ABSTRACT

Testicular cancer comprises different neoplasms, depending on the cell of origin and the typical age at presentation, but germ cell-derived tumors constitute the vast majority of cases. Testicular germ cell tumors (TGCT) can be diagnosed in every age group, but more than 90% of cases occur in young men. These tumors, comprising seminoma and nonseminoma, are derived from germ cell neoplasia in situ (GCNIS). Pathogenesis of TGCT associated with GCNIS partly overlaps with that of other developmental disorders of the male reproductive system within the testicular dysgenesis syndrome (TDS). Testicular somatic cell neoplasms, known as sex cord-stromal tumors, are relatively rare, but can have endocrine manifestations, such as precocious puberty or gynecomastia. In addition to its malignant features, cancer of the testis represents a developmental, endocrine, and reproductive problem. These issues are the focus of this chapter, and emphasis is given to aspects that are of interest to endocrinologists, including pediatric endocrinologists and andrologists. Management of invasive testicular tumors is largely handled by urologists and oncologists, thus only general information on surgical treatment, radiotherapy, and chemotherapy is presented. Impact of cancer treatment on the endocrine system, co-morbidities, fertility issues, and quality of life issues are also briefly reviewed. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Testicular cancer comprises a number of different neoplasms, depending on the cell of origin and the typical age at presentation (1, 2). Although several cell types in the testis can undergo neoplastic transformation, germ cell-derived tumors constitute the vast majority of cases of testicular neoplasms. The relative distribution depends on age: in young adult men nearly all tumors are germ cell tumors, whereas in patients aged 70 years or older, a large proportion of lymphomas and secondary carcinomas can be expected (2). In other words, as explained in detail further in the text, germ cell cancer can be diagnosed in every age group, but more than 90% of cases occur in young men, and this subgroup is the main focus of this chapter. Pathogenesis of testicular germ cell tumors (TGCT) of young adults partly overlaps with that of other developmental disorders of the male reproductive system, within the testicular dysgenesis syndrome (TDS) (3, 4, 5). Somatic cell tumors in the testis, known as sex cord-stromal neoplasms are relatively rare, but are also discussed in this chapter. These neoplasms can have endocrine manifestations due to their origin from endocrine cells.

In addition to its malignant features, cancer of the testis represents a developmental, endocrine, and reproductive problem. These issues are the focus of this chapter, and emphasis is given to aspects that are of interest to endocrinologists, including pediatric endocrinologists and andrologists. The contribution of andrologists and endocrinologists to the overall management of patients with testicular cancer is very important, especially concerning early diagnosis, fertility issues, testosterone deficiency, and the impact of treatment on the quality of life of the patients, the majority of whom are young adults. We have to emphasize that only very general information on surgical and oncological treatment options (e.g., chemotherapy) is presented here. However, urologists and oncologists, who are responsible for the clinical management of testicular tumors, would also benefit from learning about the pathogenesis and andrological aspects of testicular cancer summarized in this chapter.

GERM CELL TUMORS (GCT)

Germ cell tumors (GCT) are characterized by extreme phenotypic heterogeneity (2). They display features of pluripotency and about half of them (nonseminomas) can differentiate into virtually any somatic tissue type within the so-called teratomas that recapitulate early embryonic differentiation (6, 7, 8). Although in comparison to other solid tissue cancers, GCTs are relatively rare, they constitute the most common form of solid tissue cancer of young age. The typical localization of GCT is the testis in males and ovary in females, but GCTs may also be found outside the gonads, thus these tumors are named extragonadal GCTs (8, 9). Extragonadal GCTs occur most often in children of both genders, preferentially along the body midline (intracranial, pineal, mediastinal) but can occur also in adults (8, 9). An increased frequency of extragonadal GCTs, especially in mediastinum, has been associated with Klinefelter syndrome (10). It is important to remember that a large proportion of cases of extragonadal GCT in retroperitoneal locations are associated with pre-malignant changes in testicles, and can be assumed early metastases of testicular neoplasms, although a multi-site development of GCT cannot be completely excluded (8, 9, 11, 12). This chapter focuses on the testicular GCT. For the extragonadal GCT in children and adults, the reader should consult specialized literature.

