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.

[Malignant Leydig Cell Tumor of the Testis : A Case Report].

A 69-year-old Japanese man was referred to our hospital for a left inguinal testicular tumor and paraaortic lymph node swelling and pleural dissemination. A left orchiectomy was performed in October 2013. Histologically, this testicular tumor was a malignant Leydig cell tumor. The antineoplastic agent mitotan was administered after the orchiectomy. Two months later, although his plasma level of testosterone had de-escalated, the para-aortic lymph node did not decrease in size. A retroperitoneal lymph node dissection was performed in January 2014. Unfortunately, three days after the surgery, the patient died due to disseminated intravascular coagulation and gastrointestinal hemorrhage of unknown cause.

Metastasized Leydig cell tumor in a dog.

We present the clinical findings, diagnosis and treatment of an 11-year old intact male Fox Terrier with a malignant Leydig cell tumor of the right testicle, which metastasized to the skeletal musculature of the left hind limb. The primary tumor and the metastasis were resected with narrow margins. The dog was treated with metronomic chemotherapy using thalidomid and dyclophosphamide. Local recurrence at the site of the metastasis and a pulmonary metastasis were present 30 months after surgery. The dog was euthanized.

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.

[Diagnosis and treatment of Leydig cell tumors]. / Diagnose und Therapie des Leydig-Zell-Tumors.

BACKGROUND: Tumors of the testes not originating from germinal epithelium are a rare entity and represent a diagnostic and therapeutic challenge. Leydig cell tumors (LCT) are rare stromal tumors of the testis. OBJECTIVES: To present current approaches in diagnostic and treatment of LCT. METHODS: A literature search in PubMed was performed and the currently available guidelines concerning LCT were evaluated. Articles and book chapters were selected based on relevance to daily practice. RESULTS: The low incidence of Leydig cell tumors not originating from the germinal epithelium, but from the stroma of the testis requires a standardized approach to determine relevant differential diagnosis and to optimize diagnosis and treatment depending on the current standard of knowledge and to determine whether it is benign or malignant. While more than 90% of LCT are benign and treatment is only restricted to the testis, malignant subtypes require radical surgical resection of the testicular and metastatic sites. CONCLUSION: A standardized diagnostic and therapeutic approach as well as a prospective registry of rare LCT could facilitate further detailed analysis to improve the understanding of tumor biology resulting in optimized therapeutic guidelines including follow-up strategies.

Evaluation of cytotoxic T lymphocyte-mediated anticancer response against tumor interstitium-simulating physical barriers.

Tumor antigen-specific cytotoxic T lymphocyte (CTL) is a promising agent for cancer therapy. Most solid tumors are characterized by increased interstitial fluid pressure (IFP) and dense collagen capsule, which form physical barriers to impede cancer treatment. However, it remains unclear how CTL-mediated anticancer response is affected at the presence of these obstacles. Using a microfluidic-based platform mimicking these obstacles, we investigated the migration characteristics and performance of anticancer response of CTLs targeting hepatic cancer cells via antigen-specific and allogeneic recognition. The device consisted of slit channels mimicking the narrow interstitial paths constrained by the fibrous capsule and increased IFP was simulated by applying hydrostatic pressure to the tumor center. We found that antigen-specificity of CTLs against the targeted cancer cells determined the cytotoxic efficacy of the CTLs but did not significantly affect the success rate in CTLs that attempted to infiltrate into the tumor center. When increased IFP was present in the tumor center, CTL recruitment to tumor peripheries was promoted but success of infiltration was hindered. Our results highlight the importance of incorporating the physical characteristics of tumor interstitum into the development of CTL-based cancer immunotherapy.

Testicular tumors of adrenogenital syndrome: From physiopathology to therapy.

Testicular tumor of adrenogenital syndrome is a rare and benign anomaly usually presenting as bilateral testicular masses. It is the most important cause of infertility in adult male congenital adrenal hyperplasia. Distinction between testicular tumors of adrenogenital syndrome and Leydig cell tumors can be problematic; it is based on clinical, histopathologic, immunohistochemical and endocrine features. Biopsy is advised in cases of longstanding tumors in infertile patients and when surgery is indicated. Fertility preservation is a key management goal in testicular tumor of adrenogenital syndrome. In stages 2 and 3, intensified glucocorticoid treatment is recommended as a first step treatment. Sparing surgical approach is preferred for tumors of stage 4 and steroid unresponsive masses. Magnetic resonance imaging is recommended before surgery. The only indication of surgery in stage 5 is testicular pain.

A novel targeted therapy of Leydig and granulosa cell tumors through the luteinizing hormone receptor using a hecate-chorionic gonadotropin beta conjugate in transgenic mice.

