Extragonadal germ cell tumors involving the mediastinum and retroperitoneum

INTRODUCTION — Germ cell tumors (GCTs) are classified as extragonadal if there is no evidence of a primary tumor in the testes or ovaries [1].

Extragonadal GCTs typically arise in midline locations, and specific sites vary with age. In adults, the most common sites, in order of frequency, are the anterior mediastinum, the retroperitoneum, and the pineal and suprasellar regions. In infants and young children, sacrococcygeal and intracranial GCTs are most common.

Mediastinal and retroperitoneal GCTs are reviewed here. The approach to the adult patient with a mediastinal mass, the pathology of mediastinal tumors, intracranial GCTs, and sacrococcygeal teratoma are presented separately.

●(See "Approach to the adult patient with a mediastinal mass".)

●(See "Pathology of mediastinal tumors".)

●(See "Intracranial germ cell tumors".)

●(See "Sacrococcygeal teratoma".)

PATHOLOGIC DEFINITIONS — Extragonadal GCTs are classified as seminomas (termed dysgerminomas in females), nonseminomatous GCTs (termed nondysgerminomas in females), mature teratomas, and immature teratomas based upon histology [1]. (See "Pathology of mediastinal tumors".)

●Seminomas – Seminomas and dysgerminomas must be distinguished from nonseminomatous and nondysgerminomatous GCTs because of the differences in prognosis and treatment. In children, these tumors are often referred to as germinomas and nongerminomas. For a tumor to be considered a seminoma, dysgerminoma, or germinoma, it must consist entirely of that single histology and cannot contain other GCT elements.

●Nonseminomatous tumors – The nonseminomatous tumors, including nondysgerminomas and nongerminomas, include yolk sac tumors, choriocarcinomas, embryonal carcinomas, teratomas, and mixed tumors that contain more than one cell line. Mixed tumors that contain an element of seminoma (or dysgerminoma/germinoma) are classified as nonseminomatous GCTs (or nondysgerminomas/nongerminomas).

●Teratomas – Mature teratomas of the mediastinum generally behave in an indolent manner, unlike testicular GCTs, where there is no clear prognostic distinction between mature and immature teratoma. In adults, immature teratomas of the mediastinum can be aggressive tumors, similar to other nonseminomas, and have a poor prognosis, whereas in prepubertal children, immature elements in a teratoma are not associated with malignant behavior [2,3]. (See "Pathology of mediastinal tumors".)

PATHOGENESIS — The pathogenesis of extragonadal GCTs is not clearly defined. Two competing hypotheses have been proposed, but there are insufficient data to determine which, if either, is correct.

●The first hypothesis is that extragonadal GCTs are derived from primordial germ cells that fail to complete the normal migration along the urogenital ridge to the gonadal ridges during embryonal development. This may be due to an abnormality in the primordial germ cell itself or in its microenvironment [4].

●The second hypothesis is that germ cells transformed in the testes undergo reverse migration [5] or represent metastatic tumors that originated from primary testicular tumors that then burned out [3]. This hypothesis is supported by genetic data suggesting that extragonadal GCTs and testicular GCTs share a common cell of origin [6,7]. The evidence for this hypothesis is strongest for retroperitoneal GCTs [8].

However, this hypothesis does not explain the biological differences seen in mediastinal nonseminomatous GCTs compared with nonseminomatous GCTs occurring in the testes or retroperitoneum. Such differences include the poorer prognosis and the greater incidence of yolk sac tumor elements and leukemia in patients with mediastinal primaries and might result from differences either in the cell of origin or in the tumor's microenvironment.

●A third hypothesis is that extragonadal GCTs arise from the thymus [3].

The following observations may be relevant to the pathogenesis of extragonadal GCTs:

●Testicular carcinoma in situ, the precursor of testicular GCTs, is found in up to 50 percent of the testes of males with retroperitoneal GCTs [9]. However, testicular biopsy is not generally indicated in the absence of evidence of a tumor on ultrasonography [10]. (See "Testicular germ cell neoplasia in situ".)

●The risk of developing a metachronous testicular GCT is significantly increased in males with extragonadal GCTs, particularly among those with retroperitoneal location and nonseminomatous histology (incidence ratios 100 and 75, respectively) [11]. The cumulative risk of developing a metachronous testicular cancer is approximately 10 percent at 10 years after the diagnosis of an extragonadal GCT. (See "Testicular germ cell neoplasia in situ", section on 'Extragonadal germ cell tumor'.)

RISK FACTORS

Klinefelter syndrome — Males with Klinefelter syndrome (KS; 47,XXY) have an increased risk for GCTs, particularly those arising in the mediastinum [12-14]. Although it is not standard practice since the absolute risk is low, clinicians may opt to screen males with KS for mediastinal GCTs [15]. (See "Clinical features, diagnosis, and management of Klinefelter syndrome", section on 'Comorbidities' and "Sex chromosome abnormalities", section on '47,XXY Klinefelter syndrome'.)

In one report from the Children's Oncology Group (COG), approximately 3 percent of pediatric males with a GCT had KS and 69 percent of those GCTs arose in the mediastinum. Among the patients with mediastinal GCTs, approximately one-third had KS. The risk of developing a GCT between ages 0 and 19 years among males with KS was estimated to be 1:4000 per year, which is 19 times higher than the risk among males without KS.

