—  SHORT COURSE #49  —

Tumors of the Testis

Sections 2 & 3 - Germ Cell Tumors of the Adult Testis
Diagnostic Aspects and Treatment Associated Lesions

Helen Michael


Examination of Testicular Tumor Specimens
Specimens should be received fresh and examined as soon as possible [1]. Difficulties in differential diagnosis between germ cell tumor types, especially between seminomas and nonseminomatous germ cell tumors, are enhanced by poor fixation. If the specimen cannot be examined promptly by a pathologist, the surgeon should bisect the testis before placing it in formalin. This procedure will enhance formalin penetration and fixation. The tunica should be examined for abnormalities. The proximal margin of the spermatic cord should be submitted separately from other sections. Any abnormal areas of the spermatic cord should be submitted, as well as sections from the middle and distal cord. These sections should be taken before sectioning the testis in order to prevent artifactual displacement of tumor into lymphovascular spaces. All areas of the neoplasm should be very thoroughly sampled, including hemorrhagic and necrotic foci and each area that appears different on gross examination. The pathology report should state the type of tumor (percent of different types in mixed germ cell tumors), presence or absence of lymphovascular space and tunica invasion, and whether the spermatic cord margin is involved by tumor.

Epidemiology
95% of primary malignant germ cell tumors of the testis are germ cell tumors. Testicular cancer accounts for less than 1% of malignant tumors in men, but it is the most common malignant tumor in men between 15 and 45 years of age [2]. The incidence rises at puberty and peaks between age 25 and 35. Nonseminomatous germ cell tumors generally occur in a younger age group than patients with pure seminomas [3, 4]. For reasons that are not clear, the incidence of testicular germ cell tumors has increased in many countries during the last half of the past century. Screening and earlier detection are apparently not responsible for the increased incidence of these neoplasms. While many agents have been hypothesized to increase the incidence of testicular cancer, the only well established associations are with cryptorchidism, a prior testicular germ cell tumor, a family history of testicular germ cell tumor, some intersex syndromes and infertility [1]. Cryptorchidism has a strong association with germ cell tumors [5]. Orchidopexy does not affect the elevated incidence of germ cell tumors, suggesting an abnormality in embryologic development that predisposes to germ cell abnormalities and may also explain familial aggregates [6, 7]. Testicular germ cell tumors associated with cryptorchidism are more often seminomas than other germ cell tumor types [8].

Seminoma
Seminoma is the most common type of testicular germ cell tumor, representing up to 50% of these neoplasms [3, 8]. Seminomas occur at an average age of 40.5 years, up to a decade later than the mean age for other germ cell tumor types [3, 9].

Seminomas most commonly present as testicular masses, but some patients have pain or a dull aching sensation in the lower abdomen. A small number present with metastatic tumor [10, 11]. Three quarters of patients have disease limited to the testis, whereas 25% have retroperitoneal involvement and 5 % have distant metastases [12] which may be asymptomatic [3]. Some patients may have a mild elevation of hCG, but seminoma is not usually associated with increased AFP [13, 14].

Testicular seminomas usually have a gross appearance that is more homogeneous than that of other germ cell types. They are typically light tan in color and uniform in appearance with a fish-flesh consistency similar to that seen in lymphomas. The average size of testicular seminomas is 5 cm. There may be a single well demarcated tumor nodule or multiple nodules which may or may not coalesce in some planes of section. Foci of hemorrhage on gross examination should suggest the possibility of choriocarcinoma; these areas need to be carefully sampled. Necrotic areas may also indicate coexistant nonseminomatous germ cell tumor components, although seminomas may sometimes display significant necrosis.

Microscopically, seminomas are typically composed of sheets of large cells with prominent and distinct cell membranes, clear to eosinophilic cytoplasm and large, primitive appearing nuclei which do not overlap. Nuclei are evenly distributed in the tumor. The mitotic rate may be high [15]. There is no convincing evidence that tumors with high mitotic activity behave more aggressively, so that some experts do not subcategorize these tumors as anaplastic seminomas [1, 16, 17, 18]. The tumor cell cytoplasm contains abundant glycogen which is easily demonstrated with a PAS stain with and without diastase. Varying amounts of fibrous tissue form septae separating nodules of seminoma. Lymphocytes are often present in the fibrous septae, and sometimes granulomas may also occur. Other patterns of seminoma include cells growing in cords or trabeculae, or tumor cells forming a solid tubular pattern [1, 19, 20]. Reticular or cribriform foci may occur due to edema separating groups of tumor cells [1, 21]. Tubular and microcystic patterns may simulate yolk sac tumor [22]. Some seminomas grow in an interstitial pattern, sparing seminiferous tubules [23]. Seminomas with a plasmacytoid pattern and cytokeratin and CD30 staining have been called "atypical seminoma" [24], but some experts do not use this term because there is no indication that they need therapy different from other seminomas [25]. Intratubular seminoma may be associated with the invasive neoplasms [26]. Some seminomas are associated with fibrotic scars that may contain calcifications; exclusion of coexistant gonadoblastoma in this situation is indicated because seminomas arising from gonadoblastomas are more often bilateral. Syncytiotrophoblast cells may be seen in seminomas both on H&E stains and with the use of stains for hCG. The presence of these cells is associated with hCG production and has no adverse prognostic significance. They are distinguished from the more aggressive choriocarcinoma by the lack of admixture of the syncytiotrophoblast cells with cytotrophoblast cells. Some seminomas display hCG staining in cells that do not have the appearance of syncytiotrophoblast [27]; these cells may represent incomplete trophoblastic differentiation or differentiation toward intermediate trophoblast [28].

