Introduction

Testicular germ cell tumors (GCT) are the most common solid neoplasms in young men aged 20 to 40 years. Histologically, GCT are differentiated into seminomatous and nonseminomatous GCT, which have different clinical, biological, and therapeutic features [1]. About two thirds of patients harbor organ-confined tumors and only 30% of men demonstrate metastases at the time of diagnosis or during follow-up. Typically, GCT metastasize to retroperitoneal, retrocrural, or mediastinal lymph nodes and the lung, whereas liver, brain, or skeletal metastases are rare [1]. Patients with metastatic GCT are classified into three different risk groups depending on serum concentrations of the tumor markers AFP, β‑hCG, and LDH, as well as on the localization of the metastatic deposits [2]. Overall survival rates differ significantly between the three risk groups, with 96%, 89%, and 67% for the good, intermediate, and poor prognosis groups, respectively [2].

Germ cell tumors typically arise in the male gonads or at extragonadal sites, in which case they are referred to as extragonadal germ cell tumors (EGCT). EGCT are located in the midline areas of the body which is due to the embryonic migration of primordial germ cells from the epiblast to the genital ridge. Although histologically similar to GCT, EGCT have distinct histological patterns which result in a biologically aggressive variant of GCT with the need for interdisciplinary care in highly specialized centers [3, 4].

Epidemiology and diagnosis

The incidence of EGCT is low, and only 2–3% of all GCT are diagnosed as EGCT, with the majority of these tumors being located in the upper anterior mediastinum (50–70%) followed by the retroperitoneum [5]. Mediastinal EGCT, however, only account for 16–20% of all mediastinal tumors, so that a proper diagnosis is necessary to rule out non-germ cell tumors and to initiate the correct treatment option with a high cure rate [6]. Besides extragonadal germ cell tumors, thymomas represent the most common pathology in the anterior mediastinum. Lymphomas and bronchogenic cysts represent the most common histology in the middle mediastinum, whereas schwannomas and neurofibromas are the most common pathologies in the posterior mediastinum [5]. In the majority of cases a biopsy specimen will be taken via CT-guided bronchoscopic or thoracoscopic routes.

Serum tumor markers alpha fetoprotein (AFP), ß-human choriogonadotropic hormone (β‑hCG), and lactate dehydrogenase (LDH) should always be measured and might be elevated in about 40% to 60% of cases. Especially if AFP and/or β‑hCG are elevated, the presence of a germ cell tumor is proven and no further diagnostic approaches with biopsy are necessary. The role of the new biomarker miR371, which has been shown to be diagnostic and predictive for GCT, has not been evaluated in EGCT. In addition, FISH analysis or PCR-based techniques can be applied to identify abnormalities of the 12p chromosome, since i(12p) or amplifications of 12p11.2-12.1 are characteristic for GCT independent of their localization [7]. Furthermore, the incidence of Klinefelter’s syndrome is highly increased in men with EGCT, so that a proper karyographic examination should be performed in all patients [8].

About 40% of potential EGCT might demonstrate some intratesticular pathology such as a calcification, cysts, and scars, which highlight the presence of a so-called burned-out tumor, so that proper urological examination is mandatory prior to initiation of treatment. Furthermore, a testicular biopsy will demonstrate the presence of germ cell neoplasia in situ (GCNIS) in about 40% of patients with extragonadal retroperitoneal GCT, whereas none of the patients with mediastinal EGCT have demonstrated GCNIS [9]. Therefore, identification of GCNIS as the common precursor cell for all GCT is only indicated in extragonadal tumors outside the mediastinum.

Pathohistology

Whereas the majority of intratesticular GCT are seminomas, nonseminomatous mixed GCT predominate in EGCT, with most of the patients harboring yolk sac tumor elements or postpubertal teratomas [10]. Pure mediastinal EGCT are rare and occur in only about 10–15% of patients. Postpubertal teratomas typically do not express serum tumor markers, so that these histologies can only be detected by biopsies. The same holds true for EGCT with malignant somatic transformation (MST), which is defined as a teratoma that develops a distinct secondary component that resembles a somatic-type malignant neoplasm, as seen in other organs and tissues (e.g., sarcomas and carcinomas) [11]. Pathohistologically, most MST components represent sarcomas, primitive neuroectodermal tumors, and adenocarcinomas, which all have a poor prognosis as compared to GCT and EGCT without MST.

On biopsy, immunohistochemical staining for SALL4, OCT3/4, GPC3, AFP, and GATA3 are typical markers for GCT [12]. In addition, staining for FOXA2 has been shown to be highly predictive for the presence of yolk sac tumor elements which usually exert a negative prognosis [13].

Besides MST, there is a high association between EGCT and the presence or the development of hematological neoplastic disease such as acute megaloblastic leukemia and myelodysplastic syndromes, which have been reported in about 6% [14]. Hematological disorders seem to arise from the same progenitor cells as EGCT does, since i(12p) was detected in EGCT tumors cells and in blasts. Hematological disorders are typically diagnosed about 6 months after diagnosis and systemic treatment of EGCT, so that patients need to be followed closely.

Clinical symptoms

Most patients with mediastinal EGCT present with symptoms resulting from compression and/or infiltration of the mediastinal structure such as dyspnea, Horner’s syndrome, arrhythmia, and pulmonary or arterial compression (Fig. 1).