DIAGNOSIS — Extragonadal GCTs are typically diagnosed with a needle or open biopsy prior to treatment. In rare cases, emergency treatment may be initiated because of severe symptoms before a tissue diagnosis is obtained, based upon tumor markers and the distribution of disease. (See "Pathology of mediastinal tumors", section on 'Germ cell tumors'.)

Differential diagnosis — The two key issues in establishing the diagnosis are the exclusion of metastasis from a primary testicular GCT and distinguishing an extragonadal nonseminomatous GCT from another type of poorly differentiated cancer:

●Metastases from a primary testicular GCT – It may be difficult to distinguish true extragonadal GCTs from metastatic tumors in which the primary gonadal lesion has regressed [16,17]. Testicular palpation is not sufficient to exclude a primary testicular GCT; ultrasonography should be performed in all patients [18]. However, a tumor involving the anterior mediastinum is unlikely to be a metastasis from a testicular primary. Primary mediastinal GCTs occur in the anterior mediastinum, whereas testicular GCTs usually metastasize to the posterior mediastinum and rarely involve the anterior mediastinum.

●Poorly differentiated carcinoma – In most cases, extragonadal GCTs can be clearly distinguished from a poorly differentiated carcinoma based upon histopathologic evaluation. In cases where the histopathologic diagnosis is no more specific than poorly differentiated carcinoma, the question arises whether to treat the cancer as a GCT. A key issue in such cases is confirming that the neoplasm is a carcinoma and not a hematologic malignancy. (See "Pathology of mediastinal tumors" and "Poorly differentiated cancer from an unknown primary site".)

Poorly differentiated carcinomas with a primarily midline distribution sometimes respond dramatically to chemotherapy, similarly to GCTs. Moreover, GCTs are the only carcinomas that present in this way that are likely to be cured with chemotherapy. Therefore, a poorly differentiated carcinoma of the retroperitoneum or anterior mediastinum should generally be treated as a GCT.

Although serum tumor markers are commonly measured in this scenario, the results do not influence treatment since because GCT chemotherapy should be administered regardless of serum tumor marker levels. Elevated serum tumor markers are also not associated with a better outcome following such treatment [19-22]. However, if tumor markers are elevated at baseline, they can be used to monitor response during treatment as well as detect disease progression.

Use of cytogenetic analysis for extra copies of chromosome arm 12p is also of limited value. Although such a finding is highly specific for a diagnosis of GCT, identification of this chromosomal abnormality has not been shown to improve outcomes [23].

Tumor markers — Extragonadal nonseminomatous GCTs are often associated with elevations in serum alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-hCG). AFP and/or beta-hCG is elevated in 85 percent of cases of extragonadal nonseminomatous GCTs. Although an elevation in AFP excludes the diagnosis of a pure seminoma, up to 50 percent of patients with extragonadal seminoma have small to moderate increases in serum beta-hCG [24]. (See "Serum tumor markers in testicular germ cell tumors".)

The frequency of tumor marker abnormalities is different when mediastinal and retroperitoneal nonseminomatous GCTs are compared. Mediastinal nonseminomatous GCTs are more likely to have elevations of serum AFP but are less likely to have pronounced elevations of beta-hCG compared with gonadal and retroperitoneal nonseminomatous GCTs.

This pattern of tumor markers was illustrated in one observational series of 635 patients of extragonadal GCTs [24]. In this study, compared with retroperitoneal nonseminomatous GCTs, mediastinal nonseminomatous GCTs were associated with a higher and more frequently elevated serum AFP (median 2548 versus 25 ng/mL; 74 versus 51 percent) and a lower, less frequently elevated serum beta-hCG (median 5 versus 335 milli-international units/mL; 38 versus 74 percent).

MEDIASTINAL GERM CELL TUMORS — Mediastinal GCTs include mature teratomas, immature teratomas, seminomas, and nonseminomatous GCTs. (See 'Pathologic definitions' above.)

Mature teratomas — Mature teratomas of the mediastinum contain well-differentiated histologic elements derived from at least two of the three embryonic cell layers (also known as the germinal layers): ectoderm, mesoderm, and endoderm (picture 1 and picture 2). Tumors containing a mixture of mature teratoma and other GCT elements (mixed tumors) should be treated as mediastinal nonseminomatous GCTs (table 1). (See "Pathology of mediastinal tumors", section on 'Mature teratoma'.)

In males, mediastinal teratomas and testicular teratomas are distinct clinical entities. Mature teratomas of the testis are not considered benign; they have metastatic potential (although less than other testicular GCTs) and are treated in a similar manner to other testicular nonseminomatous GCTs. In contrast, mature teratomas of the mediastinum are considered benign. (See "Anatomy and pathology of testicular tumors", section on 'Teratoma' and 'Treatment' below.)

Clinical manifestations — Mature teratomas of the mediastinum tend to grow slowly, and as a result, they are more likely than other mediastinal GCTs to be diagnosed incidentally while they are still asymptomatic (image 1) [25].

Symptoms (chest pain, cough, dyspnea, and bronchial obstruction and postobstructive pneumonia) are generally due to compression and obstruction of surrounding organs [26,27]. Erosion into an adjacent bronchus can rarely lead to expectoration of hair (trichoptysis) or sebaceous debris [27]. Erosions into the pericardium, adjacent vascular structures, or through the skin to form a draining fistula are rare but serious complications [26,28].

