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INTRODUCTION

Testicular cancer is the most common malignancy occurring in young adult men. In addition to its neoplastic and malignant features, this disorder also represents a developmental, endocrine and reproductive problem. These issues are in focus in this chapter, and emphasis is upon the aspects that are of interest for endocrinologists, including pediatric endocrinologists. Histopathology is mentioned only briefly, and the reader interested in histology is referred to specialised pathology textbooks. As far as management of testicular tumours is concerned, very general guidelines are given here; the details can be found in the oncological literature.

Testicular cancer comprises a number of different diseases. The testis consists of several types of cells which form two main anatomical and functional compartments: the seminiferous tubules and the interstitial space. Nearly all of the main cell types in the testis can undergo neoplastic transformation, but germ cell-derived tumors constitute the vast majority of cases of testicular neoplasms. Somatic cell tumors, known as sex cord-stromal neoplasms and Leydig cell tumors are relatively rare. They are, however, discussed in detail in this chapter, because being derived from endocrine active cells, they have endocrine manifestations.

GERM CELL-DERIVED TUMORS

Testicular tumors derived from germ cells are by far the most frequent neoplasms of the testis and comprise approximately 90-95% of cases (1). They are unique in comparison with other solid tumors for several reasons. Most of them occur in young adults. These tumors originate early in life and have a common preinvasive precursor, carcinoma in situ (CIS) which transforms further into overt tumors in young adulthood (2, 3). Germ cell tumors have very high propensity to apoptosis and are extremely radio- and chemosensitive (4). About half of them can differentiate and form histologically variable forms. Epidemiology of testicular germ cell cancer recently attracted growing attention, because the incidence has been steadily rising in recent decades (5-10). These aspects will be discussed in more detail in subchapters below.

Histopathology and Classification of Germ Cell Tumors

Germ-cell-derived testicular tumors are characterized by a striking variety of morphological forms which have been difficult to classify. Two nomenclatures; the so-called British Classification (1) and the WHO Classification (11) are the most commonly used. A newer proposal by Grigor (12), based on biology and natural history of germ cell tumors has been slowly gaining popularity. In addition, Ulbright and colleagues (13) have proposed a new classification that combines elements from both, the British and the WHO classification. The readers with interest in histopathology are referred to this excellent work (13). Recently, Oosterhuis has also proposed a new classification of human germ cells tumors (both male and female) which includes five entities: I- teratomas and yolk sac tumors of infants, II– seminomas and nonseminomas of adolescents and adults, III- spermatocytic seminomas of the elderly, IV- dermoid cysts of the ovary, and V- gestational trophoblastic neoplasia (14). For use by non-pathologists, a simple division of the most common germ cell tumors of the young adults into preinvasive CIS, seminoma, nonseminoma and combined tumors is sufficient (Table 1).

Some examples of histological features of testicular germ cell tumours are shown here in Figures 1-4 (The figures are reproduced below). Morphology of CIS cells resemble closely that of immature germ cells (gonocytes). CIS cells are located inside seminiferous tubules, most frequently in a single row along the basement membrane (Figure 1). Seminoma cells are morphologically very close to CIS cells and proliferate as a homogeneous tumor, which retains features of germinal lineage (Figure 2). Nonseminomatous tumors display a variety of histological forms (Figure 3 and 4) and differentiate along an embryonic lineage (embryonal carcinoma, teratoma, teratocarcinoma) or extra-embryonic tissue components (yolk sac tumor and choriocarcinoma). Teratomas are sometimes associated with rarely observed carcinoid tumors, which may be associated with carcinoid syndrome (15). The combined tumors contain elements of seminoma and nonseminomatous tumours but clinically are treated as nonseminoma. Both seminoma and nonseminoma originate from CIS and are mainly observed in young adult men (2, 3, 13, 16). In other age groups, germ cell tumors are rare. In early childhood, however, there is a small peak of infantile tumors (mainly yolk sac tumor and mature teratoma), while in older age practically the only type of germ cell tumor is spermatocytic seminoma (Table 1, see above). Neither infantile tumors, nor spermatocytic seminoma are preceded by CIS and they most probably have a different pathogenesis (3, 17-19). A separate type of gonadal germ cell tumor is gonadoblastoma, a lesion which occurs almost exclusively in children or young individuals with disorders of sexual differentiation, predominantly with gonadal dysgenesis e.g. 45XO/46XY (20). Gonadoblastoma consists of groups of cells resembling gonocytes or CIS cells, which are nested in small stromal cells similar to granulosa cells. The clinical course is usually benign, however, gonadoblastoma can sometimes transform into a malignant germ cell tumor.