We investigated the antitumoral efficacy, endocrine consequences, and molecular mechanisms underlying cell death induced by the Hecate-chorionic gonadotropin (CG)beta conjugate, a fusion protein of a 23-amino acid lytic peptide Hecate with a 15-amino acid (81-95) fragment of the human CGbeta chain. Transgenic (TG) mice expressing the inhibin alpha-subunit promoter (inhalpha)/Simian Virus 40 T-antigen (Tag) transgene, developing luteinizing hormone (LH) receptor (R) expressing Leydig and granulosa cell tumors, and wild-type control littermates were treated either with vehicle, Hecate, or Hecate-CGbeta conjugate for 3 weeks. Hecate-CGbeta conjugate treatment reduced the testicular and ovarian tumor burden (P < .05), whereas a concomitant increase (testis; P < .05) or no change (ovary) in tumor volumes occured with Hectate treatment. A drop in serum progesterone, produced by the tumors, and an increase in LH levels occured in Hecate-CGbeta treated mice, in comparison with vehicle and Hecate groups, providing further support for the positive treatment response. Hecate-CGbeta conjugate induced a rapid and cell-specific membrane permeabilization of LHR-expressing cells in vitro, suggesting a necrotic mode of cell death without activation of apoptosis. These results prove the principle that the Hecate-CGbeta conjugate provides a novel specific lead into gonadal somatic cell cancer therapy by targeted destruction of LHR-expressing tumor cells.

Sertoli-Leydig tumors of the ovary. A clinicopathologic study of 64 intermediate and poorly differentiated neoplasms.

The clinical and pathologic features of 64 Sertoli-Leydig tumors of the ovary with intermediate and poor differentiation were studied. The neoplasms occurred mainly in young women. Fifty-four percent of the patients presented with clinical evidence of a hormonally active tumor, and 38% were virilized. The remaining 46% had nonspecific symptoms. Sixty-two patients had tumors confined to one ovary at operation (Stage Ia), while only two patients presented with pelvic metastases (Stage III). The prognosis was generally favorable; the 5- and 10-year actuarial survival rates were 92%. Unilateral salpingo-oophorectomy was effective treatment for Stage Ia Sertoli-Leydig tumors in young women. Microscopically, 44 of the neoplasms were of intermediate differentiation and 20 were poorly differentiated. Heterologous elements (mucinous epithelium, striated muscle, cartilage) were present in 16 neoplasms. The pathologic features that correspond with development of metastases were poor differentiation, the presence of heterologous mesenchymal elements, frequent mitotic figures in stromal cells, and rupture of the neoplasm.

Ovarian Sertoli-Leydig cell tumors. A clinicopathological analysis of 207 cases.

The clinical and pathological features of 207 ovarian Sertoli-Leydig cell tumors from our consultation and hospital files were reviewed. The patients ranged in age from 2 to 75 (average 25) years. Seventy-five percent of them were 30 years of age or younger and less than 10% were over 50 years of age. One-third of the patients presented because of unequivocal evidence of androgen excess, and an additional 10% had a history suggesting androgen excess; most of the remaining patients complained of abdominal swelling or pain. At operation, 97.5% of the tumors were Stage I, 1.5% were Stage II, and 1% were Stage III. Both ovaries were involved in 1.5% of the cases. The tumors ranged from microscopic to 51 cm in diameter (average 13.5 cm); 15% of them were ruptured. Thirty-eight percent of the tumors were solid, 58% were solid and cystic, and 4% were cystic. The solid tissue was typically lobulated and yellow. On microscopic examination, 11% of the tumors were well differentiated, 54% were of intermediate differentiation, 13% were poorly differentiated, and 22% contained heterologous elements according to the criteria of the World Health Organization; a prominent retiform pattern was present in 15% of them. Follow-up was obtained for 164 patients. The tumor was clinically malignant in 18% of them. The prognosis correlated most meaningfully with the stage and degree of differentiation of the tumor. The high-stage tumors were all clinically malignant. All the well-differentiated tumors were benign, but 11% of those of intermediate differentiation, 59% of the poorly differentiated tumors, and 19% of those with heterologous elements were malignant. In a few cases radiation therapy, chemotherapy, or a combination of the two, in addition to surgical excision, was of benefit in the management of the malignant tumors.

[Malignant interstitial cell tumor of testis with a marker enzyme (author's transl)]. / Metastasierender Leydig-Zell-Tumor des Hodens mit einem Markerenzym.