Imaging studies — Chest radiography, whether performed incidentally or because of symptoms, typically shows an anterior mediastinal mass, with calcification reported in 26 percent of mature teratomas [26]. In some patients, well-formed teeth or bone are seen on plain film, findings that are very suggestive of the diagnosis.

Computed tomography (CT) and magnetic resonance imaging (MRI) are helpful in localizing lesions and determining the spatial relationships with surrounding structures. They can also characterize densities within the lesion suggestive of fat, sebaceous material, or cystic elements (image 1) [29,30].

Treatment — The treatment of mature mediastinal teratomas is surgical excision, and this is almost always curative [31,32]. Resection generally is through a median sternotomy or posterolateral thoracotomy, depending upon the location of the tumor, although thoracoscopic resection is occasionally possible [26,33].

Subtotal resection with relief of compressive symptoms is performed if benign teratomas cannot be excised completely without endangering surrounding vital structures. If only subtotal resection is possible, it is not clear that additional treatment with chemotherapy or radiation therapy (RT) offers any benefit, and observation is appropriate. Mature teratomas are relatively insensitive to both chemotherapy and RT [26,33].

Immature teratomas — Teratomas of the mediastinum exist on a continuum ranging from purely mature to predominantly immature (picture 3). These tumors are rare enough that clinically meaningful criteria for defining immaturity are not well established. Immature teratomas are characterized by mature elements from all three germinal layers, which are mixed with immature tissue. Macroscopically, immature teratomas form cystic masses with areas of hemorrhage and necrosis. (See "Pathology of mediastinal tumors", section on 'Immature teratomas'.)

Treatment — The optimal treatment for immature mediastinal teratomas is uncertain. Radical resection is indicated but is often carried out after four cycles of cisplatin-based chemotherapy with either etoposide, ifosfamide, and cisplatin (VIP (table 2)), or bleomycin, etoposide, and cisplatin (BEP, (table 3)). Either regimen is a reasonable option. However, the benefits of chemotherapy and the optimal timing in relation to surgery have not been established in randomized trials due to the rarity of the disease. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Some experts prefer VIP over BEP in these patients since they generally require major thoracic surgery at the conclusion of chemotherapy and may be at risk for serious bleomycin-related postoperative pulmonary complications (eg, pneumonitis and pulmonary fibrosis) [34]. However, other experts prefer BEP over VIP because they have not observed severe postoperative pulmonary complications in mediastinal GCT patients treated with BEP [35], and VIP is associated with greater hematologic toxicity [36,37]. (See "Bleomycin-induced lung injury".)

Although primary, immature, mediastinal teratomas in adults often have a poor prognosis, long-term survival has been reported with preoperative chemotherapy and aggressive surgical resection [38]. Immature teratomas containing elements of other GCTs should be treated like other mediastinal nonseminomatous GCTs, ie, with four cycles of VIP or BEP chemotherapy followed by resection of any residual disease. (See 'Mediastinal nonseminomatous GCTs' below.)

If secondary somatic malignant differentiation (ie, teratoma with malignant transformation) is present without other GCT elements, resection is the treatment of choice. When resection is possible, the outcome is similar to other patients with teratoma. However, if these tumors are unresectable or have metastasized, they are generally incurable. If the transformation is limited to a single cell type, tailored chemotherapy directed towards that cell type may result in major responses and even long-term survival in selected patients [39], but it is unclear whether such tailored chemotherapy is more effective than standard GCT chemotherapy. (See "Anatomy and pathology of testicular tumors", section on 'Teratoma with somatic-type malignancy'.)

In children, immature mediastinal teratomas behave similarly to mature teratomas (ie, as benign tumors) and should be completely excised. (See 'Mature teratomas' above.)

Mediastinal seminoma — Mediastinal seminomas constitute approximately one-third of malignant mediastinal GCTs and 2 to 4 percent of mediastinal masses (picture 4A-B) [40]. (See "Pathology of mediastinal tumors", section on 'Seminomas'.)

Mediastinal seminomas occur predominantly in males between the ages of 20 and 40 [31]. Although it is uncommon for testicular seminoma to metastasize to the mediastinum in the absence of retroperitoneal lymph node involvement [18], all males with mediastinal seminoma should undergo careful testicular palpation and ultrasonography. Orchiectomy is generally indicated in the event of suspicious findings. Mediastinal dysgerminomas (the female counterpart to seminomas) are rare in females with histologically normal ovaries.

In order for a GCT to be classified as a seminoma in males or a dysgerminoma in females, no other histologic element of a GCT can be present, and serum alpha-fetoprotein (AFP) must be normal (unless liver disease or another medical condition exists to explain the AFP elevation) (picture 4A-B). Tumors consisting of a mixture of seminoma and other tumor types are termed mixed GCTs and are treated as nonseminomatous GCTs. (See 'Mediastinal nonseminomatous GCTs' below.)

Clinical manifestations

●Symptoms – Primary mediastinal seminomas are typically slow growing and can be very bulky by the time they cause discomfort. The majority (75 percent) are symptomatic at the time of diagnosis.

