Cryptorchidism and testicular cancer in the dog: unresolved questions and challenges in translating insights from human studies†.

Cryptorchidism, the failure of one or both testes to descend into the scrotum, and testicular cancer show a strong correlation in both dogs and humans. Yet, long-standing medical debates persist about whether the location of undescended testes directly causes testicular cancer in humans or if both conditions stem from a common origin. Although testicular cancer is a prevalent disease in dogs, even less is known about its cause and correlation with testicular descent in this species. This review investigates the relation between these two disorders in dogs, drawing insights from human studies, and examines key biomarkers identified thus far. In addition, it explores potential causal links, including the impact of temperature on maturing testicular cells and a potential shared genetic origin. Notably, this literature review reveals significant differences between men and dogs in reproductive development, histological and molecular features of testicular tumors, and the prevalence of specific tumor types, such as Sertoli cell tumors in cryptorchid dogs and germ cell tumors in humans. These disparities caution against using dogs as models for human testicular cancer research and underscore the limitations when drawing comparisons between species. The paper concludes by suggesting specific research initiatives to enhance our understanding of the complex interplay between cryptorchidism and testicular cancer in dogs.

Testicular Neoplasms With Sex Cord and Stromal Components Harbor a Recurrent Pattern of Chromosomal Gains.

A small subset of testicular sex cord-stromal tumors, designated as Sertoli-stromal cell tumors (SSCTs), comprises a mixture of Sertoli, spindle, and/or Leydig cells. The clinicopathologic features of these tumors have not been studied in any detail, and their molecular features are unknown. We, therefore, assessed the morphologic and genomic features of 14 SSCTs, including 1 tumor with features similar to the ovarian Sertoli-Leydig cell tumor (SLCT) with retiform tubules. The median age of the patients was 24 years (range, 10-55 years), and the median tumor size was 2.3 cm (range, 0.7-4.7 cm). All tumors showed Sertoli-like sex cord cells arranged in variably developed tubular structures, typically also forming nests and cords. These imperceptibly blended with a neoplastic spindle cell stroma or, in the SLCT, vacuolated to eosinophilic Leydig cells. Genomic analysis demonstrated the presence of a hotspot loss-of-function DICER1 mutation in the SLCT (patient 1) and hotspot gain-of-function CTNNB1 mutations in the tumors of patients 2 and 3, with both CTNNB1 variants being interpreted as possible subclonal events. The mutations were the only relevant findings in the tumors of patients 1 and 2, whereas the tumor of patient 3 harbored concurrent chromosomal arm-level and chromosome-level copy number gains. Among the remaining 11 tumors, all of those that had interpretable copy number data (9 tumors) harbored multiple recurrent chromosomal arm-level and chromosome-level copy number gains suggestive of a shift in ploidy without concurrent pathogenic mutations. The results of the present study suggest that CTNNB1 mutations (likely subclonal) are only rarely present in SSCTs; instead, most of them harbor genomic alterations similar to those seen in testicular sex cord-stromal tumors with pure or predominant spindle cell components. A notable exception was a testicular SLCT with morphologic features identical to the ovarian counterpart, which harbored a DICER1 mutation.

Successful Neoadjuvant Chemotherapy and Surgical Removal of a Nonmetastatic Testicular Round Cell Tumor in a Solomon Island Eclectus Parrot (Eclectus roratus solomonensis).

An intracoelomic mass was palpated on an annual exam of a 24-year-old male Solomon Island eclectus parrot (Eclectus roratus solomonensis). The initial diagnostic workup included a complete blood count, plasma biochemistry panel, and coelomic ultrasound. Computed tomography was highly suggestive of a testicular mass. Tamoxifen and the gonadotropin-releasing hormone agonists leuprolide and deslorelin were administered as neoadjunctive endocrine therapies. Biopsy and histologic examination confirmed a testicular mass consistent with a round cell tumor. Four doses of carboplatin 15 mg/kg IV were administered as neoadjunctive chemotherapy, and testicular size decreased by approximately 95%. The remaining gross tumor was removed via orchidectomy with clean but narrow margins. Seven months following surgery, a contrast CT scan did not show any evidence of recurrence of or metastasis from the original mass. This is the first report of successful treatment of a testicular tumor in a psittacine with neoadjuvant chemotherapy and orchidectomy.

