Abstract
Testicular tumors in the prepubertal period are rare. Germ cell tumors (GCTs) account for 71 % (most are pure yolk sac tumors and teratomas-prepubertal type), and gonadal stromal tumors account for 29 % of prepubertal testicular tumors. Unlike testicular tumors in adults, about 70–75 % of prepubertal tumors are benign. There are several differences between GCTs occurring in children and those of adults from the histogenetic, histopathologic, molecular biology and biologic behavior points of view. Cryptorchidism does not play an important role as an underlying factor. The peritumoral parenchyma rarely shows germ cell neoplasia in situ (GCNIS) which suggests that GCTs in prepubertal boys have a different origin from those in adolescents and adults. Both YSTs and teratomas in childhood are diploid, unlike the same tumors in adults which show isochromosome 12p in 80 % of cases. This chapter also reviews the morphological characteristics of GCNIS both in childhood and adult testis and its differential diagnosis with delayed maturation of gonocytes and atypical germ cells.
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Introduction
Testicular tumors in the prepubertal period are rare. The annual incidence is estimated to range from 0.5 to 2.0 per 100,000 boys, accounting for 1–2 % of all solid pediatric tumors although it is increasing [1, 2]. The age distribution of prepubertal testicular tumors is bimodal, with one peak occurring in the first 2 years of life and a second occurring in young adulthood. The frequency of the distinct testicular tumors in pediatric age varies among series, depending on whether the adolescence period is included or not. Germ cell tumors account for 71 % (yolk sac tumors [YSTs], 49 %; teratomas, 13 %; seminoma and mixed germ cell tumors, 9 %), and gonadal stromal tumors account for 29 % of prepubertal testicular tumors [3]. About 70–75 % of prepubertal tumors are benign [4].
Germ Cell Tumors (GCTs)
There are several differences between GCTs occurring in children and those of adults from the histopathologic, molecular biology and biologic behavior points of view. Most are pure YSTs or teratomas [5, 6]. GCTs account for 71 % of testicular tumors in childhood versus 96 % in adulthood. Cryptorchidism does not play an important role as an underlying factor, as fewer than 40 cases have been reported in undescended testes [7]. By contrast, ethnicity is important: prepubertal tumors are more frequent in Asian-Pacific Islanders than in white men, while the incidence is lowest among blacks [8]. The peritumoral parenchyma rarely shows germ cell neoplasia in situ (GCNiS) also known as carcinoma in situ (CIS), which suggests that GCTs in prepubertal boys have a different origin from those in adolescents and adults [9].
Moreover, it should be emphasized that the cytokinetic profile for the same histologic tumor type is different. YSTs in prepubertal children show chromosome 1 imbalances, loss of 6q, and chromosome 20 anomalies [10–13], while isochromosome 12p is present in 80 % of adult cases and enlargement of 12p segments is found in the remaining adult cases. Both YSTs and teratomas in childhood are diploid [14].
GCTs appearing in pubertal age or immediately afterward do not have any morphologic, immunohistochemical, or cytogenetic differences with respect to adult GCTs [15–18].
Yolk Sac Tumors, Prepubertal Type
This is the most common testicular tumor in infancy and childhood, accounting for about 70 % of pediatric GCTs [19]. The age of onset varies from birth to 9 years of age, with a peak incidence at 18 months. Most YSTs in children are pure, unlike those in adults [20]. One case associated to microlithiasis has been reported [21].
Clinical Features
The most common presentation (>90 %) is of a painless scrotal mass. A hydrocele is associated with a testicular tumor in 15–50 % of cases [22], and in 6 % of patients, metastasis has been reported as the first finding [23]. One percent of YSTs are bilateral, while in unilateral cases, there is a slight predilection for the right testis. The diameter ranges between 2 and 4 cm. Ninety percent of patients have significant elevation of serum alpha-fetoprotein (AFP) [24]; this should, however, be interpreted with caution as such elevation can overlap with normal levels. Regarding AFP levels in infants, it should be taken into account that 50,000 ng/mL is considered normal at birth; the level then decreases progressively to 10,000 ng/mL at 2 weeks, 300 ng/mL at 2 months, and 12 ng/mL at 6 months [25].
Pathologic Features
The macroscopic appearance of YST in children is a solid, white to gray mass replacing most of the testicular parenchyma. The cut surface is microcystic, myxoid, or gelatinous. Small foci of necrosis and hemorrhage can be observed (Fig. 4.1).
Yolk sac tumor. The whitish multinodular tumor replaces two-thirds of the testicular parenchyma
Numerous microscopic patterns including microcystic, endodermal sinus, papillary, solid, glandular, myxomatous, sarcomatoid, macrocystic, polyvesicular vitelline, hepatoid, enteric, and parietal patterns can be found in YSTs [20, 26–28].
The microcystic pattern is the most common and is characterized by a reticular pattern that recalls a disorganized spider web of cells with large intracellular vacuoles (Fig. 4.2). The cytoplasm is reduced to a thin peripheral ring resembling false lipoblasts, as the vacuoles do not contain lipid. Cells can also be arranged around variably sized small cysts. In this case the cells are small, benign in appearance, and with numerous hyaline globules.
Microcystic pattern of yolk sac tumor showing cells with a large vacuole in the cytoplasm and microcysts created by cords of cells surrounding the extracellular space
The glandular pattern is defined by the presence of glandular or tubular structures, simple or complex, and contiguous to other patterns such as microcystic, myxomatous, solid, or polyvesicular vitelline. Glands may present intestinal differentiation (enteric pattern). In other cases the glands show subnuclear vacuoles resembling secretory endometrium. These glands can be distinguished from teratomatous glands by the lack of a smooth muscle component and the absence of other teratomatous elements.
The myxomatous pattern consists of a proliferation of spindle or stellate cells dispersed in a mucopolysaccharide-rich stroma. This pattern usually has a prominent vascular network described as “angioblastic mesenchyme” [27]. The cells resembling extraembryonic mesenchyme are pluripotential, with the capacity to form differentiated tissues such as the skeletal muscle, cartilage, or bone. The differential diagnosis with teratoma is established by the absence of other surrounding teratomatous elements.
The endodermal sinus pattern consists of a central vessel surrounded by tumor cells, contained within a cystic space lined with flattened tumor cells. The papillary structures are termed glomeruloid or Schiller-Duval bodies because they resemble the endodermal sinus of the placenta of the rat and are responsible for the name by which this tumor was previously known, endodermal sinus tumor. These bodies, although not very numerous, are characteristic of YST (Figs. 4.3 and 4.4).
Endodermal sinus pattern of yolk sac tumor showing numerous cystic spaces with glomeruloid structures inside that are formed by tumor cells
Schiller-Duval body in a yolk sac tumor with microcystic pattern
The papillary pattern is recognized by the presence of numerous small papillae, with or without a fibrovascular core, that project into cystic spaces. The cells are cubical or low columnar with hobnail nuclei, resulting in a jigsaw configuration.
