Testis Sparing Surgery for Benign Testicular Masses: Diagnostics and Therapeutic Approaches.

PURPOSE: Small benign testicular masses are often misinterpreted as germ cell tumors and immediate inguinal orchiectomy is performed. We analyzed the diagnostic and therapeutic workup of testicular masses to improve preoperative stratification algorithms. MATERIALS AND METHODS: We performed a retrospective, single center analysis of the records of 522 patients diagnosed with primary testicular masses of unknown malignant potential. RESULTS: A total of 28 patients (5%) showed a primary benign tumor after resection, including Leydig cell tumors in 9 (32%), epidermoid cysts in 9 (32%), adenomatoid tumors in 8 (29%) and Sertoli cell tumors in 2 (7%). The median volume of benign tumors was significantly less than that of malignant tumors (0.75 cm3, range 0.1 to 2.1 vs 15, range 4.5-39.9, p ≤0.001). At a cutoff of 2.8 cm3 tumor volume most accurately differentiated between benign and malignant disease, and it was a predictor of malignancy with 83% sensitivity and 89% specificity (OR 1.389, 95% CI 1.035-1.864, p = 0.029). Symptom duration in patients with benign tumors was significantly longer (365 days, range 25.5 to 365 vs 20, range 7 to 42, p ≤0.001). Also, tumor markers were unaltered in benign lesions. In patients with benign tumors significantly more fertility disorders or cryptorchidism were found (p ≤0.001) as well as a tendency toward lower testosterone (3.9 µg/l, range 0.9 to 4.9 vs 5.3, range 3.5 to 6.8, p = 0.084). Testis sparing surgery was performed in 22 of all patients (79%) with benign tumors. There was no case of relapse during followup. CONCLUSIONS: Nongerm cell tumors should be considered when small testicular masses have a volume of less than 2.8 cm3 and there are hormone disorders or normal tumor markers. Immediate orchiectomy should be avoided, favoring testis sparing surgery.

Anti-Müllerian hormone: a potentially useful biomarker for the diagnosis of canine Sertoli cell tumours.

BACKGROUND: Testicular tumours are common in dogs and in many cases do not give rise to clinical signs. In other cases, signs of feminization, hyperpigmentation or alopecia may be observed, most commonly associated with Sertoli cell tumours (SCT). Although these signs are often associated with elevated concentrations of oestradiol, analysis of oestradiol may give inconclusive results due to large variations among individuals. Other biomarkers are therefore needed. Anti-Müllerian hormone (AMH) is expressed by the Sertoli cell. In humans, AMH has been shown to be a specific marker of Sertoli cell origin in gonadal tumours. Using immunohistochemistry, AMH has been shown to be a useful marker of immature and neoplastic Sertoli cells in dogs. The aim of the present study was to evaluate the clinical relevance of AMH analysis in peripheral blood in the diagnostic workup of dogs with suspected testicular tumours. RESULTS: Blood was collected from 20 dogs with a palpable testicular mass and from 27 healthy controls. Serum was analysed for oestradiol-17ß using a RIA and for AMH using an ELISA. The Mann-Whitney U test was used to compare hormone concentrations between different groups. All control dogs had AMH concentrations ≤ 10 ng/mL, except one outlier that had a concentration of 43 ng/mL. Six dogs with SCT or mixed tumours containing SCT had AMH concentrations higher than 22 ng/mL, significantly higher than AMH concentrations in control dogs (P = 0.0004). Concentrations between 10 and 22 ng/mL were found in about half of the dogs with non-neoplastic testicular pathologies or with testicular tumours other than SCTs. Age did not significantly affect concentrations of AMH in the control dogs. CONCLUSION: AMH was shown to be a promising biomarker for the diagnosis of Sertoli cell tumours in dogs.

Testicular superoxide dismutase activity, heat shock protein 70 concentration and blood plasma inhibin-alpha concentration of dogs with a Sertoli cell tumor in a unilateral cryptorchid testis.