Molecular Correlates of Aggressive Behavior and Biological Progression in Testicular Sertoli Cell Tumors.

Sertoli cell tumor (SCT) is the second most common type of sex cord-stromal tumor in men, and ∼10% exhibit malignant behavior. Although CTNNB1 variants have been described in SCTs, only a limited number of metastatic cases have been analyzed, and the molecular alterations associated with aggressive behavior remain largely unexplored. This study evaluated a series of nonmetastasizing and metastasizing SCTs using next-generation DNA sequencing to further characterize their genomic landscape. Twenty-two tumors from 21 patients were analyzed. Cases were divided into metastasizing SCTs and nonmetastasizing SCTs. Nonmetastasizing tumors were considered to have aggressive histopathologic features if they exhibited ≥1 of the following: size >2.4 cm, necrosis, lymphovascular invasion, ≥3 mitoses per 10 high-power fields, severe nuclear atypia, or invasive growth. Six patients had metastasizing SCTs, and the remaining 15 patients had nonmetastasizing SCTs; 5 nonmetastasizing tumors had ≥1 aggressive histopathologic feature(s). Gain-of-function CTNNB1 or inactivating APC variants were highly recurrent in nonmetastasizing SCTs (combined frequency >90%), with arm-level/chromosome-level copy number variants, loss of 1p, and CTNNB1 loss of heterozygosity occurring exclusively in CTNNB1-mutant tumors with aggressive histopathologic features or size >1.5 cm. Nonmetastasizing SCTs were almost invariably driven by WNT pathway activation. In contrast, only 50% of metastasizing SCTs harbored gain-of-function CTNNB1 variants. The remaining 50% of metastasizing SCTs were CTNNB1-wild-type and harbored alterations in the TP53, MDM2, CDKN2A/CDKN2B, and TERT pathways. These findings suggest that ∼50% of aggressive SCTs represent progression of CTNNB1-mutant benign SCTs, whereas the remaining ones are CTNNB1-wild-type neoplasms that exhibit alterations in genes of the TP53, cell cycle regulation, and telomere maintenance pathways.

Characteristic ultrasound appearance of a rare testis tumor: Bilateral multiple large-cell calcifying Sertoli cell tumor.

Characteristic ultrasound features of large cell calcifying Sertoli cell tumor (LCCSCT), including hypoechoic masses with amorphous coarse calcifications can aid in differentiating this tumor from other entities. Bilateral multiple LCCSCTs almost always show a benign course; therefore, defining the diagnosis with sonographic findings is crucial to avoid unnecessary orchiectomy.

Fertility sparing surgery in sex-cord stromal tumors: oncological and reproductive outcomes.

Sex cord stromal tumors are rare neoplasms, frequently diagnosed in young women often as early-stage disease. In patients who desire to preserve fertility, when possible, unilateral salpingo-oophorectomy with peritoneal surgical staging is a safe alternative to radical treatment. In this review, we analyze the available literature on the obstetrical outcomes after fertility-sparing surgery in a total of 255 patients with sex cord stromal tumors. We found that the spontaneous conception rate in granulosa cells tumor is encouraging (88.5%). In particular, juvenile granulosa cell tumors are associated with a more successful pregnancy rate than adult granulosa cells tumors (11/26 (42.3%) in juvenile granulosa cells tumors compared with 28.5% in adult granulosa cell tumors, respectively.) On the other hand, the results of obstetrical outcomes in Sertoli-Leydig cells tumors are less promising (7/36 (19.4%)). Unfortunately, no evidence on this topic is available for sex cord tumor with annular tubules due to the low incidence. Regarding the oncological outcomes of 900 cases of sex cord stromal tumors treated conservatively, data are reassuring with comparable outcomes between patients treated with conservative and radical surgery. Given the limited available data on this rare tumor, further studies are needed to evaluate the safety of conservative approaches and to define the obstetrical outcomes in this patient population.