The solid pattern consists of sheets of uniform cells with clear cytoplasm and well-defined borders. Cells show marked pleomorphism and atypia (Fig. 4.5). The solid pattern of YST is almost always associated with other patterns, most commonly microcystic/reticular (75 %), glandular (35 %), and myxoid (25 %). This tumor may resemble a seminoma that, although rarely, can present in late childhood and puberty, but fibrous septa and a lymphoid component are absent in YST. Moreover, the immunophenotype is different [29].
Solid and microcystic patterns of a yolk sac tumor. Numerous eosinophilic bodies can be observed in the cytoplasm of tumor cells
The sarcomatoid pattern consists of a spindle cell proliferation commonly inside a microcystic pattern.
The macrocystic pattern usually arises from the coalescence of microcystic spaces to form a large cyst. The cells lining the cysts are flattened and show mild atypia.
The polyvesicular vitelline pattern is characterized by the presence of cysts with a central constriction producing two vesicles that remain connected, dispersed in a myxoid stroma (Fig. 4.6). The name refers to the image observed when the secondary yolk sac is formed in a normal embryo. The epithelium lining the second vesicle is commonly columnar, which contrasts with the flattened epithelium of the original cavity. The cells frequently show hyaline globules. The occasional presence of glands with mucous cells or cells with brush borders is interpreted as a differentiation of this second cavity. There is an established parallelism with gastrointestinal differentiation from the secondary yolk sac in the normal embryo.
Polyvesicular vitelline pattern of yolk sac tumor. Vesicle-like structures with a partial constriction lined with flattened epithelium in a myxoid stroma
The hepatoid pattern is also interpreted as a differentiation from yolk sac. It is characterized by clusters of polygonal cells arranged in sheets, nests, or cords. The cells have large, round, vesicular nuclei with prominent nucleoli. Atypia and mitosis are common. The cytoplasm may be clear, slightly amphophilic or basophilic, and may contain hyaline globules. This pattern is more common in adult tumors than in children and is almost always focal.
The parietal pattern has extensive and irregular deposits of extracellular basement membrane. Tumor cells are arranged surrounding or inside these masses. This pattern is named after the resemblance of the thick basement membrane (Reichert’s membrane) of the parietal layer of the vitelline sac of rodents.
Most times YST is formed by different patterns in a myxoid or fibrous stroma or a highly cellular mesenchyme. The most common patterns are microcystic, solid, and myxomatous. The polyvesicular vitelline, sarcomatoid, and parietal patterns are rare. The glandular and parietal patterns are most often seen after chemotherapy.
Immunohistochemistry
Most tumor cells show positivity for cytokeratins and glypican-3 by immunohistochemistry, while staining for OCT3/4 is uniformly negative. Placental-like alkaline phosphatase (PLAP) positivity is found in 39–85 % of tumors [26]. AFP is focally observed in most tumors except for those with a hepatoid pattern that is diffuse, with or without a relationship with hyaline globules. Fifty percent of tumors show positivity for alpha-1 antitrypsin, while vimentin is positive in YSTs with myxomatous and sarcomatoid patterns. Laminin is characteristically positive in the parietal pattern. The enteric glands express carcinoembryonic antigen [28].
Biologic Behavior
YSTs in children have a much better prognosis than those in adults [30]. The prognosis of pediatric YST is correlated with age, with slower growth rates and lower grades of malignancy observed in younger children. In children younger than 5 years, the incidence of metastasis is no higher than 5 %, which increases to 20 % in adults [31]. The most common route of dissemination is hematogenous and the lung is the most common metastatic location [22]. In stage I YSTs, orchiectomy is sufficient, or even testis-sparing tumor excision and follow-up with chest and abdominal imaging and serum AFP measurement, as these tumors are not associated with GCNiS in the peritumoral parenchyma. Survival rates in stage I are higher than 80 % [32, 33]. In case of recurrence or metastasis, patients can be successfully treated with platinum-based chemotherapy (etoposide, carboplatin, and bleomycin) [34–36].
Teratoma, Prepubertal Type
Teratoma is the second most common testicular GCT in pediatric age according to the Prepubertal Testicular Tumor Registry of the American Academy of Pediatrics [37]. However, there is reason to believe that its incidence has been underestimated and that the real number is not accounted for in large series as not all cases are included because of their benign behavior. The incidence of teratomas may actually be higher than that of YSTs [38–40]. The median age at presentation is 13 months. Some cases have been reported in the neonatal period [41], and teratomas are unusual in children older than 4 years of age. Testicular teratomas in children are different from teratomas in adults in many aspects. Teratoma is not associated with other forms of GCT and bilateralism is exceptional in children [42]. A wide variety of congenital malformations such as spina bifida, retrocaval ureter, hemihypertrophy, and hernia can be associated with testicular teratomas. A total of 30 cases have been reported of teratomas originating in intra-abdominal undescended testes [43].
Clinical Features
Most patients with testicular teratomas present with a testicular mass detected during clinical exploration. Some teratomas contain large cysts filled with mucus or fluid that can be misdiagnosed as hydrocele [44] or may contain simple cysts [45], delaying the diagnosis by 6 months on average [46]. Ultrasonography is a useful method to identify a well-delimited, partially cystic intratesticular lesion. In teratomas occurring at prepubertal age, serum markers such as beta-HCG and AFP show normal levels except for teratomas with intestinal glands, which show moderate elevation of AFP.
Pathologic Features
Macroscopically, teratomas are cystic tumors with solid areas. The cysts may measure up to 1 cm in diameter and contain mucous, watery fluid or keratin. Solid areas may contain cartilage or bone.
Microscopically, teratomas are neoplasms that can show endoderm-, mesoderm-, or ectoderm-derived tissues in a disorganized or organoid arrangement. Like teratomas, postpubertal type childhood teratomas can contain mature and immature tissues. Mature teratomas contain cysts lined with squamous, ciliated respiratory-type or intestinal-type epithelium next to smooth muscle, cartilage, bone trabeculae, neuroglia, choroid plexus, and occasionally pigmented epithelium and pancreatic tissue (Figs. 4.7 and 4.8). Immature teratomas contain different types of immature tissues such as neuroepithelium (small cells in tubular or rosette arrangement) and blastema (nodular collections of cells with hyperchromatic nuclei and scant cytoplasm with or without tubular structures inside). The seminiferous tubules in the peripheral parenchyma show hypertrophic or multinucleated germ cells.
Cystic organoid teratoma in a 10-year-old boy. The spherical formation resembles a complete intestinal wall. The remaining content of the cyst is made up of abundant keratin material
Mature teratoma with islands of hyaline cartilage and cysts lined with nonkeratinized epithelium and glandular structures
Dermoid cyst is a variant of prepubertal, type teratoma, uncommonly present in childhood [47, 48]. Macroscopically, it consists of one large cavity filled with cellular detritus and hair. Microscopically, all epidermal and dermal components are represented. Sebaceous glands are usually numerous (Figs. 4.9 and 4.10). Some authors accept as dermoid cysts tumors containing in their walls other tissues such as smooth muscle, adipose tissue, cartilage, bone, thyroid, salivary gland, gastrointestinal tissue, respiratory-type epithelium, and mature neural tissue [49].