Figure 1. Preinvasive carcinoma in situ (CIS) . A. hematoxyllin-eosin staining showing general features of the histologic pattern. B. CIS cells visualised immunohistochemically with an anti-PLAP antibody.

Figure 2. Histology of seminoma, one of the most frequent germ cell neoplasms. A. General appearance of seminoma, a homogeneous tumor comprised of seminoma cells and white blood cell-infiltrate. B. Higher magnification: tumor cells closely resemble CIS cells

Figure 3. Embryonal carcinoma: an undifferentiated component of nonseminoma. A. General view of the tumor mass. B. Higher magnification: the cells resemble embryonic stem cells.

Figure 4. An example of a teratoma - a nonseminomatous germ cell tumor that can differentiate along any cell type lineage.

Epidemiology and Risk Groups

In absolute numbers, testicular cancer is a rare disease. However, the average age-adjusted incidence of testicular germ cell tumors of young adult type has been markedly increasing in several countries of the world (10). The incidence is greatest among Caucasians in particular in the North-West of Europe (6) and in the North America (7), and the lifetime risk of the disease is now approaching 1 per 10000 in Denmark, parts of Switzerland and Germany (6, 8). The incidence is remarkably variable geographically and dependent on the ethnic background (Figure 5). For example, there is three fold higher incidence in Denmark in comparison to a nearby Finland, another Scandinavian country. Black populations have a very low incidence of testicular cancer and no significant rise has been noted, even in the highly developed areas, such as USA (21). On the other hand, indigenous Maoris of New Zealand have a very high incidence of the disease (22). Analysis of data collected in cancer registries in Scandinavian countries revealed another interesting feature of epidemiology of testicular cancer; the rise in the incidence correlated with the calendar year of birth rather than with the age at diagnosis (23). For unexplained reasons, cohorts born at wartime had lower incidence then men born just before or after the war (24). This striking birth cohort effect has been later found in American studies as well (7, 9).

Figure 5. A graph illustrating striking regional and ethnic differences in the incidence of germ cell cancer.

As mentioned before, testicular germ cell 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 are at particularly high risk of developing germ cell neoplasia. These individuals have frequently abnormal karyotype, but at least a fragment of chromosome Y is present (25, 26). Despite variability in phenotypic sex, the intersex gonads that develop germ cell tumors usually contain some testicular structures. An association with testicular cancer has been noted in a number of developmental abnormalities, such as the androgen insensitivity syndrome (27), Down's syndrome (28), cryptorchidism (29, 30), 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 or body weight of the mother, and neonatal jaundice (31-35). Patients with a unilateral testicular germ cell tumor are also at an increased risk to develop a new primary testicular tumor of the contralateral testis, the presence of testicular atrophy increases the risk considerably (36). Whether or not male infertility ought to be included on the list of risk factors for testicular cancer was a matter of controversy, but recent studies provided additional evidence suggestive for pathogenetic link between the two diseases. Sperm counts in men with testis cancer are often very low; markedly lower than one would expect in a man with one functioning testis only (37). Furthermore, men with testis cancer had significantly fewer children than controls prior to development of their tumour (38). Furthermore, it was later demonstrated that patients with testicular cancer had decreased offspring sex ratio, or fewer boys than girls, and their overall standardised fertility rate ratio was also significantly reduced (39). A recent study done by the same group documented abnormal semen characteristics in men who later developed testicular cancer (40). The association of poor testicular function, atrophy, maldescent and abnormal testicular differentiation with testicular germ cell cancer led to a hypothesis that poor gonadal development and testicular neoplasia are etiologically linked (41). A new concept of testicular dysgenesis syndrome (TDS), in which testicular cancer is the rarest, but also one of the most severe symptoms, was then proposed (42). A schematic representation of testicular dysgenesis syndrome is depicted in Figure 6. Since then, histological studies provided additional evidence that dysgenetic features, such as undifferentiated tubules or hyaline bodies are not uncommon among men referred to andrological clinics (43, 44).