Medullary bone in male budgerigars (Melopsittacus undulatus) with testicular neoplasms.

Medullary bone is a calcium-rich, labile bone normally occurring in female birds with each egg-laying cycle. The stimulus for formation of medullary bone is, in part, the cyclic increase in serum estrogens produced by preovulatory ovarian follicles. Increased bone density due to formation of medullary bone, particularly in pneumatic bones, has been termed polyostotic hyperostosis, even if physiologic. This study investigated the formation of medullary bone in nonpneumatic (femur) and pneumatic (humerus) bones in sexually mature male budgerigars submitted for autopsy. Of the 21 sexually mature male budgerigars submitted for autopsy, 7 (33%) had medullary bone in 1 or more bones examined. All 7 male budgerigars with medullary bone had a testicular neoplasm, which was morphologically consistent with a testicular sustentacular cell tumor, seminoma, or interstitial cell tumor. Medullary bone was not present in the 14 cases with other diseases. Medullary bone formation in pneumatic and nonpneumatic bones can occur in male budgerigars with testicular neoplasms. Radiographic increases in medullary bone density, particularly in the humerus, could provide antemortem indication of testicular neoplasia in male budgerigars.

Ovarian Sertoli Cell Tumor with Immature Prepubertal-like Sertoli Cell Component: A Case Report and Literature Review.

The Sertoli cell tumor of the ovary is a rare ovarian tumor with non-specific symptoms. According to the literature, endocrine manifestations occur in two-thirds of patients, but testosterone production is extremely rare. Typically, it is a unilateral benign tumor of the ovary that most commonly presents in adolescents and young women of childbearing potential. We report a 29-year-old patient, previously diagnosed to have polycystic ovarian syndrome, who presented with complaints of amenorrhea for the past three years. A transvaginal ultrasound scan revealed polycystic structure ovaries and a solid cystic formation of 32 × 31 mm size with strong blood flow in the left ovary. The laboratory tests reported an elevated testosterone level. During laparoscopic surgery, a solid, yellowish tumor was removed and the left ovary was resected. Histological examination revealed a left ovary Sertoli cell tumor with an immature prepubertal-like Sertoli cell component. Following surgery, the serum testosterone levels returned to normal and the menstrual cycle became regular. Due to the substantially low incidence of ovarian Sertoli cell tumors, information on their clinical behavior, morphologic spectrum, optimal management, and prognosis is limited. They are characterized by a wide variety of clinical manifestations, treated surgically, and, if diagnosed at an early stage, have good prognosis. We emphasize the extraordinarily rare clinical presentation of this case report.

Prepubertal gynecomastia is not always idiopathic: case series and review of the literature.

Although pubertal gynecomastia is a common clinical presentation of adolescent males, prepubertal gynecomastia is uncommon and mostly idiopathic. However, pathological causes of prepubescent gynecomastia are encountered in clinical practice. This manuscript carries an important message to general pediatricians, to care about exclusion of pathological causes for every patient of prepubertal gynecomastia. We present four different patients with pathological gynecomastia. One of them revealed to be secondary to Sertoli cell tumor, while the second patient describes trauma as a rare cause of prepubertal true gynecomastia. To the best of our knowledge, this is the first time to report occupational trauma as a cause of true gynecomastia as confirmed by pathological specimen, in a prepubertal boy. The third patient presented with retro-areolar mass and bloody nipple discharge secondary to mammary duct ectasia and had favorable self-limited course. Hyperprolactinemia secondary to neglected congenital hypothyroidism was the cause beyond gynecomastia in the fourth patient and this cause has been reported only once in the literature.Conclusion: Despite being rare, pathological causes of prepubertal gynecomastia are encountered in clinical practice, and full investigations including breast and testicular ultrasound are needed to exclude any pathology before diagnosing idiopathic gynecomastia. Repeated friction of the breast can lead to true gynecomastia not only to pseudogynecomastia as previously known. What is Known: • It has been reported that trauma can cause pseudogynecomastia due to hematoma or fat necrosis. • Prepubertal gynecomastia is mostly idiopathic. What is New: • Long-term breast trauma can cause true gynecomastia (adenosis). • Although being mostly idiopathic, pathological causes of prepubertal gynecomastia must be ruled out.

