Enucleation for prepubertal leydig cell tumor

PURPOSE: Leydig cell tumors in children are rare, comprising only 4% to 9% of all primary testis tumors in prepubertal males. Almost all of these boys present with isosexual precocious pseudopuberty associated with increased testosterone, low gonadotropin levels and a testis mass. We present our experience with testis sparing enucleation of Leydig cell tumor in prepubertal boys. MATERIALS AND METHODS: Two patients presented with isosexual precocious puberty at ages 6 and 9 years. Each patient had a well circumscribed, painless testicular mass, increased serum testosterone (101 and 444 ng/dl [normal 0 to 25]), normal gonadotropins and negative alpha-fetoprotein levels. Both patients underwent successful enucleation of the testis mass following proper testis oncological surgical principles. RESULTS: Both patients had normalization of the serum testosterone following enucleation of the Leydig cell tumor. At 9 and 44 months of followup they have maintained normal ipsilateral testicular volume compared to the contralateral gonad, and 1 patient entered puberty spontaneously at 1 year postoperatively. Neither patient suffered any morbidity, and both have presumably benefited from preservation of the involved gonad with preserved testicular volume. CONCLUSIONS: Prepubertal boys with isosexual precocious pseudopuberty, an isolated testis mass, increased testosterone and low or normal gonadotropin levels can reliably be diagnosed with Leydig cell tumors. Based on the ability to establish the diagnosis preoperatively and the universal benign behavior of unilateral, prepubertal Leydig cell tumor, we believe these patients are best treated with testis sparing enucleation of the tumor. In view of the high likelihood that this tumor in prepubertal boys is benign, a transscrotal surgical approach should be considered.     

Gynecomastia in association with a complex tumor of the testis secreting chorionic gonadotropin: studies on the testicular venous effluent

The levels of progesterone, 17 alpha-hydroxyprogesterone, androstenedione, testosterone and estradiol were measured in the testicular venous effluent from a testis containing a complex malignant tumor associated with gynecomastia and increased serum levels of beta-human chorionic gonadotropin. An abnormally low testosterone/estradiol ratio was encountered (83 in the peripheral serum and 101 in the spermatic venous effluent). On the basis of the available data no delineation could be made as to the relative contributions to estradiol production of tumor tissue and Leydig cells.     

Metachronous contralateral Leydig cell tumor of the testis: conservative treatment

Leydig cell tumors are the primary nongerm cell tumors of the testis, comprising approximately 1 to 3% of all testicular neoplasms. These tumors are bilateral in 5 to 10% of cases. Hypoechoic testicular nodule associated to a child virilising syndrome or adult gynecomastia with negative testis tumor markers (AFP, B-HCG) show a high index suspicion for this entity. We report a case of metachronous contralateral Leydig cell tumor in a 32 years old man with a 9 year interval between presentations, in which we performed local excision of the lesion. Diagnostic an therapeutic aspects are reviewed in literature. Since preoperative diagnosis of Leydig cell tumors in difficult and clinical course unpredictible, radical orchiectomy has been the standard treatment. Emphasis is made on conservative management opportunity in patients with only one testis, small tumors (less than 2.5 cm) with biopsies from tumor bed negative and wishes to remain fertile and/or refuses androgen supplementation. Follow-up is mandatory by performing scrotal ultrasounds. CT scan, Chest X-Ray, tumor markers and hormone determinations (testosterone, estradiol, progesterone, LH and FSH).     

Rapid development of Leydig cell tumors in a Wistar rat substrain.