The common presenting symptoms are illustrated by a series of 52 patients with mediastinal seminoma [24]:

•Chest pain – 39 percent

•Dyspnea – 29 percent

•Cough – 22 percent

•Weight loss – 19 percent

•Superior vena cava syndrome – 12 percent

•Fever – 6 percent

•Nausea – 6 percent

●Tumor markers – Serum beta-human chorionic gonadotropin (beta-hCG) is elevated in approximately one-third of patients [24]. However, such elevations are typically modest in mediastinal seminomas.

Very highly elevated beta-hCG levels (greater than 1000 or 5000 IU/L) may indicate the presence of nonseminomatous GCT elements. Although data are limited for a specific cutoff level, we generally treat tumors with a beta-hCG >5000 IU/L as a nonseminomatous GCT because these tumor marker levels are almost always seen in tumors where choriocarcinoma or embryonal carcinoma have been reported on histopathology. This issue is more problematic for mediastinal seminomas than testicular seminomas because the histopathological diagnosis is typically based on a core biopsy rather than resection of the entire primary tumor (orchiectomy) where the tumor can be more completely examined. The risk of a sampling error and missing nonseminomatous elements is thus greater for mediastinal tumors. (See 'Tumor markers' above and "Serum tumor markers in testicular germ cell tumors", section on 'False-positive hCG'.)

Seminomas do not produce AFP. An elevated serum AFP is inconsistent with the diagnosis of a pure seminoma and indicates that nonseminomatous elements are present, even if the histopathologic diagnosis is pure seminoma. Such tumors are treated as nonseminomatous GCTs. (See 'Treatment' below.)

●Sites of metastatic disease – The majority of mediastinal seminomas have metastasized by the time they are detected, most often to the lymph nodes and less commonly to lungs, bone, and/or liver [24]. Detection of extramediastinal spread is important because the presence of nonpulmonary visceral metastases is associated with a poorer prognosis. CT imaging is essential to evaluate the primary tumor, retroperitoneal lymph nodes, and liver. The presence of retroperitoneal lymphadenopathy is uncommon in the setting of primary mediastinal seminoma and may be more suggestive of a testicular or retroperitoneal primary tumor.

Treatment — Seminomas are exquisitely sensitive to both cisplatin-based chemotherapy and RT, regardless of location. The relative merits of chemotherapy, RT, and surgery have not been evaluated in randomized trials, and treatment recommendations are based largely upon observational studies and extrapolated from the treatment of advanced testicular seminomas [24,41].

Males with mediastinal seminomas without evidence of nonpulmonary organ metastases are classified as good-risk GCTs by the International Germ Cell Consensus Classification (IGCCC) and have a five-year survival rate of more than 90 percent [41,42]. Most centers prefer chemotherapy to RT for patients with mediastinal seminoma, even when disease is limited to the mediastinum. Retrospective data show improved progression-free survival with cisplatin-based chemotherapy, and there is an increased risk of cardiovascular events, secondary malignancies, and other toxicity following mediastinal RT [24,41]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

Chemotherapy — For patients with mediastinal seminomas and no metastases to organs other than the lungs, chemotherapy regimens that are widely used are three cycles of BEP chemotherapy (table 3) or four cycles of etoposide plus cisplatin (EP) without bleomycin (table 4). These regimens are similar to those used to treat advanced testicular seminoma. In patients who have previously received RT to the chest or mediastinum, who have underlying lung disease, or who are older than 50 years of age, the EP regimen (table 4) is preferred due to an increased risk of bleomycin lung toxicity [43]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good risk' and "Bleomycin-induced lung injury", section on 'Risk factors'.)

Patients with mediastinal seminoma and metastases to the liver, bones, or other nonpulmonary organs should be treated with four cycles of BEP chemotherapy (table 3). Patients with metastases to organs other than the lungs who cannot tolerate bleomycin should receive four courses of VIP (table 2). As noted above, for patients who have received RT to the chest or mediastinum or have underlying lung disease or who are over 50 years of age, we typically use a bleomycin-free regimen [43].

Cisplatin-based chemotherapy was evaluated in an observational series of 635 patients with extragonadal GCTs [24]. This study included a subgroup of 103 patients with either mediastinal or retroperitoneal seminomas who were treated with either chemotherapy (75 percent), RT (6 percent), or a combination of chemotherapy and RT (19 percent). For the patients with mediastinal and retroperitoneal seminomas, five-year progression-free survival was 88 and 77 percent respectively; five-year overall survival was 88 percent for both groups. Among the patients with seminomas, chemotherapy was associated with a higher five-year progression-free survival compared with RT, although the small number of patients treated with radiation (n = 3) limits the reliability of these data [41]. (See 'Residual mass' below.)

Radiation therapy — In those rare patients who are not candidates for chemotherapy, primary RT (35 to 50 Gy) is an acceptable alternative strategy in the absence of bulky or metastatic disease [25]. If RT is used, the radiation portals should include the mediastinum and bilateral supraclavicular fossae. Careful treatment planning is essential to avoid unnecessary toxicity to the lungs, heart, and other surrounding tissues.

Mediastinal radiation has been associated with coronary artery disease, valvular heart disease, diastolic dysfunction, and constrictive pericarditis. In addition, an increased frequency of late breast, esophageal, and lung cancers, as well as other malignancies, has been reported. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

Surgery — In general, surgical resection or debulking plays no role in the initial management of seminomas because of the typical presence of bulky and/or metastatic disease [24]. Complete surgical excision may be performed in the unusual case in which a mediastinal seminoma is discovered when very small and localized. Adjuvant therapy is not typically required for such small lesions that are discovered incidentally or surgically resected before a diagnosis is made.