The proportions of Sertoli cell tumor (SCT), seminoma and Leydig cell tumor in 50 dogs with unilateral testicular tumors were 52%, 36% and 12%, respectively. The rate of occurrence of SCT in the cryptorchid testis was very high (71%). The testicular superoxide dismutase (SOD) activity, testicular heat shock protein (HSP) 70 concentration and peripheral blood plasma inhibin (INH)-alpha concentration of 10 dogs with a unilateral cryptorchid testis and no testicular tumors, 10 dogs with SCT in a unilateral cryptorchid testis and 10 normal dogs, all aged 5-15 years, were measured in order to identify high risk factors for the occurrence of SCT in the canine cryptorchid testis. The mean SOD activity in cryptorchid testes and SCTs was significantly lower and higher, respectively, than in normal testes (both P<0.01). The mean HSP 70 concentration in both cryptorchid testes and SCTs was significantly higher than in normal testes (both P<0.01). The mean plasma INH-alpha concentration of the cryptorchid and SCT dogs was significantly lower and higher, respectively, than in normal dogs (P<0.05 and 0.01, respectively). The low SOD activity in the cryptorchid testis, low blood plasma INH-alpha concentration of the cryptorchid dogs and high HSP 70 concentration in the SCTs may be related to the occurrence of SCT and tumor cell proliferation in canine cryptorchid testes.

Very high alpha-fetoprotein in a young man due to concomitant presentation of hepatocellular carcinoma and Sertoli cell testis tumor.

Studies reported that there is a close relationship between hepatocellular carcinoma (HCC) and testis carcinoma. Both tumors can be presented as synchronal tumors, or as testicular metastases of HCC or as hepatic metastases of testicular tumor( [7] ). HCC is one of the most common malignancies worldwide and the incidence of HCC increases with age( [8] ). The relationship between hepatitis B incidence and HCC rates is also well recognized. Alpha fetoprotein (AFP) is produced by 70% of HCC. Though a level of AFP >400 ng/mL is diagnostic for HCC, in the presence of active hepatitis B infection, the cut-off level should be considered to be at least 1 000-4 000 ng/mL. Like HCC, germ cell tumors of the testis also release AFP; but it is shown that some of Sertoli cell tumors of testis can also release AFP( [10] ). Herein we have reported about the first case of HCC in the literature which is presented concomitantly with Sertoli-Leydig tumor of testis, leading to extremely high level of AFP in a 21-year-old man.

Blood plasma concentrations of oestradiol-17beta, testosterone and testosterone/oestradiol ratio in dogs with neoplastic and degenerative testicular diseases.

Oestradiol-17beta and testosterone blood plasma concentrations were measured in dogs with Leydig-cell tumours (n=20), Sertoli-cell tumours (n=6), seminomas (n=9), unilateral inguinal cryptorchidism (n=7), abdominal cryptorchidism (n=9, one bilateral), degenerate scrotal testicles (n=6, two bilateral), and animals with normal scrotal testicles (n=20). The testosterone/oestradiol ratio (testosterone concentration [ng/mL]x100/oestradiol concentration [pg/mL]) was calculated.A considerably higher oestradiol concentration was found in dogs with Sertoli-cell tumours (29.0, 14.4-48.3 pg/mL; median, minimum-maximum; P=0.0256, Mann-Whitney test) and lower oestradiol levels were found in animals with seminomas (12.0, 3.4-17.6 pg/mL; P=0.0025) compared to the healthy control group (18.0, 8.6-31.5 pg/mL). Testosterone concentration was decreased in dogs with Sertoli-cell tumours (0.08, 0.03-0.77 ng/mL) when compared to the control group (1.95, 0.05-3.70 ng/mL; P=0.0012). Testosterone/oestradiol ratios differed from the control (9.6, 0.58-35.8) only in dogs with Sertoli-cell tumours (0.32, 0.06-2.80; P=0.0005). Clinical signs of feminization were observed in five dogs with Sertoli-cell tumour and one dog with a Leydig-cell tumour, and were more often associated with decreased testosterone/oestradiol ratios than with an increased oestradiol-17beta concentration.

Sertoli cell proliferations of the infantile testis: an intratubular form of Sertoli cell tumor?