Dermoid cyst. The encapsulated cyst comprises the testicular parenchyma
Dermoid cyst partially lined with skin and adnexal pilosebaceous structures as well as respiratory-type epithelium in the septa. Note several islands of cartilage as another component
Epidermoid cyst is defined as an encapsulated cyst lined with keratinized stratified flat epithelium without skin adnexal structures [50]. The keratin masses that fill the cyst produce a characteristic ultrasonographic image resembling onion layers or a dartboard. Most authors consider this lesion as nontumoral and some consider it a as monodermal teratoma. Epidermoid cysts are rare in the pediatric age [51].
Testicular primary carcinoid tumors have been reported as monodermal teratomas [52].
Biologic Behavior
The biologic behavior of teratomas in prepubertal age is benign, independent of their maturity or immaturity (unlike teratomas in adulthood). The nonmalignant behavior justifies enucleating or testis-sparing surgery in cases of bilateral tumors or unique testis [53]. This biologic behavior is related to the absence in childhood (except in 1 reported case [54]) of GCNiS in the residual parenchyma, as previously mentioned [55]. In adolescents, orchiectomy and evaluation with the same protocols as used in adult GCTs are recommended. A small percentage of pediatric teratomas have a malignant somatic component, as is frequently observed in adult testis. In these unusual cases, treatment should be completed with chemotherapy or surgery depending on the nature of the malignant component [56].
Other Germ Cell Tumors
Some cases of embryonal carcinoma [34], seminoma [57], and mixed GCT [58] have been reported in childhood and more frequently adolescence. These tumors have a very aggressive behavior, presenting as metastatic disease at diagnosis [59, 60]. After puberty, these tumors are similar to those in adults [61].
Gonadoblastoma
Gonadoblastoma is a mixed tumor composed of a mixture of germ cells and cells resembling Sertoli/granulosa cells arranged in a preferably nodular pattern in an ovarian-type stroma [62]. It characteristically arises in dysgenetic gonads in patients with disorders in sexual differentiation who have either the whole or a part of the Y chromosome in their genome. The most common clinical entities where gonadoblastoma develops are 46XY pure gonadal dysgenesis (patients with bilateral streak gonads) [63–65], mixed gonadal dysgenesis (streak gonad on one side and testicular dysgenesis in the contralateral testis), dysgenetic male pseudohermaphroditism (both gonads with testicular dysgenesis features), ovotesticular disorder [66], patients with Turner syndrome and Y chromosome residual material [67, 68], and androgen receptor insensitivity. Exceptionally, gonadoblastoma has been observed in a normal testis [69].
Eighty percent of patients with gonadoblastomas are phenotypically female, and 20 % are phenotypically male [70]. The TSPY1 gene (which encodes a testis-specific protein) located at the GBY locus in the centromeric portion of the short arm of the Y chromosome is involved in the genesis of most gonadoblastomas [71, 72]. Gonadoblastoma is assumed to arise from OCT3/4-positive surviving germ cells in undifferentiated gonadal tissue of dysgenetic gonads [73].
The size varies from microscopic to 8 cm in diameter [74]. The tumors are solid and gray or yellow in color. Most gonadoblastomas arise from streak gonads. The remainder arise from testes with a thin and poorly collagenized tunica albuginea resembling the ovarian cortex, with irregular cellular cords or tubules that go through the albuginea to reach the testicular surface [75]. One-third of patients have bilateral gonadoblastomas.
Gonadoblastoma cells are arranged in nests or cords and less frequently in a diffuse pattern; the same tumor can show different patterns. Gonadoblastoma is composed of two types of cells. The first type is germ cells appearing like gonocytes or with seminoma-like morphology because of their large size, voluminous nuclei with one or two nucleoli, and pale cytoplasm. Mitosis can also be seen. The second type of cells is smaller cells with ovoid hyperchromatic nuclei and Charcot-Böttcher filaments in their cytoplasm like Sertoli cells that are admixed with germ cells. Cells with Sertoli features are arranged as an outer palisade in the nodules and around eosinophilic bodies or hyaline nodules that are dispersed by the tumor and formed by basement membrane material (Fig. 4.11). These tumors show prominent calcifications that arise from hyaline bodies. Leydig cells can be observed in the stroma among cords or nests.
Gonadoblastoma. Nests made up of two cell types. The smaller cells have hyperchromatic nuclei and are arranged above the basement membrane and surrounding the abundant eosinophilic matrix. The larger cells have clear cytoplasm and prominent nucleoli
Immunohistochemistry
Gonocyte-like cells express OCT3/4, PLAP (Fig. 4.12), c-kit, TSPY, and D2-40 [76], while Sertoli/granulosa cells show inhibin in their cytoplasm and SOX9 and more commonly FOXL2 in the nuclei [77]. Leydig cells are inhibin and calretinin positive.
Gonocyte-like cells of a gonadoblastoma show PLAP membranous immunostaining
Gonadoblastoma is considered to be an in situ neoplasia precursor of infiltrating tumors like germ cell neoplasia, in situ. The level of testicularization of the gonad will determine the histologic composition of the precursor lesion, either gonadoblastoma or GCNiS [78]. When germ cells proliferate, they actively destroy the nodular arrangement of the tumor and infiltrate the gonad, giving rise to any type of GCT, although the most common are seminoma and dysgerminoma [79] (Fig. 4.13). Gonadectomy is recommended in all cases because of the infiltrating ability of the tumor.
Dysgerminoma originated from gonadoblastoma. Remnants of gonadoblastoma can be recognized with Sertoli/granulosa cells and Call-Exner bodies
The differential diagnosis of gonadoblastoma in childhood includes fetal gonadoblastoid testicular dysplasia (abnormally differentiated testicular parenchyma that is associated with Walker-Warburg syndrome) as well as ureter malformations and renal cystic dysplasia. The peripheral testicular parenchyma shows a crescent-like zone with spherical or irregular solid nests, cords, and malformed tubules that are embedded in an undifferentiated stroma. Each structure is composed of three cell types: cells with vesicular nuclei and vacuolated cytoplasm, cells with hyperchromatic nuclei, and germ cell-like cells. However, gonocyte or dysgerminoma-like cells are absent unlike gonadoblastomas.
In postpubertal patients, Sertoli cell nodules colonized by GCNiS cells may be misinterpreted as gonadoblastoma. Sertoli cell nodules are common in cryptorchid testes of postpubertal patients without any intersexual condition. Sertoli cell nodules colonized by GCNiS cells are usually in the vicinity of seminoma or seminiferous tubules with GCNiS. Sertoli/granulosa cells express both SOX9 and FOXL2, and this is evidence of their incomplete differentiation. In contrast, Sertoli cell nodules with GCNiS show diffuse and intense positivity for SOX9 and SF-1 and absence of immunoexpression for FOXL2 as evidence of their complete differentiation [80].