Sertoli Cell Tumors of the Testes: Systematic Literature Review and Meta-Analysis of Outcomes in 435 Patients.

BACKGROUND: Sertoli cell tumors (SCTs) of the testes are rare, and the literature provides only weak evidence concerning their clinical course and management. The objective of this study was to summarize evidence on SCTs' clinical presentation, clinicopathological risk factors for malignancy, treatment options, and oncological outcomes. MATERIALS AND METHODS: Data sources included Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and Web of Science. Published case reports, case series, and cohorts were included. Data on clinicopathological variables, treatment of local or metastatic disease, site of metastasis, or survival were extracted from each study considered in this paper, and associations between clinicopathological variables and metastatic disease were analyzed. Whenever feasible, data on individual patients were collected. RESULTS: Of the 435 patients included, only one (<1%) showed local recurrence after testis-sparing surgery (TSS). Three patients underwent adjuvant retroperitoneal lymphadenectomy. Fifty patients presented with metastases, located in the retroperitoneal lymph nodes (76%), lungs (36%), and bones (16%); median time to recurrence was 12 months. Risk factors for metastatic disease included age, tumor size, necrosis, tumor extension to the spermatic cord, angiolymphatic invasion, and mitotic index. Patients with metastases had a median life expectancy of 20 months. In six patients, metastasectomy resulted in complete remission. CONCLUSION: Our findings suggest that few local recurrences result after TSS, and no adjuvant therapy can be regarded as a standard of care. Several risk factors are predictive of metastatic disease. Surgery leads to remission in metastatic disease, whereas systemic treatment alone does not result in long-term remission. IMPLICATIONS FOR PRACTICE: Testicular Sertoli cell tumors usually present without metastatic disease and show low local recurrence rates after testis-sparing surgery; no adjuvant therapy option can be regarded as a standard of care. Patients with risk factors should undergo staging investigations. Those with metastatic disease have poor prognoses, and metastasectomy may be offered in selected cases.

Metastatic testicular Sertoli cell tumor in a free-ranging cryptorchid adult spotted seal Phoca largha in North Slope, Alaska, USA.

This case describes a metastatic Sertoli cell tumor (SCT) with lymphatic spread to the abdominal and thoracic lymph nodes, pancreas, and adrenal gland in an adult spotted seal Phoca largha. The neoplasm was composed of tubules lined by palisading neoplastic cells separated by a variably dense fibrous stroma. This pinniped was 1 of 2 cryptorchid seals and the sole case of genital neoplasia among 70 ice seals necropsied by the North Slope Borough from 2012 to 2017. Overall, SCTs are rarely reported in marine mammals.

Case Report of Misleading Features of a Rare Sertoli Cell Testicular Tumor.

Testicular Sertoli cell tumors are extremely rare. Generally, they are benign neoplasms, which belong to a group called sex cord-stromal tumors. In this article, we present a case report of a Sertoli cell tumor, which was accidentally discovered during a urological consultation of a 42-year-old male. An ultrasound showed a 2.1 x 2.2 cm hypoechogenic, hypervascular tumor in the middle third of the left testicle. Serum tumor markers (α-fetoprotein, alkaline phosphatase, ß-human chorionic gonadotropin, and lactic dehydrogenase) were all within the normal range. Rapid microscopic evaluation of fresh frozen sections during the operation was inconclusive, which led to a decision not to perform a radical orchiectomy immediately. On formalin-fixed paraffin-embedded (FFPE) sections, the tumor histology showed atypical patterns, and immunohistochemical analysis was performed in order to determine the type of neoplasm and differentiate it from other types of testicular tumors, so as to assign the further course of treatment. Radical inguinal orchiectomy was performed. The final pathology report showed a tumor with no predictive signs of aggressive behavior, which most closely resembled a Sertoli cell tumor.

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.

Patterns of Care and Survival Outcomes for Malignant Sex Cord Stromal Testicular Cancer: Results from the National Cancer Data Base.