In 78% of the Wistar rats (substrain U) studied, spontaneous Leydig cell tumors developed between the ages of 12 and 30 months. The first signs of tumor development, in the form of nodules of Leydig cells, were already apparent in 1-month-old U-rats. These nodules of Leydig cells were found in all animals studied. In no other strain of rats has this type of abnormality been observed at such an early age. The first Leydig cell tumors were noticed between the ages of 12 and 14 months. The tumor tissue appeared to have developed from a rapid, focal outgrowth of a nodule. The tumor Leydig cells were found to be sensitive to the cytotoxic action of the specific Leydig cell toxicant ethane dimethane sulphonate (EDS), although not all tumor cells were killed. Inhibin-like immunoreactivity could be detected in both normal and tumor Leydig cells, and plasma levels varied considerably within the different groups of rats. Moreover, no significant changes in plasma levels of inhibin-like immunoreactivity were found during the aging period when Leydig cell tumors were formed or after EDS administration when nearly all Leydig cells were killed. Therefore, the possible contribution of Leydig cells and tumor cells to the total content of inhibin-like immunoreactivity in the testis and plasma may be of less importance than expected. Some significant fluctuations in plasma testosterone concentrations were found during aging; however, there appeared to be no correlation between plasma testosterone levels and the appearance of large Leydig cell tumors. This indicates that testosterone production by tumor cells is limited.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leydig cell tumor of intra-abdominal testis

A patient with bilateral cryptorchidism and gynecomastia due to Leydig cell tumor involving the left intra-abdominal testis is described. Raised serum estrogen, low serum testosterone, and ultrasonic demonstration of a tumor in the left testis allowed the diagnosis to be suspected preoperatively. The relevant literature is reviewed.     

Carcinoma in situ of the testis in the presence of contralateral germ cell tumor

Carcinoma in situ (CIS) of the testis is considered a precursor of germ cell tumor. Diagnosis is made by biopsy, a procedure which is justifiable for patients with increased tumor risk. This group includes patients with testicular tumors who may develop contralateral second malignancies. After obtaining contralateral biopsies from 21 such patients we found one CIS. Treatment consisted of local irradiation (20 Gy) of the remaining testis. No clinical side effects were observed. In a control biopsy 6 months later, no evidence of CIS was found. Leydig cells were morphologically normal. Nine months after therapy, plasma testosterone levels were still normal, LH and FSH levels were increased. Long-term observations are needed to assess the value of radiotherapy as compared to orchiectomy.     

Endocrinology of testicular neoplasms

The hypothalamic-pituitary-testicular axis finely regulates levels of circulating sex steroids--especially testosterone and estradiol--and spermatogenesis. Testosterone, directly as an androgen and as a prehormone for estradiol, regulates LH secretion at both hypothalamic and pituitary levels. Leydig cells, principally under the control of LH, produce testosterone. Sertoli cells, under the control of FSH, and sensitive to intratesticular levels of testosterone, produce estradiol. This locally produced estrogen seems to be necessary for maturation of the germ cells. An abnormality in this sensitive control system, leading to elevations in gonadotrophins or steroid levels, may be etiologically important in both germ cell and nongerm cell neoplasia. Testicular cancers are associated frequently with endocrinologic manifestations, which may be more disabling to the patient than the malignant potential of the tumor, especially with childhood Leydig cell tumors. Estrogen dominance with an elevated estrogen/testosterone ratio can be seen in any testicular neoplasm and may result in gynecomastia. It may be due to a decrease in circulating testosterone or to an increase in estrogens. Virilization is seen frequently in Leydig cell tumors of adolescents. Further elucidation of hormonal interrelationships should lead to better understanding of the genesis of testicular neoplasia and to more effective therapy.     