Pediatric-Type GCTs (Type I) in Adults
Several types of GCNiS, varying from mature teratomas to monophyletic immature teratomas to YSTs, have been reported in adults that, except for the patient’s age, have all the characteristics of pediatric GCTs (type I). These tumors differ from adult GCTs in the following features [81]:
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Absence of GCNiS in the peripheral parenchyma confirmed by OCT3/4 and PLAP.
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Absence of testicular scar or burned-out tumor.
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Absence of inflammatory infiltrates; minimal infiltrates or plasma cell inflammatory infiltrates are accepted.
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Demonstration by FISH of two centromeres in chromosome 12 and absence of 12p excess.
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Complete spermatogenesis.
The behavior of this group of tumors is benign, and the recommended treatment should be orchiectomy or even testis-sparing surgery.
The origin of type I GCT in adults is probably a germ cell that is directly reprogrammed to pluripotentiality without going through a GCNiS stage. Like their pediatric counterparts, these tumors probably originate in the neonatal period or some years later, presenting clinical symptoms in puberty or adulthood [82].
Germ Cell Neoplasia In Situ (GCNiS)
Germ cell neoplasia in situ presumably originates during fetal life from gonocytes that do not differentiate properly and maintain their original immature and multipotent features. Morphologic, immunohistochemistry, and genetic profile similarities support this hypothesis [83–85]. The microscopic morphology of GCNiS in childhood is different from GCNiS in adults. Before making a diagnosis of GCNiS in infancy or childhood, it is important that one is familiar with the following features: (a) GCNiS features in adult testis, (b) proliferation and differentiation of fetal germ cells, (c) the most useful criteria in the differential diagnosis between a delay in gonocyte maturation and GCNiS in postnatal life, and (d) knowledge of situations with atypical-looking germ cells but without enough criteria to establish a diagnosis of GCNiS.
GCNiS Features in Adult Testis
Germ cell neoplasia in situ is the preinvasive phase of all types of GCTs except for pediatric GCTs and spermatocytic tumor. It is usually found in groups of small seminiferous tubules devoid of spermatogenesis that probably belong to the same lobule. These small tubules are often separated by larger tubules with complete spermatogenesis. The tumor cells are typically confined to the basal compartment of the seminiferous tubule, displacing Sertoli cells luminally. GCNiS cells are large cells with clear cytoplasm because of the high glycogen content and a sharply defined plasma membrane. The nuclei are large, spherical, and hyperchromatic, often with one or two prominent nucleoli and coarse chromatin (Fig. 4.14). Mitosis can be observed. Sertoli cells commonly show spherical instead of the normal triangular nuclei. The nucleoli are central but small, suggesting incomplete maturation [83]. Sertoli cell dysfunction is probably established in fetal life, leading to a defect in the mechanisms of interaction between Sertoli and germ cells and a consequent defect in gonocyte maturation. In 50 % of cases, GCNiS cells acquire infiltrating capacity after 5 years, and a GCT develops [86]. GCNiS cell transformation into seminoma is slower than transformation into a nonseminomatous tumor, which is related to the more aggressive behavior of the latter.
GCNiS cells above the basement membrane displacing Sertoli cells toward the lumen of the tubule. The cells are large and show one or two prominent nucleoli
The classical immunohistochemical markers of GCNiS are the transcription factor OCT3/4 [87, 88] and PLAP [89] (Fig. 4.15). GCNiS cells are also positive for the AP2 transcription factor AP2γ [90], podoplanin [91, 92], and c-kit [93]. OCT3/4 is expressed in the nuclei, whereas PLAP shows membranous expression. Most cells that express OCT3/4 also express PLAP. The average nuclear DNA content of CIS cells is about 4C.
PLAP immunoexpression in the membrane of GCNiS cells
Proliferation and Differentiation of Fetal Germ Cells
Three different morphologic and immunohistochemical types of germ cells have been identified in the testis during the fetal period; these types represent three different stages in the differentiation from primordial germ cell to spermatogonium. One characteristic feature of human fetal testis is the concurrence during several months of the three cell types as opposed to the homogeneous population of gonocytes in other mammalian species.
Gonocytes
Once the primordial germ cells in the genital ridge are surrounded by cells deriving from the coelomic epithelium (pre-Sertoli cells), they transform into gonocytes: gonocytes are identified in the center of the seminiferous cords separated from the basement membrane by Sertoli cells. Gonocytes are large cells that have spherical euchromatic nuclei with one or two nucleoli [94, 95]. The gonocyte immunophenotype is OCT3/4, c-kit, and PLAP positive and melanoma-associated antigen 4 (MAGEA4) negative [96–98].
Intermediate Cells
Intermediate cells (transitional gonocytes) are morphologically similar to gonocytes, although they differ in their distribution in the seminiferous cords and in their immunophenotype. Intermediate cells are located in the periphery of the seminiferous cords in contact with the basement membrane. Their immunophenotype is negative for both c-kit and MAGEA4, whereas they show weak or negative staining for OCT4 and positive staining for proliferating cell nuclear antigen (PCNA), indicating active proliferation. It has been suggested that when these cells get in contact with the basement membrane, they lose their pluripotency and start to differentiate.
Fetal Spermatogonia
Fetal spermatogonia (or pre-spermatogonia) are grouped at the periphery of the seminiferous cords above the basement membrane. They are the germ stem cells of the adult testis. Immunohistochemistry shows MAGEA4 staining, and the cells are negative for c-kit and PCNA.
At the tenth week of gestation, most germ cells are gonocytes; at approximately the 15th week, many intermediate cells are present together with gonocytes, and fetal spermatogonia can be observed for the first time. From the 22nd week onward, most germ cells are fetal spermatogonia. Some gonocytes persist even after birth. Most of them differentiate into spermatogonia between 30 and 90 days after birth at the stage known as mini-puberty; the remainder undergo apoptosis. The lack of synchronization of these stages in the human fetal testis may serve to protect the number of spermatogonial stem cells (and thus future fertility) from various insults that may occur throughout fetal life.
In summary, in parallel with germ cell differentiation, a change in the expression of several proteins takes place. PLAP is positive mainly in young gonocytes and less in pre-spermatogonia. The largest number of positive cells is observed in the first trimester of gestation, decreasing as gestation progresses (Fig. 4.16). At birth PLAP is positive only in isolated cells (less than 1 per tubule) and located in the center of the tubule. C-kit is expressed in the second and third trimesters of gestation in a similar proportion in gonocytes and pre-spermatogonia. OCT3/4 is most expressed in the first trimester and the first half of the second trimester (4–6 cells per tubule), mainly in gonocytes. Its expression decreases to three cells per tubule in the second half of the second trimester. At the end of gestation, positivity is only observed in isolated gonocytes in the center of the tubule. TSPY is positive throughout gestation exclusively in spermatogonia. Ki67 is predominantly expressed in gonocytes up to the 24th week. From that week onward, the number of positive gonocytes and pre-spermatogonia is similar. The number of positive cells decreases as gestation progresses. At birth positivity persists only in isolated gonocytes in the center of the tubule, and pre-spermatogonia seem to have entered a quiescent period [97, 99] (Table 4.1).
