—  SHORT COURSE #49  —

Tumors of the Testis

Section 1 - Testicular Germ Cell Neoplasms:
Classification and Pathogenesis

John Srigley


General Introduction
Testicular cancer is uncommon accounting for <1% of malignancies in males. The great majority of testicular cancers are of germ cell origin with most cases occurring in young patients between the ages of 15 and 40 years. [1] Descriptive epidemiologic studies are mainly derived from medical and death records dealing with the broad category of "testis cancer". Since germ cell tumors account for about 95% of these cases, epidemiologic extrapolations cannot be made to the other rare malignant testicular tumors such as sex cord-stromal neoplasms. After the sixth decade of life, most testicular cancers are represented by lymphoma and metastatic disease along with some uncommon sex cord-stromal tumors.

Classification of Testicular Germ Cell Tumors
The currently accepted global classification system of testicular germ cell tumors is the one recently published by the World Health Organization (table 1). [2] This system is built on the previous World Health Organization classification and on the Armed Forces Institute of Pathology fascicle on testicular tumors from the third series (1999). [3, 1] The latter classification has more expanded categories than the newly released WHO system. In both systems, the importance of intratubular germ cell neoplasia and tumors of pure histologic type and mixed histology are recognized.

Another classification system proposed by the British Testicular Tumor Panel (BTTP) is commonly used in Europe and is based on the work of Collins and Pugh. [4] In the BTTP system, tumors are classified as seminoma or teratoma with the latter divided into undifferentiated, intermediate and trophoblastic categories. [5] The WHO/AFIP systems are widely used in North America and many other parts of the world, and are preferred over the BTTP system for a number of reasons. The BTTP system groups together different germ cell categories of potentially different biological behavior; for instance, malignant teratoma intermediate, includes entities such as teratoma and embryonal carcinoma, teratoma and yolk sac tumor and teratoma with somatic malignancy (i.e. sarcoma, carcinoma). Additionally, the histologic categories in the BTTP system do not correlate well with serum tumor markers that are of great importance for clinical management. A comparison between the two systems is shown in table 2. For the purpose of this course, the WHO/AFIP systems will be used.

Table 1: WHO Histological Classification of Germ Cell Tumours of Testis

Intratubular germ cell tumours
Intratubular germ cell neoplasia, unclassified
Other types
Tumours of one histological type (pure forms)
Seminoma
Seminoma with syncytiotrophoblastic cells
Spermatocytic seminoma
Spermatocytic seminoma with sarcoma
Embryonal carcinoma
Yolk sac tumour
Trophoblastic tumours
Choriocarcinoma
Trophoblastic neoplasms other than choriocarcinoma
Monophasic choriocarcinoma
Placental site trophoblastic tumour

Teratoma
Dermoid cyst
Monodermal teratoma
Teratoma with somatic type malignancies
Tumours of more than one histological type (mixed forms)
Mixed embryonal carcinoma and teratoma
Mixed teratoma and seminoma
Choriocarcinoma and teratoma/embryonal carcinoma
Others

Table 2: Comparison of Nomenclature of the WHO-based System and the British Testicular Tumour Panel (BTTP) Classification
Modified WHO Classification BTTP Classification
Tumors of One Histologic Type __________
Seminoma Seminoma
Spermatocytic seminoma Spermatocytic seminoma
Embryonal carcinoma Malignant teratoma, undifferentiatead (MTU)
Yolk sac tumor Yolk sac tumour (pure neoplasms only)
Teratoma
Mature Teratoma, differentiated (TD)
Immature TD
With a sarcomatous or carcinomatous component Malignant teratoma, intermediate (MTI)
Choriocarcinoma (pure) Malignant teratoma, trophoblastic (MTT)
Mixed Germ Cell Tumors __________
Embryonal carcinoma and mature and/or immature teratoma MTI
Yolk sac tumor and mature and/or immature teratoma MTI
Seminoma and teratoma Combined tumor (seminoma and TD)
Seminoma and embryonal carcinoma Combined tumor (seminoma and MTU)
Choriocarcinoma and embryonal carcinoma MTT
Choriocarcinoma and teratoma MTT
Choriocarcinoma and seminoma Combined tumor (MTT and seminoma)

From: Ulbright TM, Roth LM. Testicular and paratesticular neoplasms. In:Sternberg SS, ed. Diagnostic Surgical Pathology. New York: Raven Press, 1994:1885-1947.