Seminomas show diffuse staining for placenta-like alkaline phosphatase (PLAP), usually with membrane accentuation [28, 29, 30, 31, 32]. PLAP positivity also occurs in other germ cell tumors, but in those neoplasms it is more focal and cytoplasmic [33]. Seminomas typically do not demonstrate much cytokeratin positivity, especially with the AE1/AE3 antibody. They stain positively for OCT 3/4, a nuclear transcription factor expressed in human embryonic and stem cells [34, 35]. The combination of a diffusely positive PLAP, negative AE1/AE3 and positive OCT 3/4 stains provides good evidence that a tumor is seminoma. Seminoma may be negative to focally positive with cytokeratin cocktail AE1/AE3 and CAM 5.2. Stains for AFP are negative in seminoma, in contrast to yolk sac tumor and some embryonal carcinomas [31, 36, 37]. CD 30 is also negative in seminomas but positive in embryonal carcinomas [38, 39, 40]. C-kit is expressed in intratubular germ cell neoplasia of the unclassified type and seminomas but not in other germ cell tumor types [41]. EMA is negative in seminoma, yolk sac tumor and embryonal carcinoma, and may be useful in identifying nongerm cell carcinomas arising from germ cell tumors.

Seminomas are sometimes misdiagnosed as lymphomas; the latter tumor usually occurs in older men and may be confirmed by a stain for CD 45.

Like other germ cell tumors, seminomas are associated with an isochromosome derived from the short arm of chromosome 12: [i(12p)]. The number of copies of this isochromosome is fewer in seminomas than in nonseminomatous germ cell tumors [42].

The most common problem in the differential diagnosis of seminoma is confusion with embryonal carcinoma, especially if fixation is poor. In contrast to seminoma, embryonal carcinomas contain cells without clearly defined cell borders and more crowded, pleomorphic nuclei that tend to overlap in paraffin sections. Embryonal carcinoma lacks the fibrous septae seen in seminomas. True glandular structures are characteristic of embryonal carcinoma and are not seen in seminomas. Stains for AE1/AE3 and CD 30 are usually positive in embryonal carcinoma and negative in seminomas. Both seminoma and embryonal carcinoma stain positively for OCT 3/4, but seminoma is c-kit positive in contrast to embryonal carcinoma. The solid variant of yolk sac tumor may also resemble seminoma. However, it is usually associated in the testis with other, more recognizable yolk sac tumor variants. It also contains smaller cells that those seen in seminomas. Edema in seminomas may simulate the reticular variant of yolk sac tumors, but the resultant cystic areas are irregular and contain desquamated seminoma cells [1, 21, 22]. Yolk sac tumor does not contain the fibrous septae with lymphocytes that are characteristic of seminoma. Stains for AFP and AE1/AE3 are positive in yolk sac tumor and negative in seminoma, and OCT 3/4 is expressed in seminoma but not in yolk sac tumor [34]. Syncytiotrophoblast cells occurring in seminoma lack the admixed cytotrophoblast component characteristic of choriocarcinoma.

Embryonal Carcinoma
While pure testicular embryonal carcinomas are rare [43], embryonal carcinoma is a component of about 40% of all testicular germ cell tumors [3, 9] and almost 90% of nonseminomatous germ cell tumors [3]. It occurs at a mean age of 32 years [3]. The vast majority of patients with this tumor present with testicular masses, but some come to attention because of metastatic disease or hormonal symptoms. Only 40 % of patients with nonseminomatous germ cell tumors have disease limited to the testis at presentation. Another 40% have retroperitoneal tumor and 20% have more advanced disease [44]. As many as 2/3 of patients whose testicular tumor is predominantly embryonal carcinoma have had metastastatic disease upon pathological staging [45].

Embryonal carcinomas are not as well circumscribed as seminomas. They are also generally smaller, with a mean diameter of 2.5 cm [46]. They are soft, reddish tan tumors, commonly with areas of hemorrhage and necrosis.

Microscopically, embryonal carcinomas are cohesive tumors which most commonly display solid, glandular and/or papillary architecture. Necrosis is common. Tumor cells do not have distinguishable cell borders, in contrast to seminoma. Cytoplasm is amphophilic and nuclei are large and irregular, often with large, prominent nucleoli. The tumor cells are so crowded that nuclei appear to overlap in paraffin sections, and the mitotic rate is very high. Associated intratubular germ cell neoplasia of the unclassified type (IGCNU) is commonly associated with embryonal carcinoma; it displays PLAP, c-kit and OCT-4 staining. Intratubular embryonal carcinoma (IEC) may also be present, usually at the periphery of the tumor. IEC stains with CD30 and OCT-4, but not with c-kit. Staining for CD30 may help identify this lesion [47]. The cells in IEC differ morphologically from those in IGCNU. Syncytiotrophoblast cells are often present in embryonal carcinoma.

Vascular invasion is very common in embryonal carcinoma, and embryonal carcinoma is the most common tumor to invade vessels in mixed germ cell tumors [1].

Immunohistochemical stains may be helpful in distinguishing embryonal carcinoma from other neoplasms [48, 49, 50]. Embryonal carcinomas do not stain for EMA, CEA or c-kit. They stain positively for PLAP, pancytokeratin (AE1/AE3 and CAM 5.2) and CD30. They also stain positively for OCT- 4 (POU5F1), a nuclear transcription factor expressed in human embryonic and stem cells [35, 51, 52], and the staining is reliable with either a monoclonal or a polyclonal antibody. NANOG is a regulator of embryonic stem cell pluripotency that is downregulated earlier in embryogenesis than OCT-4. Like OCT-4, NANOG is also expressed in embryonal carcinoma but not in more differentiated germ cell tumors [53]. Some embryonal carcinomas may display focal AFP positivity which may represent partial transformation to yolk sac tumor. Syncytiotrophoblast cells stain display hCG staining.

Most embryonal carcinomas contain the [i(12p)]. There is a correlation between the number of copies of the isochromosome and the aggressiveness of the tumor [54]. The number of copies of this isochromosome is greater in nonseminomatous germ cell tumors than in seminomas [55]. Recent studies [56] indicate that 12p gain is a functionally significant change that leads to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Some authors [57] have shown that deregulated apoptosis may be a factor in the histogenesis of embryonal carcinoma. Survivin (an inhibitor of apoptosis) is expressed at high levels in undifferentiated testicular germ cell tumors and in normal testis but not in mature teratomas. Its expression correlates with the amount of differentiation in testicular germ cell tumors.