We report on six boys with intratubular Sertoli cell proliferations (ISCPs), studied by routine histologic methods, electron microscopy, and immunohistochemistry of anti-müllerian hormone (AMH), inhibin alpha-subunit, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), proliferative cellular nuclear antigen, and p53, and carefully followed for extended periods with periodic clinical examinations, testicular ultrasonographies, and determinations of serum levels of AMH and inhibin B. Peutz-Jeghers syndrome was found in four of six patients, and gynecomastia occurred in five of six patients. One boy had isosexual pseudoprecocity. ISCPs were observed as multiple foci of seminiferous tubules with large and proliferated Sertoli cells replacing germ cells and limited by the basement membrane. Mitotic figures, atypia, and/or interstitial invasion were not observed. Bilateral ISCPs were the only pathologic finding in three patients (patient nos. 1-3) and were associated with a microscopic tumor that resembled a large-cell calcifying Sertoli cell tumor (LCCSCT) in a fourth patient (patient no. 4). In the two remaining patients (patient nos. 5 and 6) ISCPs and LCCSCT were found in both testes. Ultrastructural examination showed large Sertoli cells, with round nuclei, sparse organelles, and some glycogen. Inhibin alpha-subunit immunolocalization was positive in the five patients in whom it was determined (patient nos. 2-6), AMH was positive in those ISCPs associated with tumors (patient nos. 4-6) and negative in isolated ISCPs (patient nos. 2 and 3); 3beta-HSD and PCNA were variable, and p53 was negative in all ISCPs. Patient nos. 1-4 have been followed for 2-19 years. One of them is currently entering puberty, the other two have already completed puberty and have testes of normal size, and the remaining one is an adult with clinically normal testes and sperm production. None of these patients had evidence of tumor development during follow-up as shown by serial ultrasonographies and serum levels of AMH and inhibin B. Patient nos. 5 and 6 who had bilateral ISCPs and LCCSCT were orchidectomized and evolved for 2-10 years after surgery without tumor recurrence. The prognostic significance of ISCPs, particularly when they are the only pathologic finding in a testicular biopsy, is a matter of controversy. Based on the long normal evolution, we recommend a conservative approach to therapy. The bilateral and multicentric character of ISCPs and their association with Sertoli tumors and Peutz-Jeghers syndrome suggest that they represent either proliferative lesions with tumorigenic potential or the intraepithelial stage in the evolution of some testicular Sertoli cell tumors.

Ageing, testicular tumours and the pituitary-testis axis in dogs.

Dogs of different ages without testicular diseases were evaluated to study possible age-related changes in hormone concentrations in serum. Dogs with testicular tumours were also investigated to study the relation between tumour type and hormone concentrations; in this study, dogs with Sertoli cell tumours, Leydig cell tumours and seminomas were included. We measured testosterone, oestradiol, LH, FSH and inhibin-like immunoreactivity concentrations in peripheral venous and testicular venous blood of these animals. In normal dogs there appeared to be no age-related changes in the concentrations of the investigated hormones, except for a significant age-related decrease in oestradiol concentrations in testicular venous blood (P<0.02). Dogs with a Sertoli cell tumour had greater oestradiol concentrations and inhibin-like immunoreactivity in both peripheral and testicular venous blood than did dogs without a neoplasm (P<0. 05). Testosterone concentrations were reduced in dogs with Sertoli cell tumours, as were FSH and LH. Feminisation occurred in eight of 13 dogs with a Sertoli cell tumour and in two of 14 dogs with a Leydig cell tumour; it was accompanied by a significantly greater oestradiol concentration than in normal dogs and in dogs with Sertoli cell tumours without signs of feminisation. Dogs with a Leydig cell tumour had greater concentrations of oestradiol and inhibin-like immunoreactivity in both peripheral venous and testicular venous blood than did dogs without a neoplasm (P<0.05). The testosterone concentration in testicular venous blood of these dogs was lower than that in dogs with normal testes. The concentration of LH in peripheral venous blood was also reduced (P<0. 05). Hormone concentrations in dogs with a seminoma were not different from those in normal dogs. It was concluded that seminomas are not endocrinologically active. In contrast, both Sertoli cell tumours and Leydig cell tumours can cause increased oestrogen production leading to signs of feminisation. These tumours also have considerable amounts of inhibin-like immunoreactivity, but only in Sertoli cell tumours does this result in a reduction in FSH concentrations, suggesting that Sertoli cell tumours secrete dimeric inhibin, whereas Leydig cell tumours presumably produce loose alpha-subunits that cross-react in the inhibin assay but are not biologically active.

Androgen-producing ovarian tumors: a clinicopathological study of 3 cases.