Epidemiology
Testicular cancer is the most common form of malignancy in young men between the ages of 15 and 45 years. The incidence of testicular cancer rises significantly around puberty, peaking between 25 and 35 years and then slowly declines to about age 60. The incidence in the United States is approximately 6 cases per 100,000 of white males. [6] While many epidemiologic studies have not separately analyzed histologic subtypes, it is known that seminomas occur in patients who are generally 10 years older than those with non-seminomatous germ cell tumors (about 40 versus 31 years, respectively). Spermatocytic seminomas occur in the older age population, averaging about 60 years. [1]

The incidence of testicular cancer in North America and many European countries has increased significantly over the last fifty years at rates of 2-5% per year leading to a doubling of the age standardized incidence every 15-25 years. [7, 8, 9, 10]

There are wide variations in the incidence of testicular cancer in the different parts of the world. [1] The highest rates, about 9 cases/100,000 males, occur in Scandinavia and Switzerland and the lowest rates in Asia and Latin America. There are significantly higher (about 5x) rates of testis cancer in white Americans compared to black Americans. [6] Interestingly, there is a high incidence of testicular cancer in Maoris in New Zealand relative to other non-white races. [11, 12]

There is an increased propensity for testicular cancer in higher social economic classes and in professional workers compared to manual workers. [13] Furthermore, an increased frequency of testicular germ cell tumors has been described in patients with acquired immunodeficiency syndrome (AIDS). [14, 15] Four factors that have not been convincingly associated with testicular cancer are tobacco use, alcohol use, radiation exposure and prior vasectomy. (1) There have been many studies showing weak associations between testis cancer and a wide variety of occupational exposures and environmental factors, however, the evidence is mostly inconclusive. [1] There are only five well established positive associations with testicular cancer for which significant data exists: (1) cryptorchidism, (2) history of prior testicular germ cell tumor, (3) family history of testicular cancer, (4) certain intersex syndromes and (5) infertility.

Cryptorchidism
Cryptorchidism is one of the best established risk factors for testicular cancer with a 4-5 times elevated risk of developing a testicular germ cell tumor compared to the general population. [16, 17, 18] The most common associated tumor is seminoma. The mechanism whereby cryptorchidism predisposes to germ cell tumor is unclear. The risk is not limited to the cryptorchid testis but the contralateral testis is also at increased risk. [19] In some patients, a dysgenetic state may relate to the development of both cryptorchidism and germ cell neoplasia. Intratubular germ cell neoplasia, unclassified type (IGCNU) is found in 2-4% of cases of cryptorchid testes. [19, 20, 21] Some have advocated for the use of diagnostic testicular biopsy to identify the presence of IGCNU. [20, 22] Follow-up studies of patients with IGCNU have shown a high rate of development of invasive germ cell malignancy (about 50% at 5 years). [23] In one large series, only 1 of more than 1,500 patients with negative testicular biopsies developed testicular cancer over a follow-up period of 8 years. [20]

History of Testicular Germ Cell Tumor
Patients with prior testicular germ cell tumors are at increased risk for developing germ cell malignancy in the residual testis. About 2-5% of patients have bilateral tumors which may be synchronous or more commonly metachronous. [24, 25, 26, 27] There is an increased risk of cancer if the residual testis is either cryptorchid or atrophic or if there is a family history of testicular cancer. [28, 29, 30] Intervals of more than a decade have been seen with metachronous testicular cancers. Biopsy of the remaining testis is an effective method of identifying patients at risk for second primary testicular germ cell tumors although this is not widely advocated by urologists in North America. [22, 29]

Familial Predisposition
Some testicular germ cell tumors appear to have a familial basis with an approximate 2% frequency of testicular cancer in first degree male relatives of patients with testis cancer compared to 0.4% in a controlled general population. [31, 32, 33, 34, 35] Brothers appear to be at highest risk (almost 10x) followed by sons (6x) and fathers (4x). There is an apparent increased risk of bilaterality in patients with familial testicular cancer. [31, 35]

Intersex Syndromes
Patients with gonadal dysgenesis who carry a Y chromosome have an increased rate of testicular germ cell malignancy often in association with a preexisting gonadoblastoma. [36, 37] Approximately 30% of gonadal dysgenesis patients develop gonadoblastoma. Seminoma is the most common tumor to occur in this situation. Additionally, patients with testicular feminization (androgen insensitivity) are at increased risk for developing a germ cell malignancy; about 5-10% develop germ cell tumors. [38, 39] Gonadal biopsy may be used to identify ICGNU in patients with gonadal dysgenesis or androgen insensitivity syndrome prior to development of an invasive tumor. [40, 41, 42, 43]