Precursor Lesions

The TGCT of young adults originate from a common precursor, germ cell neoplasia in situ (GCNIS), initially termed carcinoma in situ (CIS) testis (13, 15). GCNIS is considered to originate from developmentally arrested immature germ cells (gonocytes) that fail to differentiate to spermatogonia (4, 16, 17). Accordingly, morphology of GCNIS cells resembles closely that of fetal gonocytes, but with more irregular chromatin in the nuclei. GCNIS cells are located inside seminiferous tubules, most frequently in a single row along the basement membrane (Figure 1).

Gonadoblastoma is a preinvasive lesion which occurs almost exclusively in individuals with disorders of sexual development (DSD). This lesion is most often found in female patients with mixed gonadal dysgenesis (45,X/46,XY) or Turner Syndrome but can also occur in males (2, 18, 19). Gonadoblastoma cells and GCNIS cells have a very similar gonocyte/oogonium-like phenotype, but the surrounding somatic cells are different; GCNIS cells are present inside seminiferous tubules, which are usually well developed but may be hypoplastic and contain immature Sertoli cells, while gonadoblastoma consists of groups of germ cells, which are nested in small stromal cells similar to granulosa cells (19, 20, 21, 22). GCNIS and gonadoblastoma can be present in the same gonad and there are also lesions with morphology in between the two entities (18, 19). The clinical course of pure gonadoblastoma may be benign, but it has a potential to transform into a malignant germ cell tumor, especially if accompanied by GCNIS and greater virilization of the patient (19, 22, 23, 24).

Figure 1.

Histology of germ cell neoplasia in situ (GCNIS). The upper panel (hematoxyllin-eosin, HE staining shows a low magnification view of GCNIS in a typical pattern with only GCNIS cells and Sertoli cells present inside tubules. The tubules with neoplasia have a smaller diameter than normal seminiferous tubules. On the right side of this image a few tubules with decreased spermatogenesis are visible. The lower left image shows a fragment of a tubule with GCNIS side-by-side with a tubule with preserved spermatogenesis; note the large GCNIS nuclei. The lower right image displays GCNIS cells visualized by immunohistochemical staining for placental-like alkaline phosphatase (PLAP).

The immunohistochemical profiles of GCNIS and gonadoblastoma cells are virtually identical and resemble very closely those of primordial germ cells and fetal gonocytes (21, 25, 26). This was subsequently confirmed by comparative studies at the transcriptional level using microarrays (17, 27, 28). Among many genes highly expressed in GCNIS cells (as well as gonadoblastoma, normal fetal germ cells and several TGCTs) the following should be mentioned because of their interesting biological function (germ cell survival or maintenance of embryonic stem cell pluripotency) and usefulness in histopathological diagnosis (24): OCT4 (29), AP2-gamma/TFAP2C (27, 30), NANOG (27, 31, 32), KIT (25, 33), TP53 (34), and LIN28 (35, 36).

In addition to protein-coding genes, GCNIS cells display a specific profile of embryonic-type micro-RNAs (miRNA); miR-371-3 cluster, miR-302 and miR-367 (37, 38). This miRNA profile is also detectable in overt TGCT, except teratoma (38), see the description in the section on serum markers.

Testicular Germ Cell Tumors (TGCT) Derived From GCNIS

As mentioned in the introduction, TGCT of young adult men display very variable histology (some examples are shown in Figure 2) and are divided into seminomas (under the main GCT category of germinomas which occur in men and women) and nonseminomas (non-germinomas) (2, 14, 39).

Figure 2.

Histology of main types of testicular germ cell tumors. The large images show a general histology pattern of a seminoma (upper panel) and two most often seen types of nonseminoma: undifferentiated embryonal carcinoma (middle panel) and teratoma, a tumor displaying differentiation into various somatic tissues (bottom panel). Small square pictures on the right show cellular characteristics in a greater magnification. All sections are stained with hematoxylin-eosin (HE).