Seminomas may be misdiagnosed as embryonal carcinoma, especially if fixation is poor. In contrast to seminoma, embryonal carcinomas contain cells without clearly defined cell borders and more crowded, pleomorphic nuclei that tend to overlap in paraffin sections. Embryonal carcinoma lacks the fibrous septae seen in seminomas. True glandular structures are characteristic of embryonal carcinoma and are not seen in seminomas. Stains for AE1/AE3 and CD 30 [58, 59, 60] are usually positive in embryonal carcinoma and negative in seminomas. Both seminoma and embryonal carcinoma stain positively for OCT-4. Embryonal carcinoma does not stain for c-kit, in contrast to seminoma. Placenta-like alkaline phosphatase is more focal and cytoplasmic in nonseminomatous germ cell tumors than in seminoma [61]. Some patterns of embryonal carcinoma may simulate yolk sac tumor. Association with other recognized patterns of yolk sac tumor favors that diagnosis. Embryonal carcinoma has larger, more pleomorphic cells than yolk sac tumor, and it lacks hyaline globules. AFP staining is only focal in embryonal carcinoma and more diffuse in yolk sac tumor. On the other hand, CD30 and OCT-4 stain embryonal carcinoma but not yolk sac tumor. While syncytiotrophoblast cells may occur in embryonal carcinoma, they are not admixed with the cytotrophoblast cells that are seen in choriocarcinoma. Large cell lymphomas may be mistaken for embryonal carcinomas. Both may stain with CD30, but positive pancytokeratin and PLAP stains support the diagnosis of embryonal carcinoma [62, 63]. Furthermore, anaplastic large cell lymphoma of the testis consistently statins with EMA [64], in contrast to embryonal carcinoma.

Recent data suggest that there is a subgroup of patients with embryonal carcinoma that have a high proliferation index (Ki67), low apoptosis and low p53 expression associated with a better survival than patients without this tumor profile [65], The infrequent identification of embryonal carcinoma in late recurrences of testicular cancer is most likely reflective of its sensitivity to chemotherapy. However, high p53 expression has been correlated with cisplatinum chemoresistance in germ cell tumors in one study [66].

Yolk Sac Tumor
This germ cell tumor, which is though to derive from either seminoma or embryonal carcinoma, displays patterns reminiscent of the embryonal yolk sac, allantois and extraembryonic mesenchyme. The tumor and its resemblance to portions of the rat placenta were described initially by Teilum [67, 68]. Pure yolk sac tumors of the testis occur in children, but after puberty yolk sac tumor in the testis is usually a component of a mixed germ cell tumor. While yolk sac tumor has been reported to occur in 44% of nonseminomatous germ cell tumors [69], it is the most frequently overlooked component of these tumors [1, 43]. Careful and thorough sectioning of the testis is necessary to detect small foci of yolk sac tumor. Some are misdiagnosed as embryonal carcinoma.

Most adult patients present with a painless testicular mass. High levels of AFP correlate with the presence of yolk sac tumor and are useful in following response to therapy as well as the development of recurrent disease. However, some yolk sac tumors do not produce AFP, and some embryonal carcinomas can produce low levels of AFP.

Foci of yolk sac tumor present in mixed germ cell tumor may be characterized on gross examination by cystic, myxoid and hemorrhagic areas. Several microscopic patterns of yolk sac tumor exist: reticular (microcystic), festoon (endodermal sinus), papillary, solid, glandular, myxoid, spindle cell, polyvesicular vitelline, hepatoid and parietal [70, 71, 72, 73, 74, 75]. Some patterns are more common than others, and some are more commonly seen after chemotherapy. Most primary yolk sac tumors contain more than one microscopic pattern.

The most common pattern of yolk sac tumor seen in pre-chemotherapy patients is the reticular or microcystic type. It displays a mesh-like pattern of spaces lined by cells which are smaller than those seen in embryonal carcinoma. Coalescence of the microcysts results in a macrocystic pattern. Sometimes, cords of cells resembling those surrounding the cysts are surrounded by myxoid tissue. The endodermal sinus (festoon) pattern is that which was originally described by Teilum as showing glomeruloid structures resembling the endodermal sinus of the rat placenta [67, 68]. This tumor variant contains Schiller-Duvall bodies, which consist of papillary processes containing connective tissue with a blood vessel. These structures, which are covered by a layer of cuboidal cells, protrude into a cavity which is also lined by typical cells of yolk sac tumor. Similar structures may occur in embryonal carcinoma, but the cells covering the papillary processes are much larger with more nuclear atypia than those seen in the endodermal sinus pattern of yolk sac tumor. Small papillae without the typical glomeruloid pattern may also occur in cystic spaces in papillary yolk sac tumor. The solid pattern of yolk sac tumor may be seen focally in primary tumors, but it is more common in postchemotherapy recurrences. It is characterized by solid nests of cells with eosinophilic cytoplasm and distinct cell borders. It lacks the overlapping, markedly pleomorphic nuclei seen in embryonal carcinoma and the fibrous septae seen in seminoma. Glandular yolk sac tumor is almost always seen in conjunction with other histologic patterns of yolk sac tumor. Both enteric and endometrioid variants occur [72, 73, 76]. Sometimes, reticular and myxoid patterns of yolk sac tumor give rise to spindle cell foci that are cytokeratin positive and are thought to resemble the extraembryonic mesenchyme (so-called "magma reticulare) of the rat placenta [70, 77]. Cytokeratin positivity supports derivation of these spindle cell areas from yolk sac tumor. The spindle cell mesenchyme also has the capacity to differentiate into skeletal muscle and cartilage, indicating a pluripotential nature of this tumor in some cases [77]. Rarely, cellular and mitotically active spindle cell areas with a sarcomatoid appearance are seen; these foci also display cytokeratin positivity. The polyvesicular vitteline pattern of yolk sac tumor is rare in testicular tumors. It displays epithelial-lined cysts with central constrictions surrounded by spindle or myxoid stroma. Teilum made the analogy with the subdivision of the primary yolk sac into the secondary yolk sac [68]. Small foci of hepatoid yolk sac tumor contain polygonal cells with eosinophilic cytoplasm and a central nucleus containing a prominent nucleolus; these cells resemble hepatocytes and stain positively for AFP. The parietal pattern of yolk sac tumor displays eosinophilic basement membrane material between tumor cells. The basement membrane material has been considered analogous to Reichert's membrane in the parietal yolk sac of the rodent [70, 76]. Small foci of parietal yolk sac tumor are often seen in nonseminomatous testicular germ cell tumors, but a predominance of this type of tumor may follow germ cell chemotherapy. Parietal yolk sac tumor may not produce AFT. Various patterns of yolk sac tumor may contain eosinophilic hyaline globules.