Figure 6. A schematic representation of testicular dysgenesis syndrome (TDS) which is a result of the poor gonadal development caused by a combination of genetic susceptibility and adverse environmental/lifestyle factors. Note that the most severe forms of TDS (intersex and testicular cancer) are also the least frequently seen, whereas the mildest forms, such as impaired spermatogenesis are quite common.

Pathogenesis of Germ Cell Cancer

The origin and pathogenesis of testicular germ cell tumors remains obscure. The high incidence of testicular cancer in subjects with congenital errors of gonadal development and sexual differentiation strongly implicates the involvement of intrauterine factors. We believe that the neoplastic transformation of germ cells is initiated by factors acting in utero, perhaps preferentially in individuals with genetic susceptibility. CIS cells and primordial germ cells (early gonocytes) look very much alike and share some distinct features, such as e.g. lack of intercellular bridges (45) and a common pattern of expression of various antigens (46, 47). In aberrant gonadal development, the pattern of expression of some of these antigens is disturbed (48). More recently, studies of the regulation of the cell cycle in normal and neoplastic germ cells provided additional evidence demonstrating that CIS cells have predominantly features of mitiotically dividing immature germ cells (47, 49-51), thus it is unlikely that they are derived from meiotic spermatocytes, as an alternative hypothesis stipulates (52).

The mechanisms of neoplastic transformation of early germ cell are not known. We hypothesize that a disturbance in the fetal programming of gonadal development may be a result of an intrauterine hormonal imbalance, which in turn may be caused by a genetic disorder or by an impact of an exogenous factor leading to a relative excess of estrogens or a deficit of androgens (42, 53). Epidemiological evidence, in particular the rising incidence of testicular cancer in well-developed countries, suggests a possible adverse influence of environmental factors. In recent decades a great number of potent natural and synthetic hormones and hormone antagonists have been identified in environment. Observations in wildlife and experiments in laboratory animals exposed to synthetic hormones suggest that these substances can cause a disturbance of hormonal milieu of the developing gonad and disturb differentiation of early germ cells (54-56). This gave rise to a hypothesis that hormone disrupters might have contributed to the reported decline in male reproduction, including testicular cancer (42, 56, 57).

Diagnosis of Testicular Neoplasia

Testicular Biopsy

At present, diagnosis of testicular neoplasia at the preinvasive stage of CIS, which is asymptomatic, is only sporadic. It happens usually in cases with unilateral testicular atrophy, in the contralateral testis in patients with unilateral testicular tumors, or in individuals from high-risk groups. Surgical testicular biopsy is currently the only sure diagnostic procedure for CIS. False-negative cases (approximately 0.03%) and post-biopsy complications are rare (see refs 58-60 for more in-debt discussion on testicular biopsy). Experience in the use of needle biopsies is limited and this method is not commonly used in the clinic. Our recommendation is to perform a contralateral biopsy at the time of surgery for the primary unilateral testicular cancer in order to exclude the presence of CIS (and bilateral neoplasia). Added benefits are a good assessment of the fertility potential of the other testicle, and a piece of mind for the patient concerning the possibility of bilateral cancer.

Technical aspects of surgical biopsy are important and care has to be taken to avoid damage to the specimen. A small piece of tissue (approx. 3x3x3 mm) should be dropped directly to a container with a fixative solution (preferably Bouin's- or Stieve's- solution, because formalin causes shrinkage artefacts). The histological examination of the biopsy, should be aided by one of methods that help to identify CIS cells, such as: i) immunohistochemical staining for one of the cell surface marker proteins (61-65) e.g. placental-like alkaline phosphatase (PLAP), M2A, OCT-3/4 or KIT (an example of immunohistochemical staining for is shown in Figure 1, see above);

1. immunohistochemical staining for one of the cell surface marker proteins (61-65) e.g. placental-like alkaline phosphatase (PLAP), M2A, OCT-3/4 or KIT (an example of immunohistochemical staining for is shown in Figure 1, see above);
2. PAS staining for glycogen stored in CIS cells (66)
3. silver staining of argyrophilic nucleolar organizer region associated proteins, AgNORs (67).