Infertility
The association between oligospermic infertility and risk of germ cell tumors is less well established than the four factors previously discussed. Male infertility patients have an elevated risk of testis cancer and IGCNU is identified in about 1% of these patients. [21] However, the inter-relations among testicular atrophy, cryptorchidism, gonadal dysgenesis and infertility make it difficult to establish infertility as an independent risk factor. [44]

Pathogenesis
From the clinical, morphologic, epidemiologic and pathogenetic perspectives, there are five main categories of germ cell tumors, two occurring in the prepubertal age range and three in postpubertal years (figure 1).

Figure 1:



The two prepubertal childhood categories are pediatric yolk sac tumor and teratoma which in some instances may be related, although they are mostly distinct entities. The three main categories of adult germ cell neoplasia are the usual forms of seminoma and non-seminomatous tumors associated with intratubular germ cell neoplasia, unclassified variety (IGCNU), spermatocytic seminoma and the rare postpubertal dermoid cysts and at least some epidermoid cysts. Pediatric teratomas and dermoid/epidermoid cysts in adults are generally considered benign germ cell neoplasms probably analogous to the common ovarian teratomas (see later section). [45] Conversely, pediatric yolk sac tumour, spermatocytic seminoma and postpubertal seminomas and non-seminomatous neoplasms including nearly all postpubertal teratomas are malignant. Most of the subsequent discussion relates to the usual postpubertal germ cell tumors (GCTs) related to IGCNU but I will return to the other pathogenetic categories later.

Usual Postpubertal Germ Cell Neoplasms
The historic model of germ cell tumor histogenesis (figure 2) suggested two divergent pathways, one leading to seminoma which was considered incapable of further differentiation and a second pathway leading to embryonal carcinoma which could subsequently differentiate into other non-seminomatous components including somatic, yolk sac and trophoblastic elements. [46]

Figure 2:




Over the years, many authors have questioned the accuracy of this conceptual framework. [1, 47] The bulk of evidence suggests that seminoma is not terminally differentiated and may in fact be a precursor for most if not all postpubertal non-seminomatous tumors. In 1988, a tetrahedron model for germ cell tumor histogenesis (figure 3) was proposed in which IGCNU and seminoma have a central role. [48]

Figure 3 [1]




Evidence in favor of this model include: (1) finding of non-seminomatous elements at autopsy in patients dying of progressing tumor after treatment for pure seminoma, [49, 50] (2) ultrastructural evidence showing early carcinomatous differentiation in some cases of seminoma, [48] (3) focal staining for cytokeratins in seminoma, [51, 52] (4) identification of seminoma showing focal evolution into yolk sac tumor supported by light microscopic immunohistochemical observations, [53] (5) identification of seminoma with trophoblastic differentiation, [54, 55] (6) similarities in morphology, phenotype and genetics of IGCNU and seminoma, (7) occurrence of marker chromosome, isochromosome 12p in seminomas, non-seminomas and IGCNU, [56] (8) ploidy studies of germ cell tumors demonstrating higher DNA content in seminomas compared to non-seminomatous germ cell tumors supporting the theory that embryonal carcinoma and other non-seminomas may evolve from seminoma through genetic instability. [57]

While in most instances non-seminomatous elements are thought to arise in the invasive compartment, it has been suggested that rarely, intratubular evolution of IGCNU may give rise to other intratubular patterns such as intratubular seminoma, embryonal carcinoma, yolk sac tumor or trophoblastic neoplasm prior to the development of invasive disease (see figure 4). [1] Interestingly, similarities in chromosomal composition of IGCNU and associated non-seminomatous tumors compared to chromosome composition of seminoma and its related IGCNU suggest that intratubular transformation may occur prior to a morphologic change of the IGCNU. [58]

Figure 4 [1]