Fetal testis (30 weeks of gestation). Most germ cells are pre-spermatogonia located above the basement membrane
GCNiS Cell Features in Childhood (Pre-GCNiS)
In childhood, seminiferous tubules with GCNiS have no lumen, and their size is similar to that of normal tubules. Gonocyte-like cells are located both in the center of the tubule and above the basement membrane. These cells show similar nuclear and cytoplasmic features to GCNiS cells in adults [100]. They occasionally show mitosis (Fig. 4.17). Like GCNiS cells, these pre-GCNiS cells are strongly positive for OCT3/4, TSPY, and PLAP and focally for SCF [101]. OCT3/4 suppresses apoptosis of gonocytes, TSPY enhances the proliferation of these cells, and SCF is a survival and growth factor for these cells [102].
Cross section of seminiferous tubule of a 9-year-old patient showing Sertoli cells in a pseudostratified arrangement and several large cells in the center, one of them in mitosis
GCNiS cells in children have DNA contents in a hypertriploid or hypertetraploid range [103, 104]. Seminiferous tubules with germ cells are arranged in small groups preferably beneath the tunica albuginea. Gonocytes in the center of the tubule retain an embryonic phenotype that persists beyond fetal development and childhood (OCT3/4 positive). These arrested gonocytes fail to differentiate due to impaired functioning of Sertoli cells in fetal development that prevents the movement of gonocytes from the center of the tubule to the periphery to get in contact with the basement membrane [105, 106]. This pattern is maintained until puberty, when the increase in hormone production produces changes in the spermatogonial niche to induce meiosis and haploid spermatozoa. At the same time that these changes take place, GCNiS cells start to proliferate. The result is a progressive transformation of a GCNiS cell phenotype from infantile to adult.
Delayed Maturation of Gonocytes Versus Infantile GCNiS
The finding of gonocyte-like cells in an infantile testis after the third month of postnatal life, when mini-puberty finishes, raises the possibility of a delay in the maturation of gonocytes instead of an infantile GCNiS. This differential diagnosis is of great prognostic importance since the malignant potential of delayed maturation of gonocytes is practically nonexistent, while infantile GCNiS has a high risk of malignant evolution [101, 107, 108]. The problem becomes more difficult when these cells appear in populations with a high risk of GCTs, such as individuals with gonadal dysgenesis, Down syndrome, and undervirilization syndromes [109]. The differential diagnosis should be supported by the age of the patient together with cytologic, histologic, immunohistochemical, and ploidy marker data. Gonocytes with delayed maturation are uniformly dispersed in the entire testis and more or less randomly placed in the seminiferous tubules instead of in groups of seminiferous tubules (Fig. 4.18). These cells have cytologic features of gonocytes located both in the center of the tubule and above the basement membrane. In spite of their similar morphology to pre-GCNiS cells, the immunophenotype is different. OCT3/4 is expressed only in germ cells with delayed maturation that are in the center of the tubule and occasionally in the cells above the basement membrane. They are also PLAP positive (Fig. 4.19). The cells in the periphery of the tubule are TSPY positive as well. SCF is negative in delayed maturation. Inconsistent OCT3/4 expression in TSPY-positive cells in the absence of SCF expression indicates a delay in maturation.
Infantile testis of a patient with 46XY disorder of sex development with Müllerian remnants showing seminiferous tubules with intratubular gonocytes both above the basement membrane and at the center of the tubule
PLAP-positive cells inside a seminiferous tubule
Atypical Germ Cells that May Simulate GCNiS
Two types of germ cells can be misinterpreted as GCNiS cells because of their morphology, especially if the specimen has not been properly fixed. These cell types are hypertrophic and multinucleated spermatogonia. Both can be seen in the testicular parenchyma peripheral to GCTs in childhood.
Hypertrophic spermatogonia characteristically have large hyperchromatic nuclei without nucleoli and clear, abundant cytoplasm. They are polyploid cells that were probably arrested in the S phase of the cell cycle [110]. They are observed in cryptorchid testes and exceptionally in normal testes. Hyperchromatic spermatogonia are numerous in seminiferous tubules surrounding teratomas and have been observed around YSTs. These cells are negative for OCT3/4 and PLAP and positive for PCNA and p53, which is a sign of their non-tumor-proliferative nature [9, 111].
Multinucleated spermatogonia commonly show three or four nuclei, but the number can be higher. The nuclei can show features of spermatogonia type A dark, A pale, or a mixture of both. Multinucleated spermatogonia have been observed in cryptorchid testis with or without GCNiS. They have not been reported in normal testes. Multinucleated spermatogonia are produced by amitotic cell division [112].
References
Kay R. Prepubertal testicular tumor registry. J Urol. 1993;150:671–4.
Coppes MJ, Rackley R, Kay R. Primary testicular and paratesticular tumors of childhood. Med Pediatr Oncol. 1994;22:329–40.
Ross JH, Kay R. Prepubertal testis tumors. Rev Urol. 2004;6:11–8.
Pohl HG, Shukla AR, Metcalf PD, Cilento BG, Retik AB, Bagli DJ, Huff DS, Rushton H. Prepubertal testis tumors: actual prevalence rate of histological types. J Urol. 2004;172:2370–2.
Schneider DT, Calaminus G, Koch S, Teske C, Schmidt P, Haas RJ, Harms D, Göbel U. Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols. Pediatr Blood Cancer. 2004;42:169–75.
Murphy FL, Law H, Mushtaq I, Sebire NJ. Testicular and paratesticular pathology in infants and children: the histopathological experience of a tertiary paediatric unit over a 17 year period. Pediatr Surg Int. 2007;23:867–72.
Mittal D, Agarwala S, Yadav DK, Pramanik DD, Sharma MC, Bagga D. Testicular tumors in undescended testes in children below 5 y of age. Indian J Pediatr. 2015;82:549–52.
Walsh TJ, Davies BJ, Croughan MS, Carroll PR, Turek PJ. Racial differences among boys with testicular germ cell tumors in the United States. J Urol. 2008;179:1961–5.
Hawkins E, Heifetz SA, Giller R, Cushing B. The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children’s Cancer Study Group. Hum Pathol. 1997;28:404–10.
Perlman EJ, Cushing B, Hawkins E, Griffin CA. Cytogenetic analysis of childhood endodermal sinus tumors: a Pediatric Oncology Group study. Pediatr Pathol. 1994;14:695–708.