Scrotal Ultrasonography

This non-invasive diagnostic method has been increasingly popular for assessment of the testicles. Testicles afflicted with CIS have frequently an irregular echo pattern that may be associated with the presence of so-called testicular microliths or hyaline bodies (68, 69). In addition, ultrasonographic examination will detect small not yet palpable tumors, and help in differential diagnosis of other conditions, e.g. orchitis, epididymitis, hydrocoele and varicocoele. However, ultrasonic microlithiasis is not always confirmed histologically, on the other hand, microliths are one of the signs of dysgenetic testes and may be seen in testicular atrophy or cryptorchidism, without CIS (69). Despite the problem of lack of specificity, a sonographic finding of testicular microlithiasis or an irregular echo patter should alert the clinician to consider malignancy (69-71). Further management depends upon several factors, mainly the age and the history of the patient. In a man older than 50, the biopsy can be omitted because of a minimal risk of CIS. In younger patients, especially those with small testicles and a history of cryptorchidism we recommend bilateral testicular biopsy.

In the vast majority of cases CIS progresses to overt tumors unnoticed. A scrotal mass is usually the first presentation of testicular cancer, with tenderness reported by only few patients. In a few percent of testicular cancer cases, the presenting symptoms are the result of metastatic disease. They are usually uncharacteristic and may include lumbar pain, palpable abdominal mass, supraclavicular lymph node enlargement and in rare cases pulmonary symptoms.

The majority of primary and metastatic germ cell tumors secrete protein products that can be detected in circulating blood. These biochemical serum tumor markers are very helpful in diagnosis and monitoring of these tumors (72). Among nonseminomatous tumours, choriocarcinoma, which resembles gestational trophoblast, produces large quantities of chorionic gonadotropin (HCG) and yolk sac tumor, which is similar in morphology to the embryonic yolk sac, secretes alpha-fetoprotein (AFP). In addition, lactate dehydrogenase (LDH) may be secreted by both nonseminoma and seminoma. LDH levels in serum tend to be higher in patients harboring tumors with an increased copy number of chromosome 12p, consistent with genomic location of the LDH gene (73). A number of immunometric assays have been developed to measure these markers (72-75). The most important in clinical practice are HCG and AFP, since they are very sensitive markers for nonseminomatous tumours, which in many cases have a more malignant clinical course than seminoma. It is important to keep in mind that germ cell tumors rarely occur in pure histological forms, and for example HCG may be sometimes detected in serum of patients with seminoma due to the presence of some giant cells in a tumor mass. In general, however, high levels of AFP and HCG are associated with nonseminoma, whereas increased concentration of LDH in the absence of AFP and HCG suggests the presence of seminoma. In preinvasive CIS and in most cases of pure classical seminoma, none of the above mentioned markers are detectable in serum. Other markers, developed for immunohistochemical diagnosis of CIS cells and tumors in tissue sections, such as PLAP and TRA-1-60, have been adapted for use as serum assays and begun to be used in clinical practice, although with mixed results (76-78).

The measurements of circulating tumor markers help in prognosis. There is a tendency for higher levels of tumor markers to be associated with a poorer prognosis. However, a careful staging is necessary in each case to decide for the most appropriate treatment strategy. In addition to serum markers, other procedures help to evaluate the spread of disease, such as bipedal lymphangiography, roentgenography of the thorax, retriperitoneal CT scan or ultrasonography. These procedures help to classify patients into one of the staging systems. The most commonly used staging systems have been developed by the American Joint Committee on Cancer, Royal Marsden Hospital, the Memorial Sloan Kettering Cancer Center and the Indiana University (79). In our center, the following staging system of testicular germ cell neoplasia is used:

1. Tumor confined to one or both testicles
2. Spread to retroperitoneum
   • retroperitoneal nodes <2 cm
   • retroperitoneal nodes >2 cm but <5 cm
   • retroperitoneal nodes >5 cm
3. Metastatic disease (spread beyond retroperitoneal nodes)
   • spread to supradiaphragmatic nodes
   • extralymphatic metastases (most frequently to lungs or liver, less commonly to CNS or bones)

Management of Cis and Germ Cell Tumors

Early diagnosis of testicular neoplasia at the stage of CIS, followed by adequate treatment of CIS is capable of preventing progression to invasive tumors. Unfortunately, the vast majority of cases progress unnoticed to overt tumors. We give here only very general guidelines concerning management of CIS. The reader should consult specialized oncological literature for details and for management options pertinent to overt tumors and metastatic disease. The following management options for CIS are available depending on a specific situation (60, 80):