PURPOSE: Sex cord stromal tumors of the testis comprise less than 5% of testicular neoplasms. Consequently, data regarding patterns of care and survival are sparse. Using a large national database, we sought to provide a more definitive analysis of outcomes and management of these malignancies. MATERIALS AND METHODS: Data were obtained from the National Cancer Data Base. Patients diagnosed from 1998 to 2011 with 2 of the most frequent sex cord stromal tumors of the testis, including Leydig and Sertoli cell tumors, were selected for study. Overall survival estimates were assessed by the Kaplan-Meier method. RESULTS: Of the 79,120 cases of testicular cancer between 1998 and 2011, 315 (0.39%) were primary malignant Leydig or Sertoli cell tumors. Median patient age was 43 years for both tumors. Of the 315 patients 250 (79%) had malignant Leydig cell tumors and 65 (21%) had malignant Sertoli cell tumors, of which 94% and 78%, respectively, were stage I. Overall survival at 1 and 5 years for stage I Leydig cell tumors was 98% (95% CI 96-100) and 91% (95% CI 85-96), and for stage I Sertoli cell tumors overall survival was 93% (95% CI 83-100) and 77% (95% CI 62-95), respectively (p = 0.015). Of patients with stage I Leydig and Sertoli cell tumors 94% and 84%, respectively, received no further treatment following orchiectomy. CONCLUSIONS: Five-year survival estimates of stage I Leydig and Sertoli cell tumors are significantly lower compared to those of stage I germ cell tumors with Sertoli cell tumors significantly worse than Leydig cell tumors. These differences in the survival of sex cord stromal tumors indicate the importance of large databases to evaluate the efficacy of treatment for rare neoplasms.

[Leydig cell, Sertoli cell and adult granulosa cell tumors]. / Leydig-Zell-, Sertoli-Zell- und adulte Granulosazelltumoren.

According to the World Health Organization (WHO) classification Leydig cell tumors, Sertoli cell tumors and granulosa cell tumors of the testes belong to the group of sex cord-stromal tumors. These tumors most frequently occur sporadically but in rare cases can be associated with syndromes. These tumor entities show characteristic morphological changes, which in combination with specific immunohistochemical markers facilitate the diagnosis. Recent results of molecular pathological investigations, especially beta-catenin mutation analysis, allow a better categorization of these tumor entities.

Biological Functions and Clinical Applications of Anti-Müllerian Hormone in Stallions and Mares.

Anti-Müllerian hormone (AMH) plays a major role in sexual differentiation, Leydig cell differentiation, and folliculogenesis. In addition, AMH has clinical value in equine practice. In stallions, AMH can serve as an endocrine marker for equine cryptorchidism and as an immunohistochemical marker for Sertoli cell tumors. Considering that AMH is also an ovarian specific product, intact mares can be differentiated from ovariectomized mares. Peripheral AMH concentrations reflect the follicular population in mares, and therefore, are useful in the assessment of ovarian reserve and reproductive life-span of aged mares. Last, AMH is particularly suitable as a diagnostic marker for equine granulosa cell tumors.

A CASE OF AN AROMATASE-PRODUCING SERTOLI CELL TUMOR PRESENTING WITH GYNECOMASTIA.

A 64-year-old man had complained of a left scrotal mass and gynecomastia since June 2012. A left testicular tumor was suspected and the patient was referred to our department in December 2013. He presented with bilateral gynecomastia and a painless left scrotal mass that was firm, smooth surfaced, and the size of large hen's egg. Levels of markers of testicular germ cell tumors were all within normal range. Endocrinological examination revealed a marked elevation in serum estradiol (E2) level. The patient underwent high inguinal orchiectomy in December 2013.The pathological diagnosis was a Sertoli cell tumor of the left testis. Immunohistochemistry revealed the expression of aromatase synthesis; we speculated that this E2 production by the tumor caused the gynecomastia.Serum E2 level normalized after the orchiectomy. Owing to the diagnosis of malignancy, retroperitoneal lymph node dissection was performed in January 2014. No lymph node metastasis was found in the specimen. The gynecomastia improved gradually, and the patient has been free of disease since the surgery.