Mostert M, Rosenberg C, Stoop H, Schuyer M, Timmer A, Oosterhuis W, Looijenga L. Comparative genomic and in situ hybridization of germ cell tumors of the infantile testis. Lab Invest. 2000;80:1055–64.
van Echten J, Timmer A, van der Veen AY, Molenaar WM, de Jong B. Infantile and adult testicular germ cell tumors. a different pathogenesis? Cancer Genet Cytogenet. 2002;135:57–62.
Harms D, Zahn S, Göbel U, Schneider DT. Pathology and molecular biology of teratomas in childhood and adolescence. Klin Padiatr. 2006;218:296–302.
Silver SA, Wiley JM, Perlman EJ. DNA ploidy analysis of pediatric germ cell tumors. Mod Pathol. 1994;7:951–6.
Visfeldt J, Jørgensen N, Müller J, Møller H, Skakkebaek NE. Testicular germ cell tumours of childhood in Denmark, 1943–1989: incidence and evaluation of histology using immunohistochemical techniques. J Pathol. 1994;174:39–47.
Chaganti RS, Houldsworth J. Genetics and biology of adult human male germ cell tumors. Cancer Res. 2000;60:1475–82.
Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005;18:S61–79.
Ulbright TM, Young RH. Testicular and paratesticular tumors and tumor-like lesions in the first 2 decades. Semin Diagn Pathol. 2014;31:323–81.
Mostofi FK. Pathology of germ cell tumors of testis: a progress report. Cancer. 1980;45:1735–54.
Teilum G. Endodermal sinus tumors of the ovary and testis: comparative morphogenesis of the so-called mesonephroma ovarii (Schiller) and extraembryonic (yolk sac-allantoic) structures of the rat’s placenta. Cancer. 1959;12:1092–105.
Drut R. Yolk sac tumor and testicular microlithiasis. Pediatr Pathol Mol Med. 2003;22:343–7.
Ahmed HU, Arya M, Muneer A, Mushtaq I, Sebire NJ. Testicular and paratesticular tumours in the prepubertal population. Lancet Oncol. 2010;11:476–83.
Kaplan GW, Cromie WC, Kelalis PP, Silber I, Tank Jr ES. Prepubertal yolk sac testicular tumors – report of the testicular tumor registry. J Urol. 1988;140:1109–12.
Tsuchida Y, Saito S, Ishida M, Omi K, Urano Y. Yolk sac tumor (endodermal sinus tumor) and alpha-fetoprotein. A report of three cases. Cancer. 1973;32:917–21.
Wu JT, Book L, Sudar K. Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res. 1981;15:50–2.
Teilum G. Classification of endodermal sinus tumour (mesoblatoma vitellinum) and so-called “embryonal carcinoma” of the ovary. Acta Pathol Microbiol Scand. 1965;64:407–29.
Talerman A. Germ cell tumours. Ann Pathol. 1985;5:145–57.
Emerson RE, Ulbright TM. The use of immunohistochemistry in the differential diagnosis of tumors of the testis and paratestis. Semin Diagn Pathol. 2005;22:33–50.
Kao CS, Idrees MT, Young RH, Ulbright TM. Solid pattern yolk sac tumor: a morphologic and immunohistochemical study of 52 cases. Am J Surg Pathol. 2012;36:360–7.
Lin JN, Wang KL, Hung IJ, Yang CP. Management of yolk sac tumor of the testis in children. J Formos Med Assoc. 1994;93:393–6.
Grady RW, Ross JH, Kay R. Patterns of metastatic spread in prepubertal yolk sac tumor of the testis. J Urol. 1995;153:1259–61.
Schmidt P, Haas RJ, Göbel U, Calaminus G. Results of the German studies (MAHO) for treatment of testicular germ cell tumors in children – an update. Klin Padiatr. 2002;214:167–72.
Zhou XJ, Zhou RS, Fan T, Han CH. Experience with the treatment of testicular yolk sac tumor in children: a report of 14 cases. Eur Rev Med Pharmacol Sci. 2014;18:3831–3.
Taskinen S, Fagerholm R, Aronniemi J, Rintala R, Taskinen M. Testicular tumors in children and adolescents. J Pediatr Urol. 2008;4:134–7.
Steffens J, Treiyer A, Calaminus G. Management of pediatric testicular tumors: diagnosis, therapy, and follow-up. Urologe A. 2009;48:359–63.
Shin YS, Kim HJ. Current management of testicular cancer. Korean J Urol. 2013;54:2–10.
Ross JH, Rybicki L, Kay R. Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: a summary of the Prepubertal Testis Tumor Registry. J Urol. 2002;168:1675–8.
Walsh C, Rushton HG. Diagnosis and management of teratomas and epidermoid cysts. Urol Clin North Am. 2000;27:509–18.
Shukla AR, Woodard C, Carr MC, Huff DS, Canning DA, Zderic SA, Kolon TF, Snyder 3rd HM. Experience with testis sparing surgery for testicular teratoma. J Urol. 2004;171:161–3.
Metcalfe PD, Farivar-Mohseni H, Farhat W, McLorie G, Khoury A, Bägli DJ. Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol. 2003;170:2412–5.
Levy DA, Kay R, Elder JS. Neonatal testis tumors: a review of the Prepubertal Testis Tumor Registry. J Urol. 1994;151:715–7.
Herek O, Ulman I, Ozcan C, Avanoğlu A. Bilateral testicular teratoma in infancy: report of a rare case treated by testis-sparing surgery. Eur J Pediatr Surg. 2004;14:209–11.
Yam B, Georgiou NA, Khullar P, Coren CV, Katz DS. Radiology-pathology conference: mature teratoma arising from an intra-abdominal undescended testis in a 7-month-old infant. Clin Imaging. 2010;34:466–71.
Lin HC, Clark JY. Testicular teratoma presenting as a transilluminating scrotal mass. Urology. 2006;67:1290.e3–5.
Di Renzo D, Persico A, Sindici G, Lelli Chiesa P. Testicular teratoma, mimicking a simple testicular cyst, in an infant. Urology. 2013;82:701–3.
Brosman SA. Testicular tumors in prepubertal children. Urology. 1979;13:581–8.
Assaf G, Mosbah A, Homsy Y, Michaud J. Dermoid cyst of testis in five-year-old-child. Urology. 1983;22:432–4.
Jesus LE, Pena CR, Leao AP. Pre-pubertal testicular dermoid cyst treated with conservative surgery. Int Braz J Urol. 2005;31:359–61.
Ulbright TM, Srigley JR. Dermoid cyst of the testis: a study of five postpubertal cases, including a pilomatrixoma-like variant, with evidence supporting its separate classification from mature testicular teratoma. Am J Surg Pathol. 2001;25:788–93.
Price Jr EB. Epidermoid cysts of the testis: a clinical and pathologic analysis of 69 cases from the testicular tumor registry. J Urol. 1969;102:708–13.