Residual mass — Following chemotherapy, many patients are left with a residual mass. Most of these masses are benign and consist of necrosis or a scirrhous or desmoplastic reaction. Residual masses ≥3 cm in diameter may contain residual malignancy in up to 30 percent of cases, based on data from testicular seminoma with metastatic adenopathy postchemotherapy [44-46]. However, unless there is histologic confirmation of residual disease, residual masses should not be empirically treated with chemotherapy or RT based on size alone, which is not always associated with the presence of viable seminoma [47,48].

The optimal treatment of a residual mass is a subject of contention, and our approach is as follows:

●Tumors <3 cm – We offer surveillance for residual masses <3 cm. Surgical resection is often technically difficult and may be unnecessary for such masses. [44-46]. The surveillance schedule is similar to that of patients with testicular seminoma who are treated with chemotherapy. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Seminoma'.)

●Tumors ≥3 cm – For residual masses ≥3 cm, we evaluate with a positron emission tomography (PET)-CT scan at least six weeks or more after completing chemotherapy. PET-negative lesions should be observed. Strongly PET-positive lesions require histopathological documentation of residual cancer by biopsy or resection. Borderline PET-positive lesions can be followed with either additional PET-CT or CT imaging in six to eight weeks.

Alternatives to PET-CT imaging include an open biopsy or close observation using periodic contrast-enhanced CT scans [44,46]. One surveillance regimen that has been used is CT imaging every three months for the first year and every six months for the second year or until normal. Further therapeutic intervention for patients undergoing surveillance is performed only for progressive disease [44].

If PET-CT is utilized, it should be obtained at least six weeks after completion of chemotherapy to avoid a potential false-positive result due to treatment-related inflammation. Data suggest that PET imaging with fluorodeoxyglucose contrast performed after chemotherapy is highly accurate in distinguishing benign from malignant residual masses [46,49].

However, a positive PET-CT scan alone is not strong enough evidence to justify additional treatment with chemotherapy or RT, due to a significant false-positive rate, and suspicious PET-positive masses must undergo tissue sampling.

In a patient with a residual mass larger than 3 cm for whom a resection or open biopsy is planned, a negative PET scan provides a reasonable basis for foregoing these procedures, unless the mass is increasing in size. In observational studies, the false-negative rate for PET imaging in masses over 3 cm in size has been reported to be zero [49,50].

Patients who have histologically confirmed, residual, viable malignancy or who develop progressive disease should generally be treated with salvage chemotherapy. RT represents an alternative approach for selected patients (eg, those in whom additional chemotherapy is not possible). (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

Prognosis — Long-term disease-free survival (DFS) is achieved in roughly 90 percent of patients treated with chemotherapy [24]. Although most patients treated with primary RT are cured, the distant relapse rate is high, and the five-year DFS rate is only 60 to 67 percent [24,51]. Most patients who relapse following primary RT can be salvaged with chemotherapy, but there is some evidence that the overall survival rate may be higher with initial chemotherapy [52].

Unlike patients with mediastinal nonseminomatous GCTs, mediastinal seminomas are not associated with secondary malignant differentiation into non-germ-cell malignancies [53]. (See 'Association with other malignancies' below.)

Mediastinal nonseminomatous GCTs — Nonseminomatous germ cell tumors (GCTs) of the mediastinum contain yolk sac tumor, choriocarcinoma, and/or embryonal carcinoma. Mixed GCTs may contain more than one cell type, as well as elements of teratoma and/or seminoma. Tumors that consist of a mixture of seminoma and teratoma are considered nonseminomatous GCTs. (See "Pathology of mediastinal tumors", section on 'Nonseminomatous GCTs'.)

In contrast to gonadal and retroperitoneal nonseminomatous GCTs, mediastinal nonseminomatous GCTs contain embryonal carcinoma less frequently, whereas yolk sac tumors (either pure or mixed with other histologies) are common (picture 5). In one series of 64 cases, 60 percent were pure yolk sac tumors, 12 percent were pure choriocarcinomas, and 9 percent were pure embryonal carcinomas [54].

Mediastinal nonseminomatous GCTs occur far more often in males than in females and usually are diagnosed between the ages of 20 and 40 years. Patients with mediastinal nonseminomatous GCTs are also at risk for developing fatal hematologic disorders. These typically display a megakaryocytic lineage and share cytogenetic abnormalities with nonseminomatous GCTs. (See 'Association with other malignancies' below.)

Clinical manifestations — Most patients with mediastinal nonseminomatous GCTs are symptomatic at presentation [54,55]. Signs and symptoms may include fever, chills, weight loss, chest pain, dyspnea, and/or superior vena cava syndrome. Gynecomastia can be seen in tumors with foci of choriocarcinoma that secrete large amounts of hCG. (See "Clinical features, diagnosis, and evaluation of gynecomastia in adults".)

Diagnosis — Most patients have an elevated serum AFP at presentation, and a sizable minority have an elevated serum beta-hCG. This pattern is so characteristic that some institutions accept elevated AFP and beta-hCG in a young adult male with an anterior mediastinal mass as de facto evidence of an extragonadal nonseminomatous GCT, and chemotherapy is sometimes started without a tissue diagnosis.