Yolk sac tumors usually stain positively for AFP and cytokeratin. Enteric glands may be CEA positive. EMA is negative in yolk sac tumors; in metastatic sites this antibody may be useful in distinguishing glandular yolk sac tumor from adenocarcinoma. In contrast to embryonal carcinoma, yolk sac tumor is CD30 and OCT-4 negative. Adult yolk sac tumors contain the [i(12p)] seen in other germ cell tumors of the adult testis.

The solid variant of yolk sac tumor may also resemble seminoma. However, it is usually associated in the testis with other, more recognizable yolk sac tumor variants. It also contains smaller cells that those seen in seminomas. Edema in seminomas may simulate the reticular variant of yolk sac tumors, but the resultant cystic areas are irregular and contain desquamated seminoma cells [1, 22, 78]. Yolk sac tumor does not contain the fibrous septae with lymphocytes that are characteristic of seminoma. Stains for AFP and AE1/AE3 are positive in yolk sac tumor and negative in seminoma, and OCT-4 is expressed in seminoma but not in yolk sac tumor [51]. Solid yolk sac tumor needs to be distinguished from seminoma [79]; stains for cytokeratin, AFP and OCT-4 are helpful in this regard. The hyaline globules and basement membrane material seen in yolk sac tumors are not observed in seminomas. Several yolk sac patterns may be confused with embryonal carcinoma. Yolk sac tumor does not display the marked nuclear crowding and extreme nuclear abnormalities seen in embryonal carcinoma. While both may display cytokeratin and APF staining, CD 30 and OCT-4 decorate embryonal carcinoma but not yolk sac tumor. Glandular variants of yolk sac tumor are distinguished from teratoma by the absence of other teratomatous elements such as muscle [80] and by positive AFP staining in the former.

The presence of yolk sac tumor in a nonseminomatous germ cell tumor limited to the testis may be associated with a decreased incidence of relapse [81, 82], whereas significant areas of embryonal carcinoma indicate more aggressive disease. On the other hand, yolk sac tumor in patients with advanced stage testicular cancer is associated with a poor prognosis [83]. It appears that yolk sac tumor has less metastatic potential than embryonal carcinoma, but yolk sac tumor is also less sensitive to germ cell tumor chemotherapy.

Next to teratoma, yolk sac tumor is the most common type of tumor seen in late recurrences (46% of patients). Yolk sac tumor also may occur along with other tumor types in late recurrences. The frequency of yolk sac tumor in late recurrences of testicular GCT may be due to its relative chemoresistance compared to other types of germ cell neoplasms. Long-term disease-free survival of patients treated with cisplatin-based chemotherapy for advanced stage testicular cancer containing yolk sac tumor (33%) is significantly poorer than that for patients whose advanced disease does not contain yolk sac tumor (65%) [49]. It is also noteworthy that the frequency of yolk sac tumor at autopsy in patients who die with testicular germ cell tumors increased significantly after introduction of cisplatin-based chemotherapy [50]. Since effective chemotherapy eradicates other types of GCTs, the relatively more chemoresistant yolk sac tumor has a poorer prognosis and may persist after destruction of more chemosensitive GCT elements. There are genetic differences between early- and late-relapsing yolk sac tumor, and these differences may be the basis for the more aggressive, chemotherapy-refractile behavior of the late recurrences of this tumor [85].

Yolk sac tumor in late recurrences often displays unusual patterns, including glandular, clear cell and parietal types [86]. In contrast, the microcystic pattern, which is the most common type of yolk sac tumor in primary testicular tumors, is infrequent in late recurrences. Damjanov et al [87] described transformation of microcystic and pseudopapillary yolk sac tumor of the ovary into disseminated, chemoresistant, parietal yolk sac tumor after cisplatin-based chemotherapy. The change in morphology was attributed to selective outgrowth of a chemoresistant clone of yolk sac tumor, a hypothesis that is consistent with the appearance of unusual forms of yolk sac tumor in late recurrences of testicular GCTs. Familiarity with these variants of yolk sac tumor is important in order to avoid misdiagnosis in patients with a remote history of testicular GCTs.

Glandular, clear cell, parietal and hepatoid patterns are especially common in late recurrences. Glandular yolk sac tumor is characterized by glands lined by columnar epithelium with clear cytoplasmic vacuoles, similar to endometrioid-like yolk sac tumor [88]. Many late recurrences display substantial solid areas, which may contain numerous clear cells. Hepatoid yolk sac tumor seen in late recurrences displays polygonal cells with densely eosinophilic cytoplasm and occasional intercellular sinusoids. Parietal yolk sac tumor is frequently seen in late recurrences; it has eosinophilic basement-membrane material between nests of cells.

Some late recurrences contain yolk sac tumor with an unusual degree of nuclear pleomorphism. No festoon or polyvesicular vitteline patterns of yolk sac tumor were identified in a large study of these neoplasms [86].