Postpubertal testicular germ cell tumors commonly display abnormalities in chromosome 12. [56, 59] Most tumors contain one or more isochromosomes 12p. The isochromosome abnormality is also detected in seminomas and non-seminomatous germ cell tumors in extragonadal locations. Up to 80% of invasive germ cell tumors contain an i(12p); it is found more frequently in non-seminomas than seminomas. Virtually all invasive postpubertal germ cell tumors also show a gain of 12p even in the absence of an isochromosome. [56] This suggests that the 12p sequences have importance in the pathogenesis of this cancer. Interestingly, IGCNU is also associated with i(12p) but not with 12p amplification, the latter of which may arise through a different mechanism. [56] The level of 12p amplification does not appear to correlate with disease stage on treatment response. [59]

It is also known that IGCNU and seminoma cells stain positively for the stem cell factor receptor c-Kit. Mutations in the c-Kit gene are commonly seen in seminoma. [60] Of great interest is the observation that an activating mutation within c-Kit affecting a specific codon (816) is associated with the development of bilateral testicular germ cell tumors. [61] The finding of a c-Kit mutation associated with bilateral germ cell tumors may allow screening for patients at increased risk and may allow for a rational approach to testis preserving treatment protocols. [59]

Some authors have suggested a model of germ cell tumour development whereby IGCNU (carcinoma in situ) arises from a primordial germ cell or gonocyte. [59] The tumors arising from the IGCNU are either primitive elements, i.e. seminoma or embryonal carcinoma, or mimic intrauterine development with both somatic and extraembryonal (yolk sac, trophoblastic) tissues. Seminomas are composed of cells similar to the primordial gonadal cells (gonocytes) and IGCNU. [59] The non-seminomatous germ cell tumors contain elements of embryonal carcinoma (a stem cell component), teratoma (somatic differentiation), choriocarcinoma (trophoblastic differentiation) and yolk sac tumor. Embryonal carcinoma cells are pluripotent cells that can differentiate into other differentiated histologic subtypes. [59]

Central Role of Intratubular Germ Cell Neoplasia
Intratubular germ cell neoplasia is defined by the presence of malignant germ cells within seminiferous tubules. Intratubular germ cell neoplasia usually occurs as an undifferentiated pattern, so-called IGCNU. Differentiated patterns of intratubular germ cell neoplasia may occasionally be seen. Intratubular germ cell neoplasia unclassified (IGCNU) was originally described by Skakkebaek as carcinoma in situ. [23, 62] The term IGCNU is preferred by many because this lesion is not epithelial and is frequently associated with seminoma, a non-epithelial neoplasm. [1] IGCNU is considered a precursor lesion for the entire spectrum of postpubertal germ cell tumors with the exception of spermatocytic seminoma and the benign dermoid/epidermoid cysts. Fifty percent (50) of patients with IGCNU detected in a testicular biopsy will develop invasive testis cancer in a 5 year period. (23,62] IGCNU is present in 2-4% of cryptorchid patients, [21] in about 5% of contralateral testes of patients with a history of germ cell tumor, [29] high rates in some cases of gonadal dysgenesis and androgen insensitivity syndrome [40, 63] and in about 0.4-1% of patients with oligospermic infertility. [21] Nearly all cases of invasive germ cell malignancy of the testis in adults display IGCNU when residual seminiferous tubules are identified. [64, 65]

At the histologic level, IGCNU is characterized by atypical germ cells with enlarged hyperchromatic nuclei and clear cytoplasm located along the basal aspect of seminiferous tubules. The chromatin pattern is vesicular, nucleoli are conspicuous and mitotic figures are frequently seen. Sertoli cells are commonly displaced towards the lumen and spermatogenesis is generally absent. Non uncommonly, IGCNU will spread in a pagetoid fashion into the rete testis. [66] In progressive cases, the seminiferous tubules can be replaced by cells of IGCNU in a pattern resembling so-called intratubular seminoma.

The cells comprising IGCNU are usually PAS positive, diastase resistant indicating cytoplasmic glycogen. The placental alkaline phosphatase stain (PLAP) is positive in more than 95% of cases. [67, 68] Antibodies against c-kit (CD117), angiotenson converting enzyme and glutathione S-transferase-p stain positively as do antibodies M2A and ND2-40. [69] Ultrastructural studies show similarities between IGCNU and seminoma. [70]

Recently, OCT3/4 (POU5F1), a member of the POU family of transcription factors has been studied in IGCNU and invasive germ cell tumors. [59, 71] This marker is expressed in pluripotent mouse and human embryonic stem cells (primordial gonadal cells). [72] The transcription factor functions as a "master switch" in differentiation by regulating cells with pluripotent potential. [73] This marker is down-regulated during differentiation. Interestingly, the OCT3/4 stains IGCNU, invasive seminoma and embryonal carcinoma but does not stain differentiated histologic patterns such as teratoma and yolk sac tumor. [73] At a practical level, OCT3/4 immunoreactivity may be used in the differential diagnosis of undifferentiated neoplasms where seminoma and/or embryonal carcinoma enter the differential diagnosis.