Testicular tumors: wide spectrum in our short casuistics

Testicular tumors occur in 0.5 to 2 per 100,000 children. They are 1-2% of all solid tumors before puberty. The clinical history, testicular and abdominal ultrasonography, alpha-fetoprotein and human chorionic gonadotropin, estrogens and androgen levels, FSH and LH determine the diagnosis. The pathology determines the specific cell. We report seven cases, three germ cell tumors: a Yolk sac tumor in a child of 18 months and two mature teratomas in children between 2 and 11 years presenting as a painless testicular mass without other symptoms. Three tumors estrumales: one derived from Leydig cells and two of the granulosa cells, a palpable testicular mass was added precocious puberty in stage II-III of Tanner in the first, second gynecomastia in Tanner stage III and the third only with testicular mass. The seventh case, Lipoma para-testicular mass palpable. The treatment was radical orchiectomy in five cases. Testis-sparing surgery in Leydig cell tumor and resection of the paratesticular mass was performed through scrotal. The Yolk sac tumor requiring chemotherapy with good outcome. Retroperitoneal lymph node dissection is not recommended in prepubertal. Historically prepubertal testicular tumors have been treated in adults. Recent testicular preservation algorithms optimize and minimize the morbidity of adjuvant therapies. Many are benign and can be treated with preservation of the testis. Localized malignant tumors can be treated by orchiectomy.     

Early detection of a contralateral second carcinoma in patients with testicular tumors caused by testicular carcinoma in situ

Carcinoma in situ (CIS) of the testis is considered to be a precursor of germ cell cancer. Diagnosis is made by the conventional biopsy technique. Only for patients at risk is a screening biopsy justifiable. This group includes patients with testicular cancer in whom the incidence of contralateral second germ cell tumors is increased. In a prospective study we found three cases of testicular CIS in biopsies from the contralateral testes of 61 such patients. All cases with a diagnosis of CIS presented with testicular atrophy (volume less than 12 ml), associated with necrozoospermia in one patient and with azoospermia in two patients. Treatment consisted in local irradiation (20 Gy) of the remaining testis to preserve Leydig cell function. In control biopsies no evidence of CIS or germ cells was found. More than 3 months after therapy, plasma testosterone levels were normal and LH and FSH levels were increased. None of the patients with negative biopsy (n = 49) who were followed up was found to have a second cancer of the contralateral testis. The average observation time so far is 17.2 months.     

Macrophage migration inhibitory factor (MIF) as a paracrine mediator in the interaction of testicular somatic cells

Originally the macrophage migration inhibitory factor (MIF) was described as a classical T-cell cytokine. Recently, a much broader tissue distribution for MIF has been revealed. We demonstrated that MIF protein and mRNA are present in the Leydig cells of the normal adult rat testis. Addition of recombinant MIF to cultures of rat seminiferous tubules resulted in decreased secretion of inhibin, whereas follistatin and activin levels remained unchanged, suggesting a paracrine role for MIF in Sertoli cell regulation. Furthermore, MIF showed unique compensatory production in the rat testis. Depletion of the original MIF source, the Leydig cells, by the specific toxin EDS prompted MIF expression by the previously negative Sertoli cells. Leydig cell re-population of the interstitial tissue by precursor cells resulted in a switch back to production by Leydig cells. Therefore, testicular MIF appears to be under very tight paracrine control. MIF has thus been identified as a new mediator in the cross-talk between Leydig cells and the somatic cells of the seminiferous tubules of the rat testis.     

Postpubertal cryptorchism. Morphofunctional study with special reference to Leydig's cells

In a group of 17 patients of postpubertal age with unilateral (n = 15) or bilateral (n = 2) cryptorchism, a significant decrease in the tubular diameter was observed, in addition to Leydig cell hyperplasia (many with cytoplasm vacuolization and/or atrophy) in both the cryptorchid testes and in the contralateral scrotal testes. The number of testosterone-positive Leydig cells in testicular tissue sections, studied with peroxidase-antiperoxidase, was diminished in the cryptorchid testes, whereas in the contralateral scrotal testes it was similar to the control group. Together with normal testosterone levels and elevated luteinizing hormone and follicle-stimulating hormone levels in peripheral blood, this leads us to think of a compensated dysfunction of the Leydig cells. This possible lower testosterone production by the Leydig cells in the cryptorchid testis is not borne out morphologically, where the volume of the organelles is similar to the contralateral scrotal testes.     