All patients reported in the literature [86, 89, 90] with late recurrences containing tumor besides teratoma have fared poorly and very few have responded to chemotherapy. A recent study has shown that alpha-Fetoprotein levels greater than 100 U/l indicate a poor prognosis in late recurrence of germ cell tumors [91]; this finding is consistent with the poor prognosis seen in histologically verified yolk sac tumor late recurrences. Late recurrences should be treated surgically if at all possible.

Choriocarcinoma
Choriocarcinoma is characterized by an admixture of malignant syncytiotrophoblast and cytotrophoblast. Pure testicular choriocarcinoma is very rare [92]. Focal choriocarcinoma is seen in some mixed germ cell tumors, but it is less common that previously discussed germ cell tumor types. It is associated with hCG production.

Choriocarcinoma is usually hemorrhagic and necrotic on both gross and microscopic examination. Blood vessel invasion by tumor is common.

Choriocarcinomas may display patchy PLAP positivity and CEA staining [93, 94]. In contrast to other germ cell tumors, choriocarcinoma may stain positively for EMA, which is located in the syncytiotrophoblast cells [93].

Choriocarcinoma needs to be distinguished from seminoma or embryonal carcinoma containing synctiotrophoblast cells. The biphasic pattern characteristic of choriocarcinoma is the key to the correct diagnosis. Syncytiotrophoblast cells in all types of testicular germ cell tumors stain with HCG and also with epidermal growth factor receptor (EGFR) [95].

Choriocarcinomas disseminate by hematogenous routes and therefore are associated with a poorer prognosis than that of other germ cell types. Increased amounts of choriocarcinoma in mixed germ cell tumors correlate with adverse outcome [46, 96, 97, 98].

Teratoma
Teratomas display differentiation toward either mature or immature somatic tissues. They most often occur as components of mixed germ cell tumors. Even patients with pure testicular teratomas often develop metastatic disease containing nonteratomatous germ cell tumor elements [98, 99, 100, 101], probably because the testicular teratoma arises from embryonal carcinoma that metastasizes before differentiating to teratoma in the testis.

The more primitive precursor may differentiate into teratoma at metastatic sites also, or the teratoma itself may metastasize. Invasion of vascular spaces by teratoma has been documented [27]. All teratomas of the adult testis have metastatic potential and represent malignant tumors, regardless of whether they contain mature or embryonal tissue components [99]. Patients typically present with testicular enlargement or symptoms related to metastatic disease.

On gross examination, teratomas are usually solid but may have cystic areas. They may contain keratinous material, mucin and cartilage. Mature teratomas may display any adult type of somatic tissue. Squamous and glandular mucosa are common. There may be a partial layer of muscle beneath glands so that structures resembling intestine or bronchi are present. Cartilage and neuroglia are also frequently identified. Immature teratomas display components of embryonal type tissue, most frequently immature neuroepithelium. Tubular structures and rosettes may be seen in the immature neural tissue, which is highly cellular with numerous mitoses. Foci resembling Wilms' tumor and tissue resembling embryonal rhabdomyoblastic tissue may also be seen. Some testicular teratomas contain somatic malignancies.

Testicular teratomas in adults all have metastatic potential, regardless of whether histologic components appear mature or immature. They derive from malignant germ cells and represent an end-stage of differentiation of a malignant tumor [102]. They contain the [i(12p)] and are associated with intratubular germ cell neoplasia of the unclassified type. They have shown the same allelic losses as non-teratomatous components of the same mixed germ cell tumor [103]. They must be distinguished from dermoid and epidermoid cysts of the testis, which are not associated with intratubular germ cell neoplasia and represent benign lesions. Metastatic teratoma is treated surgically, with excellent results.

A recent, large study of the histology of late recurrences [86] showed that teratoma is the most common type of tumor in late recurrences (60% of patients), although other types of recurrent tumor are often present in addition to the teratoma. Patients whose late recurrences contain only teratoma have a good prognosis, with 79% free of disease at last followup [86]. Cystic trophoblastic tumor, a postchemotherapy lesion in which cystic spaces are lined by mononucleated trophoblast cells with smudged nuclei and only rare mitotic figures, behaves like residual teratoma [104]

Mixed Germ Cell Tumors
Mixed germ cell tumors contain more than one of the tumor types listed above. They represent the majority of nonseminomatous germ cell tumors [3, 105]. The diagnosis of malignant mixed germ cell tumors should include a list of its components with the approximate percentage of each germ cell tumor type. Clinical presentation is the same as that seen for other germ cell tumors.

The gross appearance of these tumors is variable, depending on the germ cell tumor components present. Microscopic examination may reveal any number and combination of germ cell tumor types. The most common association of tumor types in mixed germ cell tumors is teratoma with yolk sac tumor [106]. A very rare component of some mixed germ cell tumors is polyembryoma, which is considered by some authorities to represent an admixture of yolk sac tumor and embryonal carcinoma [1, 107], sometimes with associated teratomatous elements. Thorough sectioning of these tumors is very important in order to identify all cell types present.

The type of germ cell tumor elements present has some prognostic significance. The presence of teratoma with embryonal carcinoma is associated with a lower metastatic rate than that seen with embryonal carcinoma alone [108]. The coexistence of teratoma may indicate a tendency of embryonal carcinoma to differentiate and therefore be less aggressive in this situation. There is a lower rate of occult metastases in patients with mixed germ cell tumors that contain a teratomatous component [109, 110, 111, 112].

The presence of yolk sac tumor also is associated with a decreased tendency for these tumors to metastasize, possibly due to a tendency toward differentiation [113].

Retroperitoneal Lymph Node Dissection Specimens
Retroperitoneal lymph node dissection (RPLND) is both a staging and a therapeutic procedure for patients with clinical stage I testicular cancer. It is also used in patients who have residual retroperitoneal masses after cisplatin based chemotherapy [114].