• Orchidectomy - is the curative treatment with the highest assured success rate. It should be always performed on a testis with CIS or localised tumour when the second testis is not affected by testicular neoplasia (including CIS).
• Radiotherapy - low dose radiotherapy is a good alternative to orchidectomy in cases of e.g. CIS present in the contralateral testis, so the patient can be spared a second orchidectomy and complete androgen replacement. The efficacy of radiotherapy with doses as low as 18 Gy was demonstrated in several studies (60, 80-82).
• Chemotherapy - is not a good option to treat CIS, because a persistence or relapse of CIS has been reported (83, 84). Furthermore, in some cases of extragonadal germ cell tumours treated with chemotherapy, testicular CIS progressed to metachronous overt testicular tumours (85).
• Surveillance - is potentially hazardous since CIS may progress to invasive cancer at any time, but may be an option after careful informed discussion of risks if the patient wishes to defer treatment temporarily for the purpose of paternity.

In cases of desired fatherhood, and in all cases of very young men, semen analysis and cryopreservation of semen samples, if viable sperms are detected, should be done.

As far as the treatment of overt germ cell tumors is concerned, orchidectomy remains the primary method. Methods of post-surgical management are variable, depending upon the histological type of tumor, stage of disease and the presence of residual retroperitoneal masses. Some centers practice a surveillance strategy in clinical stage I patients (tumor confined to the testis) (86, 87). The most common post-surgical management is radiotherapy in association with systemic combination chemotherapy with various cytotoxic drugs, such cisplatin, etoposide, bleomycin, vinblastine and methotrexate (88, 89). Monitoring of serum markers is obligatory for accurate prognosis and assessment of treatment, especially in metastatic disease (90, 91). Other biological prognostic factors have been proposed in recent years, such as copy number of isochromosome 12p , degree of neovascularisation, and expression of protooncogenes, proliferation markers and adhesion proteins, but these factors are not fully reliable in the low-stage disease (91-93). Whatever the parameters used, it is very important to make a dynamic assessment of the progress through the early stages of chemotherapy. With the exception of some teratomas, germ cell tumors are in general highly sensitive to both radio-and chemotherapy and have become a model of a highly curable malignant disease, with more than 80% of patients reaching a complete remission (88). However, late relapses are observed in some cases, especially in nonseminomas, therefore lifetime follow-up is advocated (94).

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 found in up to 40 % of cases (95-98). Classification of the tumors shown in Table 2 has been recently reviewed by Cheville (99) and Ulbright et al. (13). Sex cord-stromal tumors are derived from somatic cells; Leydig cells, and Sertoli/granulosa cells. Despite 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 is the best serum marker for this purpose (100-102).

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. 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 so-called Sertoli-cell-only syndrome (Del Castillo syndrome), cryptorchidism, or Klinefelter's syndrome (103). 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.

The mechanism of Leydig cell hyperplasia in the human male is still poorly understood. The disruption of hypothalamo-pituitary-testicular axis leading to an excessive stimulation of Leydig cells by LH can play a central role (103). However, molecular pathways remain largely unknown in the vast majority of cases. In a small subset of cases structural changes of the LH receptor (104, 105) and G proteins (106, 107) were detected. Constitutively activating mutations of LH receptor cause early Leydig cell hyperplasia and precocious puberty (104, 108). Similarly, constitutively activating mutations of Gs-protein in Leydig cells lead into hyperplasia and endocrine hyperactivity (107, 109). However, Leydig cell hyperplasia is distinct from tumors that are usually solitary, and the role of the LH receptor and G protein mutations in the tumorigenesis may be limited to few cases (105, 107). 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 one to three percent of testicular neoplasms and occur in all age groups (for reviews, see 109-111). Approximately 20 % are found before the age of 10, most often between five and ten years of age. Precocious puberty is the presenting symptom in these cases. Tumors produce androgens, mainly testosterone that cause pubertal development: 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 is gonadotropin independent, and therefore LH and FSH remain low in spite of external signs of puberty. 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. In adults, gynecomastia is found in approximately 30 % of patients (111). The excessive androgen secretion rarely causes notable effects in adults. Gynecomastia is sometimes associated with loss of libido, impotence, and infertility.

Leydig cell tumors are always benign in children and can be treated with surgical enucleation when the tumor is encapsulated (97), whereas in adults malignant tumors have been found in 10-15 % of patients, and inguinal orchidectomy remains the treatment of choice (110). 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 (111, 112) (see Fig. 7). Malignant tumors are hormonally active only in exceptional cases (13, 112). Benign tumors can be treated by orchidectomy, whereas an additional retroperitoneal lymphadenectomy should be considered when the gross or histological features suggest malignancy (112). Malignant tumors have not responded favorably to conventional chemotherapy and irradiation (112). 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 (111, 112). 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 (111-113).