Testicular biopsies can detect ICGNU in high risk patients with high sensitivity. [74] Two 3 mm testis biopsies can detect most cases of IGCNU. Some have advocated screening in patients with a history of cryptorchidism, prior testicular cancer and somatosexual ambiguity. [29]

IGCNU when detected is usually treated by orchidectomy or radiation. Chemotherapy may eradicate IGCNU but this is not considered a totally effective form of therapy. [29, 69]

Other forms of intratubular germ cell neoplasia may occasionally be seen. Intratubular seminoma usually occurs simultaneously with invasive seminoma. It is characterized by a complete filling of seminiferous tubules by seminoma cells in contrast to IGCNU where the cells are located along the basal aspect of the tubules. [1, 69] The cells of intratubular seminoma have the same morphologic, histochemical and immunohistochemical features as IGCNU. Occasionally, a striking granulomatous reaction can be seen in relationship to intratubular seminoma. [1]

Intratubular spermatocytic seminoma can be seen in association with invasive spermatocytic seminoma. [1, 69] It is characterized by the same polymorphous grouping of cells that characterizes the invasive component. Intratubular embryonal carcinoma is occasionally seen, usually in association with invasive embryonal carcinoma or mixed germ cell tumor. [1, 69] The cells of intratubular embryonal carcinoma are large polygonal cohesive cells similar to invasive embryonal carcinoma. They often show central comedo-like necrosis and occasionally calcification is identified.

Other rare forms of intratubular neoplasia comprising yolk sac tumor and trophoblastic neoplasia are distinctly rare. [1, 47]

Spermatocytic Seminoma
The pathogenesis of spermatocytic seminoma is poorly understood. [75] It constitutes 1-2% of testicular germ cell neoplasia and occurs with an incidence of about 0.2 cases per 100,000 population. [1, 69] This tumor is distinct from usual postpubertal seminoma on a number of grounds: (1) it is not associated with IGCNU although intratubular spermatocytic seminoma may be identified, (2) it is not typically associated with a lymphocytic stromal reaction, (3) it does not occur in the ovary or other extratesticular germ cell tumor sites, (4) it is not a component of mixed germ cell tumor, (5) only a single case of documented metastatic disease is reported, [76, 77] (6) immunohistochemical markers of usual seminoma including PLAP and CD117 are negative in spermatocytic seminoma. [69]

Spermatocytic seminoma has a distinctive meiotic-type of chromatin structure in some cells. It has been proposed that this tumor develops from meiotic cells. [78] Nevertheless, haploid DNA values have not been identified. [79, 80] Furthermore, lectin binding studies do not provide support for spermatogenic differentiation. [81]

Recent studies utilizing markers for germ cell differentiation and for the transition from mitoses to meiosis have shed some light on the histogenesis of spermatocytic seminoma. [75] Proteins that are commonly identified in gonocytes and spermatogonia including Chk2, MAGE-A4 and NSE are consistently expressed in spermatocytic seminoma whereas markers such as TRA-1-60 which is expressed in embryonic germ cells but not in normal adult testis are undetectable in spermatocytic seminoma. Furthermore, the p19 oncogene involved in the transition from mitosis to meiosis in germ cells is not detected in spermatocytic seminoma. The expression pattern of the above markers suggests that spermatocytic seminoma originates from a premeiotic germ cell which has lost embryonic traits and is committed to the spermatogenic lineage but has not yet passed the meiotic checkpoint. Further studies are required to consolidate this hypothesis.