However, we recommend histologic confirmation in all patients if it can be safely accomplished, unless the clinical scenario demands immediate treatment. Histologic confirmation is clearly required in the roughly 10 percent of patients with normal serum tumor markers.

Treatment — Mediastinal nonseminomatous GCTs are aggressive tumors that are often metastatic at presentation [54,56]. A multimodality approach is generally used, utilizing chemotherapy initially, followed by surgery to resect any residual masses.

Systemic chemotherapy — Primary mediastinal nonseminomas are classified as poor risk by the IGCCC. Initial treatment consists of four cycles of cisplatin-based chemotherapy as is used in patients with poor-risk advanced, testicular GCTs. The standard regimens used are either VIP (table 2) or BEP (table 3). Further details on studies that compare these regimens in patients with advanced nonseminomatous GCTs are discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Intermediate- and poor-risk advanced disease'.)

The efficacy of VIP compared with BEP appears to be similar, so the choice of therapy is based on clinician preference and the ability to monitor or minimize the risk for bleomycin toxicity. Four cycles of VIP are preferred by some oncologists for primary mediastinal nonseminomas because these patients will typically undergo a thoracotomy or sternotomy for resection of residual disease. This may require prolonged exposure to high partial pressures of oxygen during surgery, which can provoke bleomycin-related pneumonitis. However, we are also comfortable treating patients with BEP if other risk factors for bleomycin pulmonary toxicity are absent and if serial pulmonary function tests are obtained to monitor diffusing capacity for carbon monoxide and vital capacity. To minimize postoperative risks in all patients previously treated with BEP, including those with mediastinal nonseminomas, we limit the excessive use of both supplemental oxygen and intravenous fluid support. (See "Bleomycin-induced lung injury".)

Data supporting the use of the VIP regimen comes from a retrospective series of 221 patients who underwent thoracic surgery at Indiana University following chemotherapy [34]. In this series, 22 of 166 patients treated with BEP developed acute respiratory distress syndrome (13 percent) versus 0 of 55 treated with VIP; prolonged ventilator use was required in 30 (18 percent) of those treated with BEP versus 2 (4 percent) of those treated with VIP. There were 11 perioperative deaths (7 percent) with BEP, 10 of which were secondary to pulmonary failure, versus no deaths in those treated with VIP. However, in another observational series from Memorial Sloan-Kettering Cancer Center, there was no significant difference in pulmonary complications among patients with primary mediastinal nonseminomas treated with or without bleomycin [35]. In addition, no fatal pulmonary complications were observed.

As with other poor-risk GCTs, early changes in the tumor markers after the first dose of therapy can be used to individualize therapy, as shown by results of the Groupe d'Etude des Tumeurs Uro-Genital (GETUG)-13 trial [57,58]. However, longer follow-up is required before incorporating this approach into standard practice. The results of this trial are discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Intermediate- and poor-risk advanced disease'.)

Surgery for residual mass — Most patients with mediastinal nonseminomatous GCTs have residual masses at the conclusion of chemotherapy. Resection of all residual masses following chemotherapy plays an integral role in the treatment of these tumors and should be performed whenever technically feasible [59]. Surgery should also be offered to patients whose serum tumor markers are rising at the completion of chemotherapy, given the poor results with salvage chemotherapy [24,60-63]. Given the complexity of these surgeries, referral to a thoracic surgeon with experience with mediastinal nonseminomas is advisable.

Following postchemotherapy surgery, no further therapy is necessary if the residual masses contain teratoma or necrosis. If viable malignancy is identified, two additional cycles of chemotherapy should be given. If a patient received four cycles of VIP prior to surgery, we offer an additional two cycles of VIP as adjuvant chemotherapy. If the patient received four cycles of BEP before their operation, we offer adjuvant chemotherapy with two cycles of either EP or VIP.

Monitoring tumor markers — Serial monitoring of serum AFP and beta-hCG is helpful in monitoring the response to therapy and detecting early recurrence. The suggested schedule is similar to that used in testicular nonseminomatous GCTs. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)

Treatment after relapse — Historically, further systemic treatment with either standard- or high-dose chemotherapy regimens is minimally effective for patients with mediastinal nonseminomatous GCTs who relapse after cisplatin-based therapy, with DFS rates of less than 12 percent. However, subsequent reports evaluating high-dose chemotherapy have been a little more favorable, with long-term DFS of up to 25 percent with this approach [24,56,62,64-69]. Further details on the treatment or relapsed and refractory GCTs are discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

As an example, a retrospective review of 79 patients treated at 11 centers reported that only 8 percent of the cohort were long-term survivors, compared with 30 percent who were initially diagnosed with primary retroperitoneal disease [24,67]. Of the 25 patients with primary mediastinal tumors who received high-dose chemotherapy with autologous stem cell transplantation at relapse, only 3 (12 percent) were long-term survivors. In subsequent observational series evaluating high-dose chemotherapy, 20 to 25 percent of patients with primary mediastinal nonseminomas achieved long-term DFS [68,69].

Association with other malignancies — Hematologic and somatic malignancies can arise in patients with mediastinal seminomatous GCTs. Further details on other subsequent malignancies in patients with testicular GCTs are discussed separately. (See "Approach to the care of long-term testicular cancer survivors", section on 'Secondary malignancies' and "Treatment-related toxicity in testicular germ cell tumors", section on 'Second malignancies'.)