Testicular leydig cell tumor in a child: a case report

A 7-year-old boy was admitted to the department of pediatrics in our hospital with the complaint of sexual precocity manifested by a growth spurt, penile enlargement and pubic hair development. He was referred to our department because of the enlarged left testis. The diagnosis of Leydig cell tumor of the left testis was suggested by hormonal laboratory data and testicular ultrasonographic investigation. Left orchiectomy was performed. The histological examination revealed the characteristics of Leydig cell tumor. Twenty-four cases of testicular Leydig cell tumor reported in the Japanese literature until 1988 are clinically analyzed. We discuss the usefulness of ultrasonography in detecting and localizing the tumor.     

Effects of local heating of the testes on the concentration of testosterone in jugular and testicular venous blood of rats and on testosterone production in vitro

Heating both testes of rats to between 39 degrees C and 41 degrees C for 30 min was apparently without effect 21 days later, but heating to between 41.5 degrees C and 43 degrees C for 30 min resulted in a significant drop in testis weight accompanied by significant rises in the serum levels of LH and FSH. There were no changes in serum testosterone concentration in the peripheral circulation although there were increases in the concentration in testicular venous blood. The ability of the heated testis to secrete testosterone in vivo in response to maximal stimulation by hCG was reduced, as judged by testosterone levels in peripheral blood, while there was a supranormal increase in testosterone levels in testicular venous blood. Maximally stimulated testosterone production in vitro by the heated testis was supranormal whereas the basal production of testosterone per testis was not different from control values. Therefore, it appears that the testosterone produced by Leydig cells from heated testes may not be secreted as effectively as in normal testes.     

Leydig cell tumor of testis.

In adult patients with Leydig cell tumor of the testis, endocrinologic signs occur in 30 per cent of the cases and often precede the onset of a palpable testicular mass. Gynecomastia is the most common endocrinologic manifestation and probably is due to increased estrogen secretion by the Leydig cells. In the patient with adrenogenital syndrome and testicular enlargement it is difficult to distinguish Leydig cell tumor from adrenal rest hypertrophy. Four patients with Leydig cell tumor and endocrinologic manifestations are discussed; three are adults who presented with gynecomastia and the fourth is a patient with congenital adrenogenital syndrome. In the adult patient inguinal orchiectomy is the treatment of choice, while in the patient with adrenogenital syndrome initial management by high-dose steroid suppression should be attempted prior to testicular exploration.     

In vitro secretion of deoxycorticosterone by a benign Leydig cell tumor of the testis

We evaluated the in vitro steroidogenic potential of a benign Leydig cell tumor of the testis. Tumor tissue was found to secrete deoxycorticosterone, progesterone, 17 alpha-hydroxyprogesterone, estradiol and testosterone into the medium. No corticosterone or aldosterone was detected. The ratio of progesterone to 17 alpha-hydroxyprogesterone was 4:1, consistent with a partial enzymatic block of 17 alpha-hydroxylase. The finding of deoxycorticosterone indicates the presence of 21-hydroxylase activity within the tumor. The high local levels of estrogen produced by Leydig cell tumors may induce this enzyme system and, together with the elevated concentrations of progesterone serving as substrate, may provide a favorable hormonal milieu for extra-adrenal deoxycorticosterone production by these neoplasms.     

Epidermoid cyst of the testis difficult to make a preoperative diagnosis on the echoic examination: a case report

A case of epidermoid cyst of the testis is presented. The patient was a 64-year-old man who complained of a painless mass in the left scrotum. Physical examination revealed a hen-egg sized enlargement of the left scrotal contents. The ultrasonographic appearance did not show a hyperechoic partition, which is called echogenic rim, a characteristic of this tumor on the echoic examination, and was homogeneous, almost similar to that of a normal testis. Because malignant testicular tumors could not be excluded preoperatively, excisional biopsy of the left testis was performed first. Histological diagnosis was an epidermoid cyst of the testis. As the left testis was almost completely occupied by the tumor and no normal testicular tissue was recognized, we performed orchiectomy additionally. Epidermoid cyst of the testis is a rare benign tumor that accounts for about 1 percent of all testicular tumors. It clinically resembles malignant testicular tumors, and orchiectomy is often performed for treatment. About 154 cases of testicular epidermoid cyst have been reported in the Japanese literature and are reviewed briefly here.     