After radical orchiectomy, germ cell tumor patients undergo evaluation to determine serum AFP and hCG levels. CT scans of the abdomen, pelvis and chest are performed. Patients who have clinical stage I disease will harbor occult metastates in 30% of cases. [115]. The cure rate for these patients is 99% with either surveillance or nerve-sparing RPLND [116].Templates for removal of lymphatic tissue in the paracaval, precaval and interaotocaval (right sided primary) and left paraaortic and preaortic areas (left sided primary tumor) in patients with stage I disease have been published [117]. Patients with advanced stage disease undergo a full bilateral RPLND instead of a template-type dissection. Post chemotherapy RPLNDs may necessitate removal of other organs.

The lymph nodes are removed en bloc because testis cancer can implant in the peritoneum if tumor is spilled during the procedure. The pathologist should attempt to dissect the individual lymph nodes in an area in order to determine the number present and the number involved by metastatic tumor. Sometimes, especially in postchemotherapy lymph node dissections, nodes may be matted together by residual tumor or fibrous tissue; this occurrence should be reflected in the pathology report. It is important to sample each lymph node, with thorough sampling of all areas that appear abnormal on gross examination. Many mixed germ cell tumors have a variegated gross appearance, and numerous sections are necessary in order to avoid overlooking residual small areas of either germ cell tumor or a nongerm cell tumor arising from the germ cell tumor. Postchemotherapy RPLNDs may contain necrosis, fibrosis, teratoma or other persistent germ cell tumor. The pathology report should state the number of lymph nodes identified in each site and the types of residual tumor identified. The presence of necrosis or fibrosis consistent with chemotherapy effect should also be noted.

Late Recurrence of Testicular Germ Cell Tumors
There was a very significant improvement in the survival of patients with testicular germ cell tumors (GCTs) when cisplatin-based chemotherapy was introduced in the late 1970's [118]. The combination of modern chemotherapy and surgical excision now results in survival of more than 90% of all patients with nonseminomatous testicular GCTs [119]. Two decades ago, patients were considered to be cured after a complete remission lasting two years [118]. Most relapses are detected in the first two years after diagnosis, and recurrence after this length of survival had been considered rare. We now know that a small number of patients, about 3% of GCT patients [89] will experience recurrences of GCTs or other tumors derived from GCTs at a later time, up to 30 years after a complete remission. Late recurrences are refractory to chemotherapy and associated with a low survival rate [89, 90]. Thirteen patients reported before the advent of cisplatin-based chemotherapy or followed only by surveillance for stage I testicular GCTs had late recurrences consisting of seminoma, yolk sac tumor, adenocarcinoma, embryonal carcinoma, choriocarcinoma, teratoma or combinations of those tumor elements [120, 121, 122, 123, 124, 125, 126, 127, 128, 129]. Many of those patients died despite receiving aggressive chemotherapy. Many more cases of late recurrences have been seen in recent times [86, 89, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140], probably because most patients now survive long enough to be at risk for late recurrences.

Baniel et al [89] studied 81 patients with late recurrences that developed 2-32 years (median 6.2 years) after complete remission. 60 % of late recurrences occurred at least five years after complete remission. Stage at initial presentation, primary tumor histology and the presence of elevated serum markers (AFP, hCG) were not associated with late recurrences. Most patients had been treated with cisplatin-based chemotherapy at the time of their initial tumor diagnosis. The most common site for late recurrence was the retroperitoneum. Chemotherapy alone left only two patients continuously disease-free after late recurrence; these two patients had not previously received cisplatin-based chemotherapy, indicationg that late recurrences are associated with chemoresistance. Treatment for late recurrences is generally surgical [89, 90].

A recent, large study of the histology of late recurrences [86] showed that teratoma is the most common type of tumor in late recurrences (60% of patients), although other types of recurrent tumor are often present in addition to the teratoma. Next to teratoma, yolk sac tumor is the most common type of tumor seen in late recurrences (46% of patients). Yolk sac tumor also may occur along with other tumor types in late recurrences. The frequency of yolk sac tumor in late recurrences of testicular GCT may be due to its relative chemoresistance compared to other types of germ cell neoplasms. Long-term disease-free survival of patients treated with cisplatin-based chemotherapy for advanced stage testicular cancer containing yolk sac tumor (33%) is significantly poorer than that for patients whose advanced disease does not contain yolk sac tumor (65%) [83]. It is also noteworthy that the frequency of yolk sac tumor at autopsy in patients who die with testicular germ cell tumors increased significantly after introduction of cisplatin-based chemotherapy [84]. Since effective chemotherapy eradicates other types of GCTs, the relatively more chemorisistant yolk sac tumor now has a poorer prognosis and may persist after destruction of more chemosensitive GCT elements.

Yolk sac tumor in late recurrences often displays unusual patterns, including glandular, clear cell and parietal types [86]. In contrast, the microcystic pattern, which is the most common type of yolk sac tumor in primary testicular tumors, is infrequent in late recurrences. Damjanov et al [87] described transformation of microcystic and pseudopapillary yolk sac tumor of the ovary into disseminated, chemoresistant, parietal yolk sac tumor after cisplatin-based chemotherapy. The change in morphology was attributed to selective outgrowth of a chemoresistant clone of yolk sac tumor, a hypothesis that is consistent with the appearance of unusual forms of yolk sac tumor in late recurrences of testicular GCTs. Familiarity with these variants of yolk sac tumor is important in order to avoid misdiagnosis in patients with a remote history of testicular GCTs.

Glandular, clear cell, parietal and hepatoid patterns are especially common in late recurrences. Glandular yolk sac tumor is characterized by glands lined by columnar epithelium with clear cytoplasmic vacuoles, similar to endometrioid-like yolk sac tumor [88]. Many late recurrences display substantial solid areas, which may contain numerous clear cells. Hepatoid yolk sac tumor seen in late recurrences displays polygonal cells with densely eosinophilic cytoplasm and occasional intercellular sinusoids. Parietal yolk sac tumor is frequently seen in late recurrences; it has eosinophilic basement-membrane material between nests of cells.

Some late recurrences contain yolk sac tumor with an unusual degree of nuclear pleomorphism. No festoon or polyvesicular vitteline patterns of yolk sac tumor were identified in a large study of these neoplasms [86].