●Hematologic malignancies – Patients with mediastinal nonseminomatous GCTs have a relatively high incidence of hematologic disorders unrelated to their prior cytotoxic chemotherapy. These include acute megakaryoblastic and myelogenous leukemia, myelodysplasia, malignant mastocytosis, and malignant histiocytosis.

In one observational series of patients with primary mediastinal nonseminomatous GCTs, approximately 6 percent subsequently developed a hematologic disorder [53]. The median time to onset of the hematologic disorder was six months, the median survival following diagnosis was five months, and no patient survived more than two years.

Hematologic malignancies associated with mediastinal GCTs may originate from a yolk sac, tumor-derived progenitor cell that can undergo hematopoietic differentiation and subsequently home to the bone marrow. In many cases, the malignant cells in these hematologic disorders have an isochromosome 12p or other evidence of derivation from the GCT [53,70,71]. In one report of six patients with mediastinal GCTs associated with hematologic malignancy, four had hematopoietic precursor cells within the yolk sac component of the tumor, which had a similar morphology and immunohistochemical profile as the leukemic cells in bone marrow [72]. Another biological study suggested that the GCT and the hematologic malignancy derive from a common precursor with parallel clonal evolution, rather than the hematologic malignancy developing directly from the differentiated GCT [73].

●Somatic malignancy – Mediastinal nonseminomatous GCTs, particularly those with teratomatous elements, can transform into sarcomas and carcinomas that are highly resistant to treatment with chemotherapy or RT. These tumors should be resected if possible [74,75]. Sarcomas are the predominant secondary somatic malignancy for patients with primary mediastinal nonseminoma and multiple histologies (multiple sarcomas or sarcoma plus carcinoma) can sometimes be observed. Further details on somatic malignancies that arise in nonseminomatous GCTs are discussed separately. (See "Pathology of mediastinal tumors", section on 'Nonseminomatous GCTs'.)

Prognosis — Mediastinal nonseminomatous GCTs are always considered poor-risk GCTs. These tumors carry a distinctly worse prognosis than seminomas or teratomas [76], with a five-year overall survival rate of about 40 to 45 percent [24,42,77]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

Our understanding is evolving of the underlying biologic basis for the increased aggressiveness and poor prognosis of mediastinal nonseminomas. TP53 alterations are present in approximately 70 percent of these patients as compared with only 4 percent of those with testicular nonseminomas [78]. Furthermore, nearly all GCT patients (gonadal or extragonadal) with TP53 alterations who required chemotherapy have been noted to have cisplatin-resistant disease. In observational studies, TP53 alterations and chromosome 3p25.3 gain (a separate molecular alteration also associated with cisplatin resistance in GCTs) have been associated with a poor prognosis [79,80].

The effectiveness of a combined-modality approach as the initial approach to treating mediastinal nonseminomatous GCTs was illustrated in a retrospective multicenter study that included 287 patients with mediastinal nonseminomatous GCTs, in which 278 patients (97 percent) were initially treated with chemotherapy [24]. The complete response rate to chemotherapy was 19 percent, and partial response with normalization of tumor markers was observed in 45 percent. Surgery was used to resect a residual mass in 143 patients (50 percent). The five-year progression-free and overall survival rates were 44 and 45 percent, respectively.

RETROPERITONEAL GERM CELL TUMORS — Retroperitoneal GCTs are generally bulky at the time of diagnosis because they usually are diagnosed as a result of symptoms. Their clinical behavior, prognosis, and management are similar to disseminated testicular GCTs [81]. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

Retroperitoneal seminoma — For patients with a retroperitoneal seminoma, systemic chemotherapy with a cisplatin-based regimen is the preferred approach, using the same regimens as for patients with advanced testicular seminoma. (See "Treatment of stage II seminoma", section on 'Stage IIC seminoma'.)

The results with this approach are similar to those for advanced testicular seminoma. In a multinational series that included 52 patients with retroperitoneal seminoma and 51 with mediastinal seminoma, the progression-free and overall five-year survival rates for the entire cohort were 87 and 90 percent, respectively [24,41]. In this series, 75 percent of patients were treated with chemotherapy alone. (See "Treatment of stage II seminoma".)

Nonbulky retroperitoneal seminomas can also be treated with primary radiation therapy (RT) in a manner similar to stage II testicular seminoma. However, there is insufficient published experience to determine the complete remission and cure rates using this approach. (See "Treatment of stage II seminoma".)

Retroperitoneal nonseminomatous GCTs — The initial therapy of patients with retroperitoneal nonseminomatous germ cell tumors (GCTs) consists of either three or four cycles of cisplatin-based chemotherapy, depending upon whether the patient falls into the good- or intermediate/poor-prognosis group. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

The results with this approach are illustrated by a multicenter series of 227 patients with retroperitoneal nonseminomatous GCTs, of whom 98 percent were treated with chemotherapy initially [24]. Of these, 101 (45 percent) underwent surgery for resection of a residual mass. The five-year progression-free and overall survival rates were 42 and 65 percent, respectively.