Regulatory cytokine expression and interstitial fluid formation in the normal and inflamed rat testis are under leydig cell control

Leydig cells have been implicated in several inflammation-related responses of the testis. Specifically, these cells produce the proinflammatory cytokines interleukin-1 (IL-1) and IL-6, stimulate macrophage recruitment, and promote interstitial fluid formation. In addition, the immunoregulatory cytokines macrophage migration inhibitory factor (MIF), transforming growth factor-beta1 (TGFbeta1), and interferon-gamma (IFNgamma) are constitutively expressed by testicular cells, including the Leydig cells. In the present study, the contribution of the Leydig cell to testicular inflammatory responses was examined in adult male rats treated with the Leydig cell-specific toxin, ethane dimethane sulfonate (EDS). Intratesticular testosterone levels were modulated by subcutaneous testosterone implants. After 10 days, animals received an injection of lipopolysaccharide (LPS) to induce an inflammatory response, or saline alone, and were killed 3 hours later. Both depletion of Leydig cells by EDS and LPS treatment caused a decrease in collected testicular interstitial fluid to about 35% of control levels, but the effects were not additive. Maintenance of intratesticular testosterone reversed the interstitial fluid decline following EDS treatment and partially prevented the LPS-induced effect. MIF, TGFbeta1, and IFNgamma were expressed in both the normal and inflamed testis at similar levels. In contrast, EDS treatment caused a significant decline in expression of all 3 cytokines, which was prevented by the testosterone implants. These data indicate that 1) expression of TGFbeta1, MIF, and IFNgamma in the testis is not dependent on the presence of intact Leydig cells but is under direct testosterone control and 2) the decline in testicular interstitial fluid during inflammation involves the Leydig cells, acting via both androgens and nonandrogenic secretions. These data provide further support for a significant role for the Leydig cell in modulating the testicular response to inflammation.     

Testicular Function in Varicocele

Testicular testosterone concentration, serum testosterone, LH and FSH, sperm count and testicular histology were evaluated in 17 patients with varicocele. Testicular testosterone was either normal or high (mean 906 ± 723 ng/g of tissue), and serum testosterone was within the normal range in most patients. Serum LH was elevated in half of the patients. The degree of testicular damage observed was extremely variable and correlated with sperm analysis. Testicular testosterone tended to be higher in patients with severe microscopic lesions of the testis.
It is concluded that even though Leydig cell function is partially altered, this deficiency is compensated by LH stimulation and therefore, failure of spermatogenesis is not secondary to low testosterone levels.,     

Testicular function in varicocele

Testicular testosterone concentration serum testosterone, LH and FSH, sperm count and testicular histology were evaluated in 17 patients with varicocele. Testicular testosterone was either normal or high (mean 906 +/- 723 ng/g of tissue), and serum testosterone was within the normal range in most patients. Serum LH was elevated in half of the patients. The degree of testicular damage observed was extremely variable and correlated with sperm analysis. Testicular testosterone tended to be higher in patients with severe microscopic lesions of the testis. It is concluded that even though Leydig cell function is partially altered, this deficiency is compensated by LH stimulation and therefore, failure of spermatogenesis is not secondary to low testosterone levels.     

Leydig cell tumor of the testis presenting male infertility: a case report

A 33-year-old male was referred to our hospital for male infertility with painless swelling of the left scrotal content. Left high orchiectomy was performed under the diagnosis of left testicular tumor. Histologically, this testicular mass was a Leydig cell tumor. We reviewed 55 cases of Leydig cell tumor of the testis previously reported in Japan, and reported the hormonal profile in our case before and after surgery.