Seminomas are most often diagnosed in the 25- to 40-year-old age group, whereas nonseminomatous tumors occur in even younger men (adolescence to 30 years). Both types originate from GCNIS (2, 16). Seminoma resembles a mass of immature germ cells; the tumor cells are morphologically very close to GCNIS cells and proliferate as a homogeneous tumor, which retains features of germinal lineage. The gene expression profile of seminoma is similar to that of GCNIS and fetal gonocytes, and virtually identical to the female equivalent of germinoma, called dysgerminoma (26, 39).

Nonseminomatous tumors display a variety of histological forms and contain undifferentiated embryonal carcinoma and somatic components partly differentiated along embryonic lineage of any tissue type (1, 2, 8). Nonseminomas also contain extra-embryonic tissue components (yolk sac tumor and choriocarcinoma). The combined or mixed tumors contain elements of seminoma and nonseminoma but are classified and clinically treated as nonseminoma, which usually has more severe clinical course than seminoma (1, 2).

Etiology and Pathogenesis of Testicular Germ Cell Cancer of Young Adults (Derived From GCNIS)

INCIDENCE TRENDS AND RISK FACTORS

Epidemiology of testicular germ cell tumors (TGCT) has attracted the growing attention of researchers, because of the steadily rising incidence (51). The incidence is remarkably variable geographically and dependent on the ethnic background (Figure 3) (52). TGCT is currently the most common malignancy of young men of white European ancestry, while it is relatively rare among Asians and Africans (52, 53, 54). Interestingly, indigenous Maoris of New Zealand have a higher incidence of testicular cancer than the white population (55).

Figure 3.

Global incidence rates of testicular cancer. Age-standardized incidence rates for testicular cancer for men of all ages in selected countries of all regions of the world, extracted from national registries. National reporting systems varied by country, and data quality may have fluctuated between regions. Reprinted from Znaor et al., Eur Urol 2014 (52).

However, the incidence rates are not stable and have been changing over time. Within populations rapid changes have been observed in recent decades. For example, the highest rates of testicular cancer have historically been observed in Norway and Denmark but much lower in the Eastern and Southern Europe. While the incidence in Denmark has been attenuating since the 1970s, an alarming rise has been noted in Finland and in Slavic Balkan countries, especially Slovenia and Croatia (52, 53, 54, 56). Similarly, a rapid increase has been noted among the Hispanic/Latin population in the United States (57). Another interesting feature of epidemiology of testicular cancer is the so-called birth cohort effect; the rise in the incidence correlated with the calendar year of birth rather than with the age at diagnosis (58). For unexplained reasons, cohorts born at wartime had lower incidence than men born just before or after the war (58).

As mentioned before, testicular cancer has an unusual age-specific incidence rate with a small peak in the postnatal period and a major peak in young adult age, starting at puberty. These periods coincide with an activation of gonadal hormones, indicating there may be a possible connection between the hormonal factors and invasive transformation of germ cells. In certain risk groups, the incidence of testicular cancer is much increased. Individuals with developmental abnormalities of the gonads and sex differentiation (DSD) are at high risk of developing germ cell neoplasia. Among these, individuals with the so-called mixed gonadal dysgenesis and the 45,X/46,XY karyotype are at particular risk of harboring GCNIS or gonadoblastoma and developing TGCT in adolescence (18, 19, 20, 23, 59, 60). An association with testicular cancer has been noted in a number of developmental abnormalities, such as cryptorchidism (61, 62), Down syndrome (63) but also low birth weight and unspecific perinatal factors, e.g., premature birth, birth order, high levels of maternal estrogens or bleeding during pregnancy, high maternal age and neonatal jaundice (62, 64). A late age at puberty and tall stature were also associated with lower and higher risk of testicular cancer, respectively (65, 66).

For endocrinologists and andrologists it is essential to know that male infertility (the type linked to TDS) is one of the commonest risk factors for testicular cancer (67). Men with TGCT have poorer semen quality and significantly fewer children than controls prior to development of their tumor (68, 69), see also the section on TDS below.