A smaller number of late recurrences display either nonteratomatous GCTs other than yolk sac tumor or somatic-type malignancies arising from germ cell tumors. These patients have a very poor prognosis unless nongerm cell tumors can be completely excised. The rarity of seminoma and embryonal carcinoma in late recurrences probably reflects their marked sensitivity to chemotherapy in the initial neoplasm.

Patients whose late recurrences contain only teratoma have a good prognosis, with 79% free of disease at last followup [86]. In contrast, only 35% of patients with nongerm cell tumors, 37% of patients with yolk sac tumor and 36% of patients with nonteratomatous GCTs other than yolk sac tumor were free of disease. All patients reported in the literature [86, 89, 90] with late recurrences containing tumor besides teratoma have fared poorly and very few have responded to chemotherapy. Late recurrences should be treated surgically if at all possible.

Somatic-type (Nongerm Cell) Tumors Arising in Patients with Testicular Germ Cell Tumors
Nongerm cell malignant tumors, including various sarcomas, carcinomas, neuroectodermal tumors, carcinoid tumors and other neoplasms usually seen outside the gonads, may arise from germ cell tumors. Nongerm cell malignant tumors arise in 3-6 % [141] of patients with metastatic germ cell tumors, and may strongly affect disease course in these patients. They are associated with an increased number of recurrences, decreased relapse-free survival and decreased overall survival [142]. The criterion for identifying somatic malignancies in germ cell tumors is stromal invasion, which is straightforward in many epithelial malignancies that invade as irregular, haphazardly arranged nests of cells identical to invasive patterns in epithelial malignancies elsewhere in the body. However, identification of invasion in mesenchymal malignancies in germ cell tumors is more difficult because they may be well circumscribed. A pure nodule of hightly atypical somatic-type cells that overgrows surrounding germ cell tumor elements and exceeds the size of one-half to one microscopic field seen with a X4 objective is now considered to represent a nongerm cell tumor [143, 144].

Nongerm cell tumors may be seen in either the primary germ cell tumor or in metastatic sites, but most have been metastatic at the time of diagnosis [141]. The type and anatomic location of the nongerm cell tumor are prognostically significant. A primary site in the mediastinum is an adverse prognostic factor [141, 145]. Nongerm cell tumors that are localized to the testis do not affect prognosis beyond that of the associated germ cell tumor, but somatic malignancies in extratesticular sites are associated with a poor prognosis [146]. Rhabdomyosarcoma and primitive neuroectodermal tumor arising in germ cell tumors correlate with adverse outcomes [141, 147, 148, 149], whereas nephroblastoma-like tumors behave like teratomas [150]. High cure rates have been demonstrated in patients whose nongerm cell tumors were carcinoma or nonrhabdomyosarcomatous, nonneural sarcomas [141].

Most of these tumors arise from teratomas [149], but some may be derived from yolk sac tumor [151]. Teratoma is the germ cell tumor most commonly associated with nongerm cell tumors [141, 146, 148, 150]. Chemotherapy is not a prerequisite for the development of these tumors because they may be seen in primary testicular tumors, but destruction of chemotherapy-sensitive germ cell tumor elements may unmask the nongerm cell tumors and allow them to then dictate the course of disease. Chromosome abnormalities typical of germ cell tumors [i(12p)] have been identified in these neoplasms, including adenocarcinoma, primitive neuroectodermal tumor and sarcoma [152]. In addition, chromosomal abnormalities associated with the somatic malignancies have been seen in cases of rhabdomyosarcoma and primitive neuroectodermal tumor [152]. Kernek et al [153] studied diverse types of nongerm cell tumors arising in patients with testicular germ cell malignancies. A gain in 12p was seen in the nongerm cell tumors arising in the setting of testicular germ cell neoplasia, whereas it did not occur in other somatic malignancies.

Sarcomas in testicular germ cell tumors
Sarcomas represent the most common type of somatic malignancy associated with testicular germ cell tumors [141, 146, 147, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161]. Most patients have had testicular mixed germ cell tumors, but several cases of sarcoma associated with spermatocytic seminoma have also been described [154, 155, 156].

Sarcomas in patients with germ cell tumors are generally not apparent on gross examination of specimens. With the exception of those sarcomas associated with spermatocytic seminoma, most sarcomas are associated with teratomas, although origin of spindle cell sarcomas from yolk sac tumor has been proposed in two men with testicular germ cell tumors [151]. A few of these tumors have been localized to the testis, but most are seen in metastatic sites (either with or without testicular involvement).

About half of these sarcomas are undifferentiated sarcomas. Most of the remainder show striated or smooth muscle differentiation. Rhabdomyosarcomas contain scattered rhabdomyoblasts with abundant eosinophilic cytoplasm scattered among small round blue cells with numerous mitoses. Actin and desmin stains are positive in these tumors. Leiomyosarcomas have spindle-shaped cells with oval nuclei. Isolated examples of chondrosarcoma, malignant giant cell tumor, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor and fibrosarcoma have been reported [149]. While these tumors may occur in primary testicular neoplasms, most patients (except those with spermatocytic seminoma) have been treated with cisplatin-based germ cell tumor chemotherapy before the diagnosis of sarcoma. Sarcomas arising in GCT patients do not respond to germ cell chemotherapy; treatment is predominantly surgical excision.

Carcinomas arising in germ cell tumors
Carcinomas are among the least common somatic neoplasms to arise from testicular germ cell tumors [141, 146, 149]. Almost all patients have received germ cell tumor chemotherapy before developing carcinoma. These lesions are not distinguishable on gross examination from metastatic germ cell tumor in retroperitoneal lymph node dissection specimens. Thorough sectioning is necessary in order to identify these neoplasms. Adenocarcinomas, squamous carcinomas and neuroendocrine carcinomas have all been reported [141, 146, 149]. These tumors display the same histologic features that are seen in similar carcinomas elsewhere in the body. They stain for cytokeratins, EMA and sometimes CEA. Stains for PLAP, AFP and hCG are negative.