The clinical course and pathological findings of 3 rare cases of androgen-producing ovarian tumors are presented. The ages of the 3 patients (Cases 1, 2, and 3, respectively) were 43, 34, and 57 years, respectively. Their preoperative serum testosterone levels were 506, 491, and 231 ng/dl, respectively. The pathological diagnoses of Cases 1, 2, and 3 were a Sertoli-stromal cell tumor of intermediate differentiation, a stromal tumor containing Leydig cells, and a stromal tumor with minor sex cord elements, respectively. Patient 1 experienced a recurrence, of a lesion at the vaginal stump 1 year and 2 months after the initial surgery. The clinical courses of Cases 2 and 3 have been non-contributory.

Significance of serum FSH levels and testicular morphology in infertile males.

OBJECTIVES: To determine the relationship between plasma levels of FSH and testicular spermatogenic patterns. METHODS: Testicular biopsies were obtained from 99 infertile men. Biopsies were performed either in order to distinguish the type of azoospermia (obstructive/non-obstructive) or because of severely subnormal semen variables. Serum FSH was measured by immunoassay (normal range is less than 7 mIU/ml). RESULTS: Statistically significant difference was detected between patients with Sertoli cell only syndrome and normal spermatogenesis, hypospermatogenesis and maturation arrest (p<0.01, p<0.01, p<0.05, respectively). No statistically significant differences were found between normal spermatogenesis, hypospermatogenesis and maturation arrest. CONCLUSION: Our study revealed that elevation of serum FSH correlates only with the appearance of Sertoli cell only syndrome. We think that azoospermic or severely oligoasthenoteratozoospermic patients with highly elevated plasma FSH levels (three times the normal) could be excluded from separate testicular biopsy, because these patients are not suitable for conventional treatments. If he is willing to undergo an IVF program the sperm will often be present, no matter what the testicular histology is to be used for assisted reproductive techniques, particularly ICSI.

Inhibin gene expression in a large cell calcifying Sertoli cell tumour and serum inhibin and activin levels.

Inhibin is a potential tumour suppressor gene product in the gonads. While inhibin gene products may have a role in tumourigenesis, serum inhibin levels can be used as a marker for ovarian tumours derived from granulosa cells. Tumours derived from Sertoli cells, testicular counterparts of granulosa cells, are rare. To assess whether inhibin could be used as a human Sertoli cell tumour marker, serum inhibin and activin levels and inhibin subunit mRNA expression in the testis were studied. Northern blot and in situ hybridization revealed abundant expression of inhibin alpha, beta A, and beta B subunit mRNAs in large cell calcifying Sertoli cell tumours found in a 12-year old boy with Carney complex. The tumours were multifocal and bilateral. Serum inhibin levels were clearly elevated at the time of the diagnosis, decreased by 50% after one of the testes was removed, and were low or undetectable after the second orchidectomy six weeks later. Activin was undetectable before the orchidectomies, while a low concentration of activin-A was measured after them. Follicle stimulating hormone (FSH) concentration increased from normal pubertal value to castration level as expected. Normal seminiferous tubules also showed inhibin subunit alpha and beta B mRNA expression, whereas inhibin beta A mRNA was expressed in normal Leydig cells. These data suggest that serum inhibin reflects Sertoli cell activity and can be used as a human tumour marker.

Androgen suppressive effect of GnRH agonist in ovarian hyperthecosis and virilizing tumours.

OBJECTIVE: Recent studies have suggested that androgen secretion by ovarian virilizing tumours may be gonadotrophin dependent. The aim of this study was to investigate the suppressive effect of GnRH agonist administration on androgen secretion in women with such tumours. DESIGN AND PATIENTS: A single i.m. injection of D-Trp-6-GnRH (GnRHa), 3.75 mg, was given to five unrelated patients referred for clinical symptoms of virilization with plasma testosterone (T) levels greater than 7 nmol/l but with normal dehydroepiandrosterone sulphate (DHEAS) levels. Diagnoses of adrenal tumour or a non-classical 21-hydroxylase deficiency were screened for by the dexamethasone suppression test, ACTH stimulation test and adrenal CT scanning, and were ruled out in all patients. The one premenopausal patient received cyproterone acetate in a dose of 50 mg twice daily for 3 weeks, starting 1 week before GnRHa administration. MEASUREMENT: Testosterone, androstenedione (A), DHEAS, 17-hydroxyprogesterone (OHP), LH and FSH plasma concentrations were measured by radioimmunoassay of blood samples taken before and 3 weeks after GnRHa. RESULTS: In each patient, GnRHa suppressed gonadotrophin levels and reduced T and A to the range for normal control women. With these results, and because accurate localization of an ovarian androgen secreting tumour could not be achieved by pelvic ultrasonography and CT scanning, exploratory laparotomy was undertaken. A Sertoli-Leydig cell tumour was found in the premenopausal patient, and granulosa cell tumour, hilus cell tumour and two hyperthecoses in the four post-menopausal patients. After bilateral ovariectomy and hysterectomy in the post-menopausal woman and after unilateral ovariectomy in the premenopausal women, androgen levels were normalized. CONCLUSIONS: In virilized women, the findings of increased serum testosterone with normal gonadotrophin levels and GnRHa suppression of gonadotrophins leading to normalization of testosterone levels, suggest that various ovarian androgen-secreting tumours, as well as hyperthecosis, are not autonomous but apparently depend upon continuous gonadotrophin stimulation.