Patients with a unilateral TGCT are also at an increased risk to develop a new primary testicular tumor of the contralateral testis. Depending on the studied population and the interval from the primary diagnosis, approximately 2 - 5% patients will be diagnosed with a second TGCT during their lifetime (70, 71, 72, 73). The majority of bilateral TGCT occur metachronously (> 6 months after the primary TGCT), some as late as 20-40 years after the primary TGCT (74). The histology of the primary tumor influences the risk only marginally, with the predominance of seminomas among the synchronous TGCTs but primary nonseminomas observed most often in younger patients with metachronous tumors developing after shorter intervals (70, 72). The presence of testicular atrophy increases the risk of bilateral neoplasia considerably (75, 76).

Testicular Dysgenesis Syndrome (TDS)

The association of testicular cancer with poor testicular function, cryptorchidism, hypospadias, and abnormal testicular development led to a hypothesis that poor gonadal development and testicular neoplasia are etiologically linked. A concept of TDS was proposed, in which testicular cancer is one of the symptoms, in addition to other phenotypes, including cryptorchidism, hypospadias, shortened anogenital distance (AGD), reduced Leydig cell function, and decreased spermatogenesis (3, 5). This hypothesis is supported by histological studies showing that dysgenetic features, such as undifferentiated tubules with visibly immature Sertoli cells, clusters of poorly differentiated tubules, or hyaline bodies, often seen in association with testicular cancer, are not uncommon among men referred to andrology clinics because of fertility problems (3, 5, 18, 71). It is important to underline that not all cases of genital malformations and infertility are a part of TDS. Milder phenotypes linked to impaired development of the testis in fetal life due to diverse environmental or lifestyle-related factors can be considered part of TDS (5, 77). Severe genital malformations caused by genetic disorders are clearly a part of DSD but there is a partial overlap between the two syndromes (18). However, TDS severity and prevalence are undoubtedly modulated by the genetic variability (polymorphisms) and epigenetics (5). A schematic representation of the pathogenesis and manifestations of TDS is depicted in Figure 4.

Figure 4.

Schematic illustration of aetiology and pathogenesis of disorders grouped within Testicular Dysgenesis Syndrome (TDS). The TDS concept implicates disturbed function of testicular somatic cells (Leydig- and Sertoli cells) caused by inherited genetic variation (gene polymorphisms) in combination with environmental /lifestyle factors acting during early development. Dysfunction of the somatic cells results in disturbed hormonal homeostasis and causes impaired germ cell differentiation. Depending on the severity of the impairment, multiple outcomes or phenotypes may occur, ranging from reduced anogenital distance (AGD), genital malformations to testicular cancer. Note that the most severe forms of TDS (disorders of sex development with gonadoblastoma (GDB) or GCNIS are the least frequently seen, whereas the mildest forms, such as impaired spermatogenesis are quite common. Modified from Skakkebæk et al., Hum Reprod 2001 (3) and Physiol Rev 2016 (5).

SEX CORD-STROMAL TUMORS OF THE TESTIS

In adults, sex cord-stromal tumors of the testis are found in less than 5% of all testicular tumors, whereas in children, these tumors are more common and account for approximately 25% of cases (123, 175, 176, 177, 178). Most of these tumors are benign, only around 5% have malignant characteristics (2). The classification of the tumors by WHO (2016) is shown in a simplified form in Table 3 (2).

Sex cord-stromal tumors are derived from testicular somatic cells; Leydig cells, and Sertoli/granulosa cells. Despite a different cell of origin, some stromal tumors are sometimes misinterpreted as seminoma. A number of features can be used to distinguish sex cord-stromal tumors from germ cell tumors; Inhibin A and B are the best serum markers for this purpose (179, 180, 181). Inhibin A appears to be a common immunohistochemical marker for sex cord-stromal tumors, including Leydig cell, Sertoli cell and juvenile granulosa cell tumors (179, 182). Sertoli cell tumors are positive for anti-Mullerian hormone (183) and GATA-4 (184), while Leydig cell tumors express steroidogenic enzymes and INSL3 (185). Other useful immunohistochemical markers, include SOX9, calretinin, CD99, SF1 (2).