Metastatic interstitial cell tumor of the testis is one of the rarest human neoplasms. This is the nineteenth case to be reported. While most of these tumors are combined with hormonal dysfunction, the present tumor, apart from its uncommon hormonal profile, is remarkable because of its capacity of producing and secreting a marker enzyme, alkaline phosphatase. No response was seen after cytostatic therapy with new antineoplastic agents, such as a combination of adriamycin and cis-diamminedichloride-platinum (II), and ifosfamide. Considering the lack of radiosensitivity, surgery is the primary modality of treatment.

Interstitial cell tumor of testis: a delicate problem.

Interstitial cell tumor of the testis is a rare tumor in humans. There have been 39 cases reported in children and 13 malignant tumors in adults. Two cases of interstitial cell tumor in childhood, 5 benign types in adults, and 2 malignant tumors are presented herein. In regard to the therapeutic consequences, a plea is made to define the malignant potential of the tumor on histologic criteria alone.

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.

Sperm antibodies and infertility in patients with testicular cancer.

The level of antisperm antibodies using the enzyme-linked immunosorbent assay (ELISA) in the serum of 48 patients with testicular cancer before and after therapy is reviewed. This is not a linear study of each patient, but some conclusions can be drawn: In a high percentage of testicular cancer patients serum antisperm antibodies can be detected: 73.3 per cent before orchiectomy and 43.7 per cent overall. The percentage of patients with antibodies decreases with adequate therapy. In patients with advanced disease there is a higher percentage of positivity (50%) for serum antisperm antibodies than in patients with low-stage disease (30%). The higher percentage of antibodies-positive patients among those with infertility patterns could be an important argument that supports the hypothesis that autoimmune pathology can play a role in oligo/azoospermia in testicular cancer patients.

Leydig cell tumors and tumors associated with congenital adrenal hyperplasia.

Testicular cancers occur at a rate of 2 cases per 100,000 males. Gonadal stromal tumors, including Leydig cell tumors and tumors of the adrenogenital syndrome, account for 1% to 3% of these neoplasms. Despite their rarity, these hormone-producing tumors are particularly interesting because of their potential for causing endocrinologic manifestations in prepubertal and adult males. They are also clinically significant, and early identification is critical to avoid profound and often irreversible developmental changes in affected children. An accurate diagnosis is important to differentiate tumors that will respond to medical management from tumors that require definitive surgical therapy.

Testicular tumors in infants and children.

Forty three children with testicular tumors have been presented. Eighty per cent of these tumors were malignant, and 60 per cent occurred in children less than two and one half years of age. Twenty of the 24 malignant germinal tumors were embryonal cell carcinomas. The mean age of the patients at presentation of these tumors was 18 months. Nine patients underwent orchiectomy alone, and five of these have died. Eleven received combined therapy, and all have survived. We currently recommend radical orchiectomy and extended unilateral retroperitoneal lymphadenectomy. If examination of the nodes reveals evidence of metastases, a bilateral dissection is done. Radiotherapy is given only in the presence of nodal metastases. Adjuvant chemotherapy with vincristine, actinomycin D, and Cytoxan is given for two years to all patients with malginant nonseminomatous germ cell tumors or sarcomas.

The influence of photodynamic reaction on R2C cells.

Photodynamic therapy (PDT) represents a therapeutic approach in which photosensitised neoplastic cells undergo destruction under effect of light. In this study we have attempted to define effects of photochemotherapy on R2C cells, sensitised with protoporphyrin IX (PpIX) and to find out whether inhibition of gene expression by cycloheximide affects development of lesions in the cells. The photosensitised cells were exposed to visible light and development of apoptotic and necrotic lesions was followed in the cells, using the fluorescent staining with propidium iodide and Hoechst 33342. The experiments demonstrated that PpIX and light, acting in parallel, induce development of apoptotic and necrotic lesions in R2C cells. Intensity of the lesions correlated with concentration of the applied photosensitiser and with duration of light exposure. Using cycloheximide, we also inhibited protein expression in cells photosensitised with protoporphyrin before they were exposed to light. In the latter case, development of apoptosis was clearly intensified which might be explained by inhibition of anti-apoptotic protein synthesis in the cells.

Leydig cell tumor of the testis. New cases and review of the current literature.

Leydig cell tumors are the most frequent non-germ cell tumors of the testis, accounting for 1-3% of all testicular tumors. They present most commonly as a testicular mass or with endocrine symptoms. We report three new cases of Leydig cell tumors that presented in different forms. The relevant literature is reviewed and the management of these tumors is discussed.

Malignant Leydig cell tumour of the testis: a case report and review of the literature.

A rare case of malignant Leydig cell tumour of the testis is presented. There was no standard therapy regimen. Leydig cell carcinoma is relatively refractory to radiotherapy and chemotherapy. So a retroperitoneal node dissection should be performed before or after chemotherapy for staging and also for therapeutic reasons.