[Sertoli-Leydig tumors in children. 2 case reports]. / Tumeurs de Sertoli-Leydig de l'enfant. A propos de deux observations.

Sertoli-Leydig tumors stem from the mesenchyma and sexual cords of the embryonic gonad. Two cases are reported. One manifested as symptoms of virilization in a 12 year old girl. The other patient developed adnexal torsion at the age of five years. Pelvic ultrasonography visualized the tumor in both cases. Increased production of ovarian androgens suggested the diagnosis in the first case. Histological studies disclosed intermediate differentiation in the first case and tubular differentiation in the second. These tumors usually exhibit low-grade malignancy and unilateral salpingo-oophorectomy ensures recovery in most instances.

Production of immunoreactive inhibin by a virilizing ovarian tumour (Sertoli-Leydig tumour).

A 59-year-old post-menopausal woman was admitted to the hospital with atypical vaginal bleeding and hirsute lower extremities. There was a high serum testosterone level (15.8 nmol/l) and also an appreciable serum immunoreactive inhibin level. No adrenal or ovarian lesions were detected by conventional imaging procedures. Selective blood sampling was performed during venous catheterization and showed that testosterone and inhibin levels were highest in the right ovarian vein. Laparotomy revealed a Sertoli-Leydig tumour in the right ovary, which was excised. Post-operatively, immunoreactive inhibin became undetectable while the testosterone level fell to 2.8 nmol/l. Specific radioimmunoassay showed a high immunoreactive inhibin content in the tumour. These findings indicate that Sertoli-Leydig tumours can produce both testosterone and immunoreactive inhibin, both of which would then inhibit LH and FSH release to produce the symptoms seen in this patient. Thus, assay of inhibin may aid in the differential diagnosis of virilizing tumours.

An unusual hormone pattern in a virilized woman affected by Sertoli-Leydig cell tumor. Report of a case.

A 24-year-old woman was admitted to hospital because of hirsutism, virilism and amenorrhea, which had appeared 6 months earlier. Endocrinological evaluation showed a slightly elevated serum level of testosterone (1.2 +/- 0.05 ng/ml), normal plasma levels of dehydroepiandrosteronesulfate (DHEA-S) (2,070 +/- 6 ng/ml), androstenedione (1.8 +/- 0.5 ng/ml) and sex hormone-binding globulin (SHBG)(42 +/- 3 nM/L); there was normal urinary 17-ketosteroid (17-KS) excretion (11.7 mg/24 h), low urinary estrogen (E) excretion (3 +/- 0.4 micrograms/24 h), suppressed basal gonadotropin concentrations (LH 0.9 microUI/ml; FSH 3.2 microUI/ml) and an exaggerated response to the LH-RH test. At laparotomy, a monolateral ovarian tumor was found, which was proved histologically to be a Sertoli-Leydig cell tumor. After tumor ablation, a regular menstrual cycle followed and progressive reduction of virilism was noted. This was followed within 4 months by complete normalization of LH, FSH, estrogen and progesterone serum levels. The responsiveness to LH-RH also became normalized. Two years after this operation, the patient had a normal pregnancy. This case of virilization in a woman affected by a benign Sertoli-Leydig cell tumor was primarily characterized by an unusual response of the hypothalamopituitary axis against an endocrinological background of notable alteration of the androgen/estrogen ratio, where the androgens were slightly increased and the estrogens greatly reduced.