Leydig Cell Hyperplasia and Tumors

Leydig cells are located in the interstitial compartment of the testis and are involved in the development of secondary male characteristics and maintenance of spermatogenesis by secretion of testosterone. Although Leydig cells in adult men are considered to be a terminally differentiated and mitotically quiescent cell type, in various disorders of testicular function, focal or diffuse Leydig cell hyperplasia is very common. Micronodules of Leydig cells are frequently seen in certain conditions associated with severe decrease of spermatogenesis or germinal aplasia, such as the Sertoli-cell-only syndrome (Del Castillo syndrome), cryptorchidism, or Klinefelter syndrome, when the nodules can be particularly florid (186, 187). A term 'Leydig cell adenoma' is used when the size of a nodule exceeds several- fold the diameter of a seminiferous tubule. It is unknown whether Leydig cell adenomas can progress further to form overt Leydig cell tumors, but even if it were the case, it is exceedingly rare. Morphological heterogeneity of hyperplastic Leydig cells is noticeable in some cases, and it has been shown that the micronodules contain a large proportion of immature Leydig cells (186, 187).

The mechanism of Leydig cell hyperplasia and larger nodules in the human male is still poorly understood. Leydig cell nodules of variable-size are common in patients with TDS and infertility, and the functional insufficiency of Leydig cells is often reflected by decreased testosterone/LH ratio whereas patients with overt Leydig cell tumors usually have an increased testosterone/LH ratio and high estradiol (186, 188). The disruption of hypothalamo-pituitary-testicular axis leading to an excessive stimulation of Leydig cells by LH can play a central role (186). This in turn leads to an increased renewal of immature, adult-type Leydig cells from their precursors. The immature cells are characterized by low numbers of Reinke crystals, a relatively high expression of a mesenchymal factor DLK1 and low amounts of INSL3 (187, 189, 190). However, Leydig cell hyperplasia is distinct from tumors that are usually solitary. Leydig cell hyperplasia and adenomas can be easily induced in rodents by administration of estrogens, gonadotropins, and a wide range of chemical compounds. Whether or not humans would be similarly susceptible to environmental effects remains to be elucidated.

Leydig cell tumors account for up to 5% of testicular neoplasms and occur in all age groups (2, 178, 191). Approximately 20% are found in boys, most often between five and ten years of age. There is perception that the prevalence of benign Leydig cell tumors among the adults is greater than previously thought, possibly thanks to improved detection of small nonpalpable nodules by modern imaging methods. Higher incidence numbers have also been reported in fertility centers that actively scan the testes of infertile patients (192).

In a subset of cases of Leydig cell tumors, activating mutations of the LH receptor (193, 194, 195) or G proteins (196, 197) can be detected. Constitutively activating mutations of LH receptor cause early Leydig cell hyperplasia and precocious puberty (193, 195, 197). Similarly, constitutively activating mutations of Gs-protein in Leydig cells or inactivation of PKAR1A (protein kinase cyclic adenosine monophosphate-dependent regulatory type 1 alpha) lead to hyperplasia and endocrine hyperactivity (178, 197). In adult Leydig cell tumors, germline fumarate hydratase mutations have been identified in a few cases which also had hereditary leiomyomatosis and renal cell cancer (199).

Precocious puberty (so-called testotoxicosis) is the presenting symptom in most of cases of Leydig cell adenomas or tumors in children, due to the excessive androgen production, mainly testosterone that causes growth of penis, pubic hair, accelerated skeletal and muscle growth, advancement of bone age, skin changes (acne, comedos, hair greasing), and adult-type odor of sweat. Androgen secretion in the pediatric cases is gonadotropin independent, and therefore LH and FSH remain low in spite of external signs of puberty (195). Approximately 10% of the boys also have gynecomastia that is caused by estrogens produced in excess due to aromatase activity in some of the tumors or peripheral aromatization of testosterone. It is important to keep in mind that transient gynecomastia or pseudo-gynecomastia can occur in newborns, in obese boys, and at puberty as a non-pathological condition (200). In adults, gynecomastia is a frequent condition with a reported prevalence of 32–65%, depending on the age and the criteria used for definition (summarized in 201). Gynecomastia is sometimes associated with loss of libido, impotence, and infertility (201). However, Leydig cell tumor is the cause in only 1-2% of cases, and the excessive androgen secretion by these tumors rarely causes notable effects in adults (202). Malignant tumors are hormonally active only in exceptional cases (2, 178).