Aneiros-Fernandez J, Arias-Santiago S, Cancela-Diez B, O’Valle F, Cachaza JA. Intratesticular epidermoid cyst: a rare tumor. J Clin Med Res. 2010;2:281–3.
Leake J, Levitt G, Ramani P. Primary carcinoid of the testis in a 10-year-old boy. Histopathology. 1991;19:373–5.
Rushton HG, Belman AB, Sesterhenn I, Patterson K, Mostofi FK. Testicular sparing surgery for prepubertal teratoma of the testis: a clinical and pathological study. J Urol. 1990;144:726–30.
Stamp IM, Jacobsen GK. Infant intratubular germ cell neoplasia. Am J Surg Pathol. 1995;19:489.
Renedo DE, Trainer TD. Intratubular germ cell neoplasia (ITGCN) with p53 and PCNA expression and adjacent mature teratoma in an infant testis. An immunohistochemical and morphologic study with a review of the literature. Am J Surg Pathol. 1994;18:947–52.
Terenziani M, D’Angelo P, Bisogno G, Boldrini R, Cecchetto G, Collini P, Conte M, De Laurentis T, Ilari I, Indolfi P, Inserra A, Piva L, Siracusa F, Spreafico F, Tamaro P, Lo Curto M. Teratoma with a malignant somatic component in pediatric patients: the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer. 2010;54:532–7.
Tanini R. On a case of testicular seminoma in infancy. Atti Accad Fisiocrit Siena Med Fis. 1964;13:107–27.
Frey P, Fliegel C, Herzog B. Testicular tumours in infancy and childhood – a review of 10 germ cell tumours and 10 non germ cell tumours. Z Kinderchir. 1990;45:229–34.
Sokoloff MH, Joyce GF, Wise M, Urologic Diseases in America Project. Testis cancer. J Urol. 2007;177:2030–41.
Cost NG, Lubahn JD, Adibi M, Romman A, Wickiser JE, Raj GV, Sagalowsky AI, Margulis V. A comparison of pediatric, adolescent, and adult testicular germ cell malignancy. Pediatr Blood Cancer. 2014;61:446–51.
Marulaiah M, Gilhotra A, Moore L, Boucaut H, Goh DW. Testicular and paratesticular pathology in children: a 12-year histopathological review. World J Surg. 2010;34:969–74.
Scully RE. Gonadoblastoma; a gonadal tumor related to the dysgerminoma (seminoma) and capable of sex-hormone production. Cancer. 1953;6:455–63.
Ng SB, Yong MH, Knight LA, Lee VK, Nadarajah S, Stoop H, Looijenga LH. Gonadoblastoma-associated mixed germ cell tumour in 46, XY complete gonadal dysgenesis (Swyer syndrome): analysis of Y chromosomal genotype and OCT3/4 and TSPY expression profile. Histopathology. 2008;52:644–6.
Ben Temime R, Chachial A, Attial L, Ghodbanel I, Makhloufl T, Koubaal A, Kourda N, Ben Jilani S, Dammak T, El May A, Rahal K. 46 XY pure gonadal dysgenesis with gonadoblastoma and dysgerminoma. Tunis Med. 2008;86:710–3.
Fernandes GC, Sathe PA, Naik LP, Kane SV. Bilateral gonadoblastomas with unilateral dysgerminoma in a case of 46 XY pure gonadal dysgenesis (Swyer syndrome). Indian J Pathol Microbiol. 2010;53:376–8.
Kini U, Bantwal G, Ayyar V, Idiculla J. Bilateral gonadoblastomas with a left sided dysgerminoma in a true hermaphrodite (disorder of sexual differentiation) with 46, XY karyotype. J Assoc Physicians India. 2008;56:549–51.
Mazzanti L, Cicognani A, Baldazzi L, Bergamaschi R, Scarano E, Strocchi S, Nicoletti A, Mencarelli F, Pittalis M, Forabosco A, Cacciari E. Gonadoblastoma in Turner syndrome and Y-chromosome-derived material. Am J Med Genet A. 2005;135:150–4.
Matsumoto F, Shimada K, Ida S. Tumors of bilateral streak gonads in patients with disorders of sex development containing y chromosome material. Clin Pediatr Endocrinol. 2014;23:93–7.
Hatano T, Yoshino Y, Kawashima Y, Shirai H, Iizuka N, Miyazawa Y, Sakata A, Onishi T. Case of gonadoblastoma in a 9-year-old boy without physical abnormalities. Int J Urol. 1999;6:164–6.
Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet. 1987;25:191–218.
Li Y, Tabatabai ZL, Lee TL, Hatakeyama S, Ohyama C, Chan WY, Looijenga LH, Lau YF. The Y-encoded TSPY protein: a significant marker potentially plays a role in the pathogenesis of testicular germ cell tumors. Hum Pathol. 2007;38:1470–81.
Hertel JD, Huettner PC, Dehner LP, Pfeifer JD. The chromosome Y-linked testis-specific protein locus TSPY1 is characteristically present in gonadoblastoma. Hum Pathol. 2010;41:1544–9.
Cools M, Stoop H, Kersemaekers AM, Drop SL, Wolffenbuttel KP, Bourguignon JP, Slowikowska-Hilczer J, Kula K, Faradz SM, Oosterhuis JW, Looijenga LH. Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads. J Clin Endocrinol Metab. 2006;91:2404–13.
Scully RE. Gonadoblastoma. A review of 74 cases. Cancer. 1970;25:1340–56.
Manuel M, Katayama PK, Jones Jr HW. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol. 1976;124:293–300.
Hersmus R, Stoop H, van de Geijn GJ, Eini R, Biermann K, Oosterhuis JW, Dhooge C, Schneider DT, Meijssen IC, Dinjens WN, Dubbink HJ, Drop SL, Looijenga LH. Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas. PLoS One. 2012;7:e43952.
Buell-Gutbrod R, Ivanovic M, Montag A, Lengyel E, Fadare O, Gwin K. FOXL2 and SOX9 distinguish the lineage of the sex cord-stromal cells in gonadoblastomas. Pediatr Dev Pathol. 2011;14:391–5.
Looijenga LH. Testicular germ cell tumors. Pediatr Endocrinol Rev. 2014;11:251–62.
Kersemaekers AM, Honecker F, Stoop H, Cools M, Molier M, Wolffenbuttel K, Bokemeyer C, Li Y, Lau YF, Oosterhuis JW, Looijenga LH. Identification of germ cells at risk for neoplastic transformation in gonadoblastoma: an immunohistochemical study for OCT3/4 and TSPY. Hum Pathol. 2005;36:512–21.
Kao CS, Ulbright TM, Idrees MT. Gonadoblastoma: an immunohistochemical study and comparison to sertoli cell nodule with intratubular germ cell neoplasia, with pathogenetic implications. Histopathology. 2014;65:861–7.