Figure 7. An example of a Leydig cell tumor.

Excessive secretion of adrenocorticotropin (ACTH) in poorly controlled 21-hydroxylase deficiency or Nelson syndrome (postadrenalectomy status) may lead to development of hyperplastic interstitial nodules called adrenal rests in the testis (110, 114) resembling Leydig cell tumor or hyperplasia. These cells are hormonally active in secreting androgens. The adrenal rests are almost invariably bilateral, whereas the Leydig cell tumors are usually unilateral. Adrenal rests can be effectively treated by appropriate glucocorticoid substitution of the patient, which leads to gradual regression of the 'tumor' in 75 percent of cases (114, 115). Endocrine evaluation covering both testicular and adrenal steroids and pituitary gonadotropins and ACTH are important to make differential diagnosis. Obviously it would be an error to orchidectomize the patients with adrenal rest tumors, since the tumors are always benign and only some of them continue to be active after appropriate glucocorticoid substitution. In these rare cases, testis sparing surgery could be considered.

Sertoli Cell Tumors

Sertoli cells are the somatic cells in the seminiferous epithelium giving structural, metabolic and hormonal support to spermatogenic cells. Sertoli cells terminally differentiate and 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 (116). Sertoli cell tumors are frequently found in association with two distinct multiple neoplasm syndromes, Carney complex and Peutz-Jegher's syndrome.

Carney complex is characterized by skin myxomas, heart myxomas, typical skin pigmentations, adrenal and testicular tumors, but other tumors can also occur (117). The testicular tumors are large-cell calcifying Sertoli cell tumors that are multifocal and bilateral (Figure 8) (118, 119). The tumors appear usually during the second decade of life (120). 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 (120). 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 or testosterone have been reported, but other tumors of Carney complex, including Leydig cell tumors, can cause endocrine manifestations (101, 121). Two genetic loci for Carney complex have been identified on chromosome 2p16 (122) and 17q23-24 (123). The genetic loci are different from those in other multiple neoplasm syndromes, including Peutz-Jegher's syndrome (124). Carney complex susceptibility gene in chromosome 17 was found to be the type I-alpha regulatory subunit of protein kinase A (125, 126), whereas the gene in chromosome 2 remains to be identified (127). Nevertheless, molecular genetic diagnosis is now available to many of these patients. Association of large-cell calcifying Sertoli cell tumors with other neoplasms, particularly heart myxomas in Carney complex and gastrointestinal tumors in Peutz-Jegher's syndrome, should be kept in mind to reach an early diagnosis of these diseases.

Figure 8. Large cell calcifying Sertoli cell tumor isolated from a 12-year-old boy. The neoplastic seminiferous tubules contain only large pale Sertoli cells and visible calcifications in the lumen (stained with PAS). Adjacent normal tubules show advanced spermatogenesis.

Sertoli cell tumors in Peutz-Jegher's syndrome can be difficult to distinguish from those found in Carney complex patients on the basis of histology. However, the Peutz-Jegher's tumors of the testis may also have features of ovarian sex-cord tumors with annular tubules (109). These tumors may have strong aromatase activity and therefore be associated with gynecomastia (128). No malignant testicular tumors have been reported in Peutz-Jegher's patients (13). Germline loss-of-function mutations in the STK11/LKB1 gene that encodes for a serine-threonine kinase causes Peutz-Jegher's syndrome in the majority of patients (129) allowing molecular genetic diagnostics. Molecular mechanisms of tumorigenesis in the absence of this putative tumor suppressor gene are not yet known.

Sclerosing Sertoli cell tumors account for approximately 5% of sex cord-stromal tumors and are distinguished from other tumors on descriptive basis (130). The age of the patients ranges from 18 to 80 years, but most of them are young adults (median age 30). Tumors are small, well-demarcated and rarely malignant. They do not show any endocrine activity. Twelve cases have been described up to now (131).

When the Sertoli cell tumors cannot be classified to any of the above-mentioned histopathological groups they are referred to as Sertoli cell tumors, not otherwise specified (NOS) (13). Out of 60 patients, only four were younger than 20 years old in the series reviewed by Young et al. (132). 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 (96), 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. Distinction between Sertoli cell tumors NOS and juvenile granulosa cell tumors can be subjective and difficult (13,95). Sertoli cell tumors can be treated by orchidectomy, and retroperitoneal lymphadenectomy is indicated only when there is radiographically detected retroperitoneal involvement (121).