In children, Leydig cell tumors are always benign and can be treated with surgical enucleation when the tumor is encapsulated (203). In adults malignant Leydig cell tumors have been found in 10-15% of patients, and inguinal orchiectomy is often used (204), while testis-sparing enucleation remains an option, if there are no signs of malignancy in the frozen preparation (205). The presence of cytologic atypia, necrosis, angiolymphatic invasion, increased mitotic activity, atypical mitotic figures, infiltrative margins, extension beyond testicular parenchyma, and DNA aneuploidy are associated with metastatic behavior in Leydig cell tumors (178, 202, 206) (see Figure 5).

Figure 5.

Histology of a Leydig cell tumor. The appearance of tumor cells resembles normal Leydig cells. A section stained with hematoxylin-eosin (HE).

Malignant Leydig cell tumors do not respond favorably to conventional chemotherapy and irradiation (204). Survival time has ranged from 2 months to 17 years (median, 2 years), and metastases have been detected as late as nine years after the diagnosis (178, 202). Metastatic Leydig cell tumors require salvage surgery, radiotherapy and intensive chemotherapy regimens but in most cases the outcome is poor (188, 207). Therefore, follow-up of patients with malignant Leydig cell tumors has to be life-long. The remaining testis may be irreversibly damaged by longstanding high estrogen levels, resulting in both permanent infertility and hypoandrogenism (202, 206).

Testicular Adrenal Rest Tumors (TART)

Excessive secretion of adrenocorticotropin (ACTH) in 21-hydroxylase deficiency (congenital adrenal hyperplasia, CAH) or Nelson syndrome (post adrenalectomy status) may lead to development of hyperplastic interstitial nodules called testicular adrenal rests tumors (TART) resembling Leydig cell tumor or hyperplasia (191, 208, 209). These cells are hormonally active in secreting androgens. It is important to remember that the adrenal rests are almost invariably bilateral, whereas the Leydig cell tumors are usually unilateral. Adrenal rests can be treated by appropriate glucocorticoid substitution of the patient, which leads to gradual regression of the 'tumor' in 75 percent of cases (208, 209). TART have to be distinguished from benign hyperplasia, adenomas and malignant Leydig cell tumors (185).

Histopathological and endocrine evaluation covering both testicular and adrenal steroids and pituitary gonadotropins and ACTH are important in the differential diagnosis (185, 208). It would be an error to orchidectomize the CAH patients with TART, since the tumors are always benign and only some of them continue to be active after appropriate glucocorticoid substitution. In the patients who do not respond well to glucocorticoid replacement, or develop fibrosis, testis sparing surgery with enucleation of the larger nodules can be considered, if the testicles have become so large that they cause discomfort for the patient (209).

Sertoli Cell Tumors

Sertoli cells are the somatic cells in the seminiferous epithelium giving structural, metabolic, and hormonal support to spermatogenic cells. Sertoli cells cease their proliferation at puberty. In rare infantile cases, multiple foci of proliferating Sertoli cells have been described and proposed to be early intratubular forms of Sertoli cell tumors (210). The classification of these tumors according to the WHO (2, 178), is shown in Table 3.