Surgical excision is necessary. The prognosis for these patients is better than that for patients with rhabdomyosarcoma or primitive neuroectodermal tumor in metastatic germ cell tumors.

Primitive neuroectodermal tumors in patients with testicular germ cell tumors
In the previous decade, the occurrence of primitive neuroectodermal tumors (PNETs) in a number of patients with testicular germ cell tumors became evident [148, 162, 163, 164, 165, 166]. PNETs may occur in primary testicular neoplasms, in metastatic sites, or in both primary and metastatic sites. Almost all reported cases of PNET in the testis have been associated with intratubular or invasive germ cell tumor elements. Teratoma has been present in the testis in most, but not all cases. Histologically, these tumors may resemble neuroblastoma, medulloepithelioma, peripheral neuroectodermal tumor or ependymoblastoma. They are composed of sheets of small round blue cells with enlarged, hyperchromatic nuclei and numerous mitoses. They may contain rosettes, Homer Wright rosettes and tubules. Immunohistochemical evidence of neuroendocrine differentiation is helpful in distinguishing these neoplasms from other small round blue cell tumors. The specific histologic type of the testicular PNET does not correlate with biologic behavior; about half of the patients in the largest series [148] developed PNET in extratesticular locations regardless of the histologic features of the testicular PNET. The most common germ cell tumor to accompany PNET in metastatic sites is teratoma. PNETs in the setting of a germ cell tumor most likely arise from teratoma. However, they often grow and metastasize independently of germ cell tumor elements. Michael et al [148] reported PNETs that were unaccompanied by GCT elements in at least some anatomic locations in 12 patients. PNET represented the sole component of all extratesticular disease in 6 patients, supporting the autonomous behaviour of these neoplasms. Fli-1, a marker expressed in Ewing's sarcoma and primitive neuroectodermal tumors, stained these neoplasms derived from germ cell tumors relatively weakly and inconsistently in our experience [167].

The significance of PNET in a testicular germ cell tumor patient is dependent on the location of disease. PNET limited to the testis does not change prognosis from that of the associated germ cell tumor. However, PNET in metastatic sites has a very poor prognosis. These tumors do not respond to germ cell tumor chemotherapy, and treatment is focused on resection. All 19 patients in the largest series [148] were either dead of disease, alive with disease, or alive with very short follow-up. Neuroblastoma chemotherapy along with radiation have been effective in a rare case [166] with widespread disease. Additional experience with these rare neoplasms is necessary to determine optimal therapy.

Nephroblastoma-like tumors associated with testicular germ cell tumors
It is important to recognize nephroblastoma-like tumors in patients with testicular germ cell tumors because they have been confused with other neoplasms with different prognostic and therapeutic implications. We have seen three cases diagnosed as PNET that showed features similar to Wilms' tumor upon review. Likewise, one case originally thought to represent a nephroblastoma-like tumor was later reclassified as a PNET, and that patient died shortly after diagnosis.

Nephroblastoma-like tumors are rare in the setting of testicular germ cell tumors. This lesion has been described in a primary testicular germ cell tumor [167]. One case [169] was unassociated with invasive germ cell tumor elements in the testis, but germ cell origin was established by the concurrence of intratubular germ cell neoplasia and demonstration of [i(12p)] in the nephroblastoma-like tumor. More recently, a case of a malignant mixed germ cell tumor of the testis which also contained nephroblastoma and rhabdomyosarcoma was reported [167]. Loss of heterozygosity was demonstrated at four DNA loci. The same pattern of allelic loss was demonstrated at all four loci in all of the different components of the primary tumor and two metastatic teratomas, supporting the germ cell origin of the nephroblastoma component. Most reported cases of nephroblastoma associated with testicular germ cell tumors have occurred at metastatic sites [150].

Nephroblastoma-like tumor is not evident on gross examination of testicular cancer specimens. Microscopically, a triphasic pattern similar to that of the classic Wilms' tumor of childhood is apparent, although the amounts of epithelium, blastema and stroma are variable. Epithelial elements include tubules and glomeruloid structures. Tubules display clear luminal spaces surrounded by epithelial cells with parallel nuclei; the nuclear pseudostratification and central fibrillary material seen in PNETs is not present in nephroblastoma-like tumors. Glomeruloid structures display papillary tufts of epithelial cells in epithelial lined spaces. Blastema surrounds the epithelial structures and consists of small round blue cells with scattered mitotic figures. Stroma contains mainly spindle cells resembling embryonic mesenchyme, but striated muscle may also be a component of the stroma and can be seen in hematoxylin and eosin-stained slides or with stains for desmin and actin. The absence of staining with specific neuroendocrine markers (synaptophysin and chromogranin) and HBA.71 is useful in excluding the possibility of PNET. Immunostains for Fli-1 are negative. Stains for WT-1 may not stain these neoplasms [168]

Most reported cases of nephroblastoma-like tumor in GCT patients have displayed coexistant teratoma [150, 170]. However, in some cases, the teratoma consisted of only rare glands at the edges of sizeable areas of nephroblastoma-like tumor. Teratoma is the most likely source of these tumors, although some may overgrow the teratoma of origin.

Rare examples of nephroblastoma-like tumor have occurred in patients who have not received chemotherapy, but most have been seen in patients with initial stage II or III disease who received cisplatin-based chemotherapy before excision of the nephroblastoma-like tumors. In contrast to the dismal outlook for patients with PNET, nephroblastoma-like tumor has a favorable prognosis. Most patients reported by Michael et al [150] were alive without disease with prolonged followup. Surgical excision appears to be adequate therapy. These tumors appear to have a prognosis similar to that for teratoma alone.

Recently, Emerson et al [167] demonstrated loss of heterozygosity at 11p13, the locus of WT1 inactivation in patients genetically predisposed to nephroblastoma; this loss may be a mechanism for nephroblastomatous differentiation in germ cell tumors.

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