Zhang C, Berney DM, Hirsch MS, Cheng L, Ulbright TM. Evidence supporting the existence of benign teratomas of the postpubertal testis: a clinical, histopathologic, and molecular genetic analysis of 25 cases. Am J Surg Pathol. 2013;37:827–35.
Oosterhuis JW, Stoop JA, Rijlaarsdam MA, Biermann K, Smit VT, Hersmus R, Looijenga LH. Pediatric germ cell tumors presenting beyond childhood? Andrology. 2015;3:70–7.
Skakkebaek NE. Possible carcinoma-in-situ of the testis. Lancet. 1972;2:516–7.
Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update. 2006;12:303–23.
Almstrup K, Hoei-Hansen CE, Wirkner U, Blake J, Schwager C, Ansorge W, Nielsen JE, Skakkebaek NE, Rajpert-De Meyts E, Leffers H. Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling. Cancer Res. 2004;64:4736–43.
von der Maase H, Rørth M, Walbom-Jørgensen S, Sørensen BL, Christophersen IS, Hald T, Jacobsen GK, Berthelsen JG, Skakkebaek NE. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Br Med J (Clin Res Ed). 1986;293:1398–401.
Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003;63:2244–50.
Jones TD, Ulbright TM, Eble JN, Cheng L. OCT4: a sensitive and specific biomarker for intratubular germ cell neoplasia of the testis. Clin Cancer Res. 2004;10:8544–7.
Hustin J, Collette J, Franchimont P. Immunohistochemical demonstration of placental alkaline phosphatase in various states of testicular development and in germ cell tumours. Int J Androl. 1987;10:29–35.
Hoei-Hansen CE, Nielsen JE, Almstrup K, Sonne SB, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E. Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors. Clin Cancer Res. 2004;10:8521–30.
Yu H, Pinkus GS, Hornick JL. Diffuse membranous immunoreactivity for podoplanin (D2-40) distinguishes primary and metastatic seminomas from other germ cell tumors and metastatic neoplasms. Am J Clin Pathol. 2007;128:767–75.
Idrees M, Saxena R, Cheng L, Ulbright TM, Badve S. Podoplanin, a novel marker for seminoma: a comparison study evaluating immunohistochemical expression of podoplanin and OCT3/4. Ann Diagn Pathol. 2010;14:331–6.
Biermann K, Stoop H, Looijenga L. c-KIT protein expression does not discriminate neoplastic from non-neoplastic intratubular germ cells. Histopathology. 2012;60:1017–9.
Niemi M, Ikonen M. Primordial germ cells in foetal and postnatal human testis. Ann Med Exp Biol Fenn. 1965;43:23–8.
Gondos B, Hobel CJ. Ultrastructure of germ cell development in the human fetal testis. Z Zellforsch Mikrosk Anat. 1971;119:1–20.
Rajpert-De Meyts E, Bartkova J, Samson M, Hoei-Hansen CE, Frydelund-Larsen L, Bartek J, Skakkebaek NE. The emerging phenotype of the testicular carcinoma in situ germ cell. APMIS. 2003;111:267–78.
Gaskell TL, Esnal A, Robinson LL, Anderson RA, Saunders PT. Immunohistochemical profiling of germ cells within the human fetal testis: identification of three subpopulations. Biol Reprod. 2004;71:2012–21.
Culty M. Gonocytes, the forgotten cells of the germ cell lineage. Birth Defects Res C Embryo Today. 2009;87:1–26.
Honecker F, Stoop H, de Krijger RR, Chris Lau YF, Bokemeyer C, Looijenga LH. Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. J Pathol. 2004;203:849–57.
Chemes H, Muzulin PM, Venara MC, Mulhmann Mdel C, Martínez M, Gamboni M. Early manifestations of testicular dysgenesis in children: pathological phenotypes, karyotype correlations and precursor stages of tumour development. APMIS. 2003;111:12–23.
Oosterhuis JW, Stoop H, Dohle G, Boellaard W, van Casteren N, Wolffenbuttel K, Looijenga LH. A pathologist’s view on the testis biopsy. Int J Androl. 2011;34:e14–9.
Stoop H, Honecker F, van de Geijn GJ, Gillis AJ, Cools MC, de Boer M, Bokemeyer C, Wolffenbuttel KP, Drop SL, de Krijger RR, Dennis N, Summersgill B, McIntyre A, Shipley J, Oosterhuis JW, Looijenga LH. Stem cell factor as a novel diagnostic marker for early malignant germ cells. J Pathol. 2008;216:43–54.
Müller J, Skakkebaek NE, Nielsen OH, Graem N. Cryptorchidism and testis cancer. Atypical infantile germ cells followed by carcinoma in situ and invasive carcinoma in adulthood. Cancer. 1984;54:629–34.
Słowikowska-Hilczer J. Nuclear DNA, content and proliferative potential of human carcinoma in situ cells in testes of intersex children. Folia Histochem Cytobiol. 2001;39:167–8.
Rajpert-De Meyts E, Jørgensen N, Brøndum-Nielsen K, Müller J, Skakkebaek NE. Developmental arrest of germ cells in the pathogenesis of germ cell neoplasia. APMIS. 1998;106:198–204.
Looijenga LH. Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights. J Pathol. 2009;218:146–62.
Müller J. Abnormal infantile germ cells and development of carcinoma-in-situ in maldeveloped testes: a stereological and densitometric study. Int J Androl. 1987;10:543–67.
Cools M, van Aerde K, Kersemaekers AM, Boter M, Drop SL, Wolffenbuttel KP, Steyerberg EW, Oosterhuis JW, Looijenga LH. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab. 2005;90:5295–303.
Cools M, Honecker F, Stoop H, Veltman JD, de Krijger RR, Steyerberg E, Wolffenbuttel KP, Bokemeyer C, Lau YF, Drop SL, Looijenga LH. Maturation delay of germ cells in fetuses with trisomy 21 results in increased risk for the development of testicular germ cell tumors. Hum Pathol. 2006;37:101–11.
Codesal J, Nistal M, Queizan A, Carretero JL, de Vega RM, Perez A, Paniagua R. Number and DNA content of hypertrophic spermatogonia in normal and cryptorchid human testes. Arch Androl. 1992;29:157–62.
Jørgensen N, Müller J, Giwercman A, Visfeldt J, Møller H, Skakkebaek NE. DNA content and expression of tumour markers in germ cells adjacent to germ cell tumours in childhood: probably a different origin for infantile and adolescent germ cell tumours. J Pathol. 1995;176:269–78.
Cortes D, Thorup J, Visfeldt J. Multinucleated spermatogonia in cryptorchid boys: a possible association with an increased risk of testicular malignancy later in life? APMIS. 2003;111:25–30.
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Nistal, M., González-Peramato, P. (2016). Germ Cell Tumors of Infancy and Childhood. In: Colecchia, M. (eds) Pathology of Testicular and Penile Neoplasms. Springer, Cham. https://doi.org/10.1007/978-3-319-27617-5_4
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