Sertoli cell tumors often occur as a part of multiple neoplasia syndromes (see below). Rare Sertoli cell tumors which do not belong to a syndrome are called ‘not otherwise specified’ (NOS). About 5% of these tumors are malignant and can metastasize. The age of patients ranges from 18 to 80 years, but most of them are young adults (median age 30). Out of 60 patients, only four were younger than 20 years old in the series reviewed by Young et al. (211). The tumors typically are composed of sex cord cells with tubular differentiation, with a subset of tumors hyalinized, previously classified as sclerosing variant (2). Some tumors often contain lipid droplets but do not show any endocrine activity. The molecular origin is known only in a small proportion of tumors with sclerosing appearance, in which CTNNB1 mutations causing nuclear accumulation of β-catenin were identified (212). The tumors occurred in descended testes and were always unilateral. An infiltrative margin was found in four cases, but most of the tumors were well demarcated. The tumors were hormonally inactive, and only two patients with alcoholic cirrhosis also had gynecomastia. Eighteen pediatric cases were reported from the Kiel Pediatric Tumor Registry (176), but perhaps the histopathologic pattern was somewhat different, because the age of the children was very young, ranging from 0 to 14 months (median 4 months). Juvenile Sertoli cell tumors often showed infiltrative growth into adjacent tissue, dense cellularity and considerable proliferative activity. However, after surgical excision no local recurrences and no metastases occurred. Thus, these patients have a good prognosis. These Sertoli cell tumors can be treated by orchiectomy, and retroperitoneal lymphadenectomy is indicated only when there is radiographically detected retroperitoneal involvement (213).

Calcifying Sertoli cell tumors, are frequently found in association with two distinct multiple neoplasm syndromes, Carney complex and Peutz-Jeghers syndrome, however in the latter syndrome, the tumors belong to a distinct ‘intratubular’ morphological group (2, 178, 214). Association of large-cell calcifying Sertoli cell tumors with other neoplasms, particularly heart myxomas in Carney complex and gastrointestinal tumors in Peutz-Jeghers syndrome, should be kept in mind to reach an early diagnosis of these potentially fatal diseases.

The Carney complex is characterized by skin myxomas, heart myxomas, skin pigmentations, adrenal and testicular tumors, but other tumors can also occur (215). The testicular tumors are large-cell calcifying Sertoli cell tumors that are multifocal and bilateral, and should be distinguished from teratomas (Figure 6) (178, 216, 217). The tumors appear usually during the second decade of life (218). Only one malignant case has been reported in association with Carney complex (in an adult patient), whereas seven malignant tumors were reported in other patients with large-cell calcifying Sertoli cell tumors (218). These patients were older than 25 years. The malignant cases were unilateral and solitary in contrast to bilateral and multifocal occurrence of testicular tumors in Carney complex. Large-cell calcifying Sertoli cell tumors are usually not hormonally active, although elevated levels of serum inhibin B or testosterone have been reported, but other tumors of Carney complex, including Leydig cell tumors, can cause endocrine manifestations (181, 213, 214).

Figure 6.

Large cell calcifying Sertoli cell tumor isolated from a 12-year-old boy. The neoplastic tubules contain only large pale Sertoli cells and visible calcifications in the lumen (stained with PAS). Adjacent normal tubules show advanced spermatogenesis.

Two genetic loci for Carney complex have been identified on chromosome 2p16 (196) and 17q23-24 (219, 220). Germline mutations identified in Carney complex most often occur in type I-alpha regulatory subunit of protein kinase A, PRKAR1A (221, 222). Inactivating mutations of phosphodiesterase 11A212 and phosphodiesterase 8B213 are associated with bilateral adrenocortical hyperplasia in Carney complex patients. Genetic variation of the phosphodiesterase 11A gene can modify the development of the testicular tumors (223). Molecular genetic diagnosis is available to many of these patients. However, only a part of the mutations occur in the germ line, and therefore genetic analysis should be performed on affected tissues, such as the tumors, in cases of somatic cell line mutations.

In Peutz-Jeghers syndrome Sertoli cell tumors are similar in appearance to those found in Carney complex patients, but can be distinguished by typical intratubular proliferation of lightly eosinophilic cells with prominent basement membrane deposits, and occasionally, features of ovarian sex-cord tumors with annular tubules (178). Thus, the tumors are described as intratubular large-cell hyalinizing Sertoli cell neoplasia. These tumors may have strong aromatase activity and therefore be associated with gynecomastia and advanced bone age (224). No malignant testicular tumors have been reported in Peutz-Jeghers patients, but they have a highly increased risk of other neoplasms, especially colorectal, breast, pancreatic and ovarian cancers (214). Germline loss-of-function mutations in the STK11/LKB1 gene that encodes for a serine-threonine kinase causes Peutz-Jeghers syndrome in the majority of patients, allowing molecular genetic diagnostics (214, 224, 225).