For those who relapse following first-line chemotherapy, salvage cisplatin-based chemotherapy is identical to that for gonadal nonseminomatous GCTs. In one large review, 30 percent of patients with relapsed retroperitoneal nonseminomatous GCTs achieved long-term disease-free survival (DFS) [67]. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

Retroperitoneal teratomas — Pure teratomas of the retroperitoneum are rare, and they are generally treated with complete surgical resection as the primary therapy [82-84]. Because the preoperative diagnosis is based on a needle or open biopsy, it is possible that complete resection will reveal the presence of nonteratoma GCT elements. In such cases, when the amount of viable GCT is small, two cycles of adjuvant chemotherapy is sufficient, typically with etoposide plus cisplatin (EP). Although data are limited to guide management, when more substantial amounts of viable GCT are present (pN3), options include three cycles of bleomycin, etoposide, and cisplatin (BEP (table 3)) or four cycles of EP (table 4), using a similar approach to good-risk testicular GCTs. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

●Extragonadal germ cell tumors – Extragonadal germ cell tumors (GCTs) are rare tumors that most frequently arise in the mediastinum and retroperitoneum in adult males. (See 'Pathologic definitions' above.)

●Mature mediastinal teratomas – Patients with a mature teratoma of the mediastinum are treated with complete surgical resection. Partial resection should be limited to patients in whom a complete resection is not technically feasible. Mature teratomas are relatively insensitive to both chemotherapy and radiation therapy (RT). (See 'Mature teratomas' above.)

●Immature mediastinal teratomas – For patients with immature teratomas of the mediastinum, we suggest four cycles of cisplatin-based chemotherapy followed by complete surgical resection, if technically feasible, rather than initial surgery (Grade 2C). (See 'Immature teratomas' above.)

•Chemotherapy options include four cycles of etoposide, ifosfamide, and cisplatin (VIP (table 2)) or bleomycin, etoposide, and cisplatin (BEP (table 3)). For patients treated with BEP, we closely monitor pulmonary function tests due to the potential for postoperative pulmonary complications at thoracic surgery following chemotherapy. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors" and "Bleomycin-induced lung injury".)

●Mediastinal seminomas – For patients with a mediastinal seminoma, we suggest cisplatin-based chemotherapy rather than RT or surgery (Grade 2C). (See 'Mediastinal seminoma' above and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

•Good-risk patients are generally treated with three cycles of BEP (table 3) or four cycles of etoposide and cisplatin (EP (table 4)).

•Intermediate-risk patients (ie, those with nonpulmonary visceral metastases) should receive four cycles of BEP or VIP (table 2) chemotherapy.

•RT is an alternative for patients who do not have bulky or metastatic disease and for whom there are contraindications to cisplatin-based GCT chemotherapy regimens.

•Mediastinal seminomas that also contain elements of other cell types or those with an elevation of serum alpha-fetoprotein (AFP) are nonseminomatous GCTs and should be treated as such. (See 'Mediastinal nonseminomatous GCTs' above.)

●Residual masses after chemotherapy for mediastinal seminoma – For patients with mediastinal seminomas treated with chemotherapy who are left with a residual mass, our treatment approach is based upon the size of the residual mass. (See 'Residual mass' above.)

•For residual masses <3 cm, we offer surveillance.

•For residual masses ≥3 cm, we evaluate with a positron emission tomography (PET)-CT scan at least six weeks or more after completing chemotherapy. PET-negative lesions should be observed. Strongly PET-positive lesions require histopathological documentation of residual cancer by biopsy or resection. Borderline PET-positive lesions can be followed with either additional PET-CT or CT imaging in six to eight weeks.

Alternatives to PET-CT imaging include an open biopsy or close observation using periodic contrast-enhanced CT scans.

●Mediastinal nonseminomatous GCTs – For patients with a mediastinal nonseminomatous GCT, we suggest initial treatment with four cycles of cisplatin-based chemotherapy, rather than surgery or RT (Grade 2C).

•Chemotherapy options include VIP (table 2) or BEP (table 3). For patients treated with BEP, we closely monitor pulmonary function due to the potential for postoperative pulmonary complications at thoracic surgery following chemotherapy. (See 'Mediastinal nonseminomatous GCTs' above and "Bleomycin-induced lung injury" and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

•For patients with a residual mediastinal mass following initial chemotherapy, we recommend complete surgical resection, if technically feasible (Grade 1A). If viable malignancy is identified, we suggest two additional cycles of cisplatin-based chemotherapy (Grade 2C). (See 'Surgery for residual mass' above.)

●Retroperitoneal seminoma – For patients with a retroperitoneal seminoma, we suggest cisplatin-based chemotherapy using the same regimens as used for patients with advanced testicular seminoma rather than RT (Grade 2C). RT may be an alternative for patients with nonbulky disease. (See 'Retroperitoneal seminoma' above and "Treatment of stage II seminoma", section on 'Stage IIC seminoma'.)

●Retroperitoneal nonseminomatous GCTs – For patients with a retroperitoneal nonseminomatous GCT, we suggest cisplatin-based chemotherapy as would be used for a testicular nonseminomatous GCT, rather than RT or surgery (Grade 2C). Depending upon whether the patient falls into the good- or intermediate/poor-prognosis group, this would include three or four cycles of treatment. This should be followed by surgical resection of any residual mass. (See 'Retroperitoneal nonseminomatous GCTs' above and "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors" and "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Philip W Kantoff, MD, who contributed to earlier versions of this topic review.