan starting at 5 weeks. Their mean survival times were 89 to 105 weeks of age. The total tumor incidences were 70 to 76.7% and 87 to 95.8% in males and females, respectively. The common neoplasmas were pituitary adenoma and adrenal pheochromocytoma in both sexes, testicular Leydig cell tumor in males and mammary gland tumors, thyroidal C-cell adenoma and uterine stromal polyp in females.

Intrascrotal tumors in the older male.

Although the greatest incidence of testicular neoplasms is in the age group 20 to 35.9% of all intrascrotal tumors occur in males over 60. They may be classified into four major groups based on the tissue origin of the tumor. The most common group comprising 50% are lymphoreticular neoplasms or lymphomas. They occur in both blacks and whites, result in a diffuse enlargement of the testis and commonly involve the epididymis and cord. Prognosis is poor and survival is usually less than two years. Germ cell tumors comprise 25% and the tumors are usually large. Most of them are the classical seminoma which has a good prognosis following orchiectomy and retroperitoneal radiation. A few are the spermatocytic seminoma which is usually benign. Three percent are teratocarcinoma with embryonal elements which is highly malignant and survival less than two years. Ten percent are tumors of gonadal stromal origin. There are two types, the Leydig cell and the more rare Sertoli cell. About one-fourth of these patients develop gynecomastia and some a decrease in libido. The prognosis is good as less than 10% of these tumors are malignant. Neoplasms of supportive and paratesticular structures comprise a heterogeneous group of benign and malignant lesions and comprise about 15% of intrascrotal tumors. Most of them have the same features as tumors of similar tissues encountered throughout the body. They are the mesothelioma or adenomatoid tumor, fibroma, rhabdomyosarcoma, leiomyoma, lipoma, liposarcoma, mucinous cystadenocarcinoma, and leiomyosarcoma. As in all intrascrotal tumors, the diagnosis, treatment, and prognosis are based on the microscopic findings after removal of the tumor.

[Ovarian tumors located in the hilus. Analysis of 126 publications of the literature]. / Tumeurs ovariennes de siège hilaire. Analyse des 126 publications de la littérature.

One hundred and twenty six reported cases of ovarian tumors located in the hilus (OTLH) are analyzed. They represent a special sub group of ovarian steroid cell tumors (former "lipid cell tumors"). A number of these neoplasms are Leydig-Berger cell tumors (LBCT), which are characterized by the presence of the crystal of Reinke, a specific proteinaceous inclusion, whose detection may be improved by new available methods. Crystal-free steroid cell tumors located in the hilus are in most cases true leydigoma of the ovary whose features are indiscernible from LBCT's. They are revealed after years of evolution by signs of hyperandrogeny or post menopausal bleeding. Plasma testosterone levels are always elevated while urinary 17 keto steroid cytoplasmic values are normal in 50% of cases. Three main features distinguish ovarian tumors located in the hilus from others ovarian steroid cell tumors: the occurrence in aged women, the small size of the tumors, and the excellent prognosis.

Prepubertal testicular and paratesticular tumors in China: a single-center experience over a 10-year period.

OBJECTIVE: Prepubertal testicular tumors are rare and fundamentally distinct from adult testicular tumors. We reviewed our 11-year experience in a single medical center of China. MATERIAL AND METHODS: This study reports the clinical characteristics, histopathologic diagnosis, treatment methods, and outcome in a series of 63 prepubertal boys who were treated between 1997 and 2008. RESULTS: A total of 63 primary prepubertal testicular and paratesticular tumors were identified. The median age at presentation was 11 months. Of these tumors, 27 (42.9%) were mature teratomas, 5 (7.9%) were immature teratomas, 21 (33.3%) were yolk sac tumors, 4 (6.3%) were epidermoid cyst, 2 (3.2%) were Leydig cell tumors, 1 (1.6%) was a mixed malignant germ cell tumor, and 3 (4.8%) were paratesticular tumors. The most common clinical presentation (95.2%) was a painless scrotal mass or swelling. Forty-eight tumors were treated with radical inguinal orchiectomy, and 15, with a testis-sparing procedure. Follow-up was available in 59 cases, range from 4 to 128 months (median, 50 months). One patient with yolk sac tumor had recurrence and progression to metastasis at the end of 4 months after surgery. Other patients were disease free at last follow-up. CONCLUSIONS: Most of the prepubertal testicular lesions were benign, and the most common histologic subtype was teratoma. Our experience with testis-sparing procedures supports the current trends that less invasive treatment should be performed for benign lesions. This study confirms the excellent cure rates obtained in children with prepubertal testicular tumors.

RITA--Registry of Industrial Toxicology Animal data: the application of historical control data for Leydig cell tumors in rats.

Historical data for Leydig cell tumors from untreated or vehicle treated rats from carcinogenicity studies collected in the RITA database are presented. Examples are given for analyses of these data for dependency on variables considered to be of possible influence on the spontaneous incidence of Leydig cell tumors. In the 7453 male rats available for analysis, only one case of a Leydig cell carcinoma was identified. The incidence of Leydig cell adenomas differed markedly between strains. High incidences of close to 100% have been found in F344 rats, while the mean incidence was 4.2% in Sprague-Dawley rats and 13.7% in Wistar rats. Incidences in Wistar rats were highly variable, primarily caused by different sources of animals. Mean incidences per breeder varied from 2.8 to 39.9%. Analyses for the dependency on further parameters have been performed in Wistar rats. In breeders G and I, the Leydig cell tumor incidence decreased over the observation period and with increasing mean terminal body weight. The incidence of Leydig cell tumors increased with mean age at necropsy and was higher in studies with dietary admixture compared to gavage studies. These parameters had no effect on Leydig cell tumor incidence in breeders A and B. Animals from almost all breeders had a considerably higher mean age at necropsy when bearing a Leydig cell adenoma than animals without a Leydig cell adenoma. Studies with longitudinal trimming of the testes had a higher incidence than studies with transverse trimming. The observed dependencies and breeder differences are discussed and explanations are given. Consequences for the use of historical control data are outlined. With the retrospective analyses presented here we were able to confirm the published features of Leydig cell adenomas and carcinomas. This indicates that the RITA database is a valuable tool for analyses of tumors for their biological features. Furthermore, it demonstrates that the RITA database is highly beneficial for the definition of reliable historical control data for carcinogenicity studies on a scientifically solid basis.

Breed differences in the proportional morbidity of testicular tumours and distribution of histopathologic types in a population-based canine cancer registry.

Histologically verified tumours submitted to the Norwegian Canine Cancer Register from 1990 to 1998 were studied (n=14,401). The proportion of testicular tumours (n=345) was 2.4%, and the breakdown of histological tumour diagnoses is presented. The frequency of the most common histopathological types was 33% interstitial (Leydig), 26.4% Sertoli and 33.9% seminomas/germ cell tumours. The average age at diagnosis was 10 years, but was significantly lower for Sertoli cell tumours (8.6 years) than for the other tumour types. Following a histopathological re-evaluation, 22.5% of the original tumor diagnoses were modified. Proportional morbidity ratios were calculated and individuals from the breeds Shetland sheepdog and Collie were five times more likely to have testicular tumours than the overall average for the registry. Breed differences in the distribution of histopathologic types were observed. Shetland sheepdog and Collie were most commonly diagnosed with Sertoli cell tumours, while all tumours from Norwegian elkhound in this material were seminomas.