Prepubertal Teratomas and Postpubertal Dermoid and Epidermoid Cysts
It has been suggested that most prepubertal (pediatric) testicular teratomas and ovarian teratomas have a similar pathogenesis. [45] Analysis of DNA and karyotype of mature teratomas of the ovary have revealed a normal 46,XX karyotype and a diploid DNA content. [82] Genetic analyses have shown that ovarian teratomas are usually homozygous for polymorphic genetic markers, a finding suggesting that they are derived from germ cells after meiosis I but before meiosis II. [83] Some degree of heterozygosity may be attributed to crossing over of chromosomes preparatory to meiosis I which more frequently involves loci distant from the centromere. [84] Ovarian teratomas are therefore thought to result from a parthenogenetic transformation of benign germ cells resulting in a benign neoplasm which emulates normal development. [84] Interestingly, the ovarian teratomas that are immature and have malignant potential also have karyotypes with only minor deviations from the 46,XX genotype. [85, 86, 87]

Like ovarian teratomas, prepubertal testicular teratomas have normal DNA content and karyotypic findings. [88, 89] No amplification of the short arm of chromosome 12 is seen and there is an absence of isochromosome 12p in pediatric teratomas. [90] The seminiferous tubules adjacent to prepubertal teratomas lack IGCNU. [91, 92] Some enlarged "atypical" germ cells have been described but these may be reactive since similar cells are seen adjacent to sex cord-stromal tumors in the pediatric age range. [93]

This finding contrasts with postpubertal teratomas which evolve from invasive germ cell tumors of conventional types, i.e. embryonal carcinoma, seminoma or yolk sac carcinoma.

In contrast to pediatric teratomas, adult teratomas are typically associated with IGCNU, display aneuploidy and may show cytologic atypia. [45] They consistently show karyotypic abnormalities including 12p amplification. [92, 94, 95, 96] Pure adult testicular teratoma is uncommon and most teratomas are components of mixed germ cell tumors. Occasionally, examples of pure teratoma are seen where metastatic sites show evidence of non-teratomatous germ cell elements including seminoma, embryonal carcinoma and yolk sac tumor. [1] Therefore, all postpubertal teratomas of usual type are considered malignant. [1, 45, 69]

It is hypothesized that the rare dermoid cysts and at least some epidermoid cysts have a similar pathogenesis to the common ovarian and prepubertal testicular teratomas. [97, 98, 99] Dermoid and epidermoid cysts of the testis lack IGCNU and show no evidence of cytologic atypia. Dermoids are typically cystic and may have intracystic hair and microscopically show a typical organotypic arrangement of skin adnexal structures and epidermis. Occasionally, other teratomatous elements may be present within these lesions. Most epidermoid cysts are considered "monodermal teratomas". It is conceivable that testicular carcinoid tumors may have a similar origin. [45]

Pediatric Yolk Sac Tumor
Yolk sac tumor is the most common testicular tumor in prepubertal children. [100, 101] The incidence is approximately 0.12 cases per 100,000 population. The usual age range is newborn to 9 years with a mean age of 1.5 years. Pure yolk sac tumor in postpubertal males is distinctly rare. [1] In adolescence and adulthood, yolk sac tumor is usually an element of mixed germ cell tumor where it has been seen in up to 44% of prospectively examined non-seminomatous germ cell tumors in one series. [102]

The pathogenesis of pediatric yolk sac tumor is poorly understood. Unlike most postpubertal germ cell tumors, it is not associated with cryptorchidism. [103] Furthermore, it occurs in equivalent frequencies in the white and black populations in contrast to usual postpubertal GCT. [103]

The relationship between yolk sac tumor and IGCNU is poorly understood. Generally, IGCNU is not identified adjacent to yolk sac tumor, however, in occasional cases, it may be seen. In rare reports, it is suggested that neoplastic intratubular germ cells are not basally located in the prepubertal testis but are dispersed at various levels within the tubule. [23, 104] The more typical pattern of IGCNU is thought to evolve with advancing age. In rare cases, an intratubular pattern of yolk sac tumor may be seen. [1, 69]

Of note, there is an absence of isochromatin 12p in pediatric germ cell tumors. It has been suggested that yolk sac tumors arise from an embryonic stem cell or an embryonic germ cell at an earlier stage of maturation than the germ cell that gives rise to IGCNU and the usual postpubertal GCTs. [59, 105]

Summary
The testicular germ cell tumors have diverse pathogenetic origins with at least four distinct developmental pathways. Advances in phenotyping and molecular biology have considerably increased our understanding of these diverse neoplasms. Nevertheless, there are probably more unanswered questions as resolved issues and additional genomic and proteomic investigations should lead to a clearer understanding of etiopathogenetic sequences and provide a basis for more focused customized therapies for patients with testicular germ cell neoplasms.

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