Patients with the Sertoli cell tumors should be treated conservatively during childhood to give them a possibility for sperm banking before orchiectomy comes necessary (226). Autosomal dominant inheritance should be considered in genetic counselling. The patients should be frequently controlled with ultrasound examinations to follow changes in the tumors size, and reproductive hormone measurements. If precocious puberty and/or gynecomastia appear, aromatase inhibitors and antiandrogens can be used to prevent estrogen formation and androgen action (219, 226). There are currently no clear guidelines for the treatment of metastatic Sertoli cell cancers, but orchiectomy and retroperitoneal lymph node dissection are usually performed combined with individualized chemotherapy and radiotherapy (227). Without surgery, the metastatic disease progresses and 20-month median survival time of patients was reported (IQR: 6–30 months) (227).

Granulosa Cell Tumors

Juvenile-type granulosa cell tumors are rare but are the most common somatic testicular tumors in infants and occur during the first 6 months after birth (2, 176, 178, 228). These tumors were described in patients with undescended testes with abnormal sex chromosomes and ambiguous genitalia (176). Prominent differentiation into follicles and immature nuclei distinguishes juvenile granulosa cell tumors from other Sertoli cell tumors that express tubular differentiation (178, 229). Most of the immunohistochemical markers in these tumor types are similar, e.g., inhibin, calretinin, but also distinct, e.g., expression of FOXL2 (229). Juvenile granulosa cell tumors always have a good prognosis (230). Testicular tumors do not show endocrine hyperactivity, in contrast to ovarian juvenile granulosa cell tumors. Aberrant WNT signaling (231) and stimulatory G-protein mediated signaling (232) have been linked with juvenile granulosa cell tumors. The patients should be managed comprehensively by a multidisciplinary DSD team, and the treatment of tumors may require orchiectomy.

Adult-type granulosa cell tumors are comparable to the ovarian tumors, but are extremely rare (2, 178, 233). These tumors occur in adults at an average age of 42 years. Twenty percent of the patients have shown gynecomastia due to the hormonal activity of the tumor. Most of the tumors are benign, but some malignant cases have also been reported (230). Mutations in FOXL2 have been reported in adult ovarian granulosa cell tumors but only few secondary mutations have been found in testicular granulosa cell tumors (234, 235). The treatment is primarily surgical.

OTHER TESTICULAR TUMORS

Other tumors occurring in the testis are divided into miscellaneous and hematolymphoid tumors (2, 178). The first group includes ovarian epithelial-type tumors, serous or mucinous cystadenomas, adenocarcinomas, Brenner tumor, xantogranuloma, and hemangioma. The hematolymphoid tumors comprise malignant lymphomas (B-cell, NK/T-cell or follicular), plasmacytoma, myeloid sarcoma and Rosai-Dorfman disease (2, 178). In addition, testicular spread of malignant acute leukemia is common in young boys, and metastases from other solid tumors including the prostate gland, colon, kidney, stomach, pancreas, and malignant melanoma can be found in the testis of adults.

ENDOCRINE PROBLEMS AND LATE EFFECTS IN TESTICULAR CANCER PATIENTS

CONCLUSION

Key take home points are shown in figure 7.

Figure 7.

Key take home points.

ACKNOWLEDGEMENTS

The authors thank Prof. Niels E. Skakkebæk for his mentorship, and the research and clinical teams at their departments for the contribution to the studies summarized in this review. The work was supported by grants from numerous foundations, with the biggest contributions from the Danish Cancer Society, the Lundbeck Foundation, the Svend Andersen Foundation, the Danish Advanced Technology Foundation, Sigrid Juselius Foundation and Novo Nordisk Foundation.

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