Sertoli-Leydig Cell Tumors

A prominent stromal component in Sertoli-Leydig cell tumor distinguishes it from pure Sertoli cell tumors (132). Leydig cells are often difficult to recognize in these tumors. Patients may have gynecomastia.

Juvenile-Type Granulosa Cell Tumors

Juvenile-type granulosa cell tumors are the most common testicular tumors in infants and occur during the first few months after birth. Harms and Kock (96) reviewed 11 patients who were all diagnosed before the age of three months. Prominent differentiation into follicles in juvenile granulosa cell tumors distinguishes them from Sertoli cell tumors NOS that express tubular differentiation (132). Most of the immunohistochemical markers in these tumor types are similar, e.g., inhibin. Juvenile granulosa cell tumors have always a good prognosis. In 6 of 26 reported patients, juvenile granulosa cell tumors have been found in undescended testes with abnormal chromosomes and ambiguous genitalia (for references see 96). Testicular tumors do not show endocrine hyperactivity, in contrast to ovarian juvenile granulosa cell tumors.

Adult-Type Granulosa Cell Tumors

Adult-type granulosa cell tumors are comparable to the ovarian tumors, but are extremely rare (less than 30 well-documented cases)(13, 109,133). 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 four malignant cases have also been reported (134).

Mixed Sex Cord-Stromal Tumors

Sex cord-stromal tumors can contain combinations of Leydig, Sertoli, granulosa, and theca cells, and are therefore called mixed tumors (109). These tumors are rare and can occur at any age. Depending on the predominant cell type the tumors may behave differently. Gynecomastia, as a sign of endocrine activity, can be found in ten percent of patients (13). These tumors are always benign in children, but in adults malignancy can be found (134). Thus, most of the patients can be treated by orchidectomy, and lymph node dissection is indicated only in cases with overt malignant features on microscopic examination (13). Inhibin alpha appears to be a common marker for sex cord-stromal tumors, including Leydig cell, Sertoli cell and juvenile granulosa cell tumors (100, 135). Sertoli cell tumors are positive for anti-Mullerian hormone (136) and GATA-4 (137). Other immunohistochemical markers are reviewed in Ulbrigth et al. (13).

ENDOCRINE PROBLEMS AND SEQUELAE OF TESTICULAR NEOPLASMS

Relative imbalance of androgen signalling (excess or deficiency) causes the most pronounced secondary endocrine symptoms associated with testicular tumors. Testosterone is produced by tumors, such as Leydig cell tumors, or by normal Leydig cells stimulated by large amounts of hCG from some germ cell tumors. In addition, aromatisation of androgens leads to a relative excess of estrogens, which causes impairment of spermatogenesis and gynecomastia (138).

Testicular dysfunction in patients with germ cell cancer, who usually are in their best reproductive age, is a serious clinical problem. Patients with testicular tumors have poor spermatogenesis even before the overt neoplasm has developed (39, 40,139,). Abnormalities include oligozoospermia, elevated LH levels, and a variable degree of testicular atrophy in the biopsy, in some cases further complicated by the presence of CIS. Examination of a contralateral biopsy in a patient with a unilateral tumor may show a similar picture; with at least 5% risk of presence of CIS cells (43). Testicular function is further disturbed by treatment of neoplasm. In recent years there is growing concern about adverse endocrinological sequelae of testicular irradiation. It has been shown that testosterone function is subnormal in testes with CIS both before and after the radiotherapy (37, 80, 82, 139). Thus, these gonads are probably more susceptible to radiation-induced damage than normal testes. Refinement of the dosage must be considered to see if a reduced dose can eradicate CIS without causing hormonal abnormalities (82). The eradication of CIS by irradiation leads also invariably to the disappearance of all germ cells and sterility. This underlines the importance of semen cryopreservation before treatment.

All patients treated for testicular cancer, who are referred to an endocrinologist or andrologist, require careful assessment of their reproductive hormones and spermatogenic capacity with respect to their future fertility, sexual potency and general well being. 

ACKNOWLEDGEMENTS

Supported by the Danish Cancer Society, the Svend Andersen Foundation and the European Commission.