Fig. 1
figure 1

Large mediastinal mass with infiltration of right upper lobe, bipulmonary metastases, and mediastinal lymph node metastases

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Prognosis

According to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification, mediastinal nonseminomatous EGCT belong to the group with poor prognosis regardless of serum concentration of tumor markers and regardless of the extent of metastatic disease, whereas mediastinal seminomas are classified in the good prognosis group [2]. Poor prognosis for typical nonseminomas was associated with a 5-year overall survival rate of 50% and 67% according to the old and the new IGCCCG classification analysis, respectively. However, survival rates in mediastinal nonseminomatous EGCT are worse, with 40% to 45% following systemic chemotherapy and residual tumor resection.

Extragonadal seminomas belong to the good prognosis group, and they have a 5-year overall survival rate of about 90% [16].

Treatment

Treatment of choice is systemic chemotherapy with three cycles of PEB (cisplatin, etoposide, bleomycin) in seminomatous EGCT and with four cycles of PEB in nonseminomatous EGCT [15]. The prognosis of patients with extragonadal seminomas has improved significantly, with a 5-year progression-free survival rate of 79% as compared to 67%, and a 5-year overall survival rate of 88% versus 72% upon comparing the new and the old IGCCCG classifications, respectively [16]. Since most of the nonseminomatous EGCT patients will require postchemotherapy resection of residual masses, the risk of bleomycin-induced lung toxicity must be taken into consideration. Therefore, repeated assessment of lung function is mandatory for patients with a high probability of postchemotherapeutic surgery. These patients might be treated initially with the PEI (cisplatin, etoposide, ifosfamide) or TIP (paclitaxel, ifosfamide, cisplatin) regime [17]. This treatment strategy is highlighted by the retrospective analysis of 158 patients with nonseminomatous EGCT who underwent postchemotherapeutic resection of residual masses: 24% of patients with bleomycin exposure experienced postoperative respiratory failure whereas none of the 17 patients without bleomycin exposure developed such a complication [18].

It is currently under debate whether patients with nonseminomatous mediastinal EGCT should be treated with first-line high-dose chemotherapy or with conventional systemic chemotherapy. This treatment suggestion is derived from a previous German multicenter trial which enrolled a total of 28 patients with nonseminomatous EGCT, all of whom were managed by first-line high-dose VIP chemotherapy followed by autologous peripheral blood stem cell transplantation [19]: 19/28 (67.8%) patients remained disease free after chemotherapy alone or with the combination of chemotherapy and surgery. This aggressive approach resulted in 2‑year PFS and overall survival of 64% and 68%, respectively, which is about 15% superior to the results achieved with conventional chemotherapy. However, since there is no level I or II evidence data and since high-dose VIP is associated with significant treatment-associated toxicities, this approach might be reserved for nonseminomatous EGCT with poor prognostic risk factors which were assessed by Hartmann et al. [20] in a cohort of 104 seminomatous and 524 nonseminomatous EGCT patients. Adverse parameters for overall survival in nonseminomatous EGCT were presence of central nervous system metastases, primary mediastinal location, liver metastases, elevation of pretreatment β‑hCG, and presence of lung metastases (Tables 1 and 2). Based on these data, the authors developed the three prognostic categories of good (seminomas only), intermediate-low, intermediate-high, and poor risk, which were associated with a 5-year overall survival rate of 89%, 69%, 55%, and 17%, respectively.

Table 1 Prognostic factors and their relation to overall survival in extragonadal germ cell tumors [19]
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Table 2 Overall survival depending on the risk category
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Treatment intensification based on the assessment of tumor marker decline at the end of one cycle of PEB might represent another treatment strategy. In the GETUG 13 study, poor-risk GCT patients, of whom 30% had nonseminomatous EGCT, were randomized to receive four cycles of PEB or two cycles of T‑BEP-oxaliplatin followed by two cycles of PEI in case of unfavorable marker decline [21]. The PFS for the dose-dense regime was superior to PEB (HR = 0.66, 95% CI: 0.44–1.00, p = 0.05), but there was no correlation between other negative prognostic markers including the presence of extragonadal GCT. Therefore, it was concluded that mediastinal nonseminomatous EGCT do not benefit from upfront dose intensification.

In summary, international guidelines recommend conventional first-line systemic chemotherapy with three to four cycles of PEB or PEI/TIP depending on the probability of undergoing postchemotherapeutic resection of mediastinal masses. In case of significantly elevated markers, adequate marker decline should be assessed at the end of cycle one and patients with unfavorable marker decline should undergo treatment intensification. First-line high-dose chemotherapy should be reserved for patients with poor adverse factors.

Unnecessary treatment delays or dose reductions should be avoided since these steps are associated with an inferior outcome. It is of utmost importance to stick to the 21-day regimes, which requires significant experience in the management of poor-risk patients. Centralization of treatment of those poor-risk patients with mediastinal EGCT is the first step to achieving optimal treatment results.

For those patients with significant comorbidities and an ECOG performance status ≥ 2, an individual treatment plan needs to be developed. PEB can usually be administered safely in patients with cardiac morbidity and a left ventricular ejection fraction > 30%. Patients with significant coronary heart disease need to be monitored closely during the treatment cycles and during the first 3 months after discontinuation of treatment due to the elevated risk of arterial and venous thromboembolic events [22]. Patients with significant pulmonary toxicity based on pulmonary function tests need to be switched to PEI (cisplatin, etoposide, ifosfamide) or TIP (paclitaxel, ifosfamide, cisplatin) [1]. In patients with significant renal impairment or in patients on dialysis, the dosage of cytotoxic drugs needs to be adapted and intermittent hemodialysis needs to be performed [23].

Postchemotherapeutic residual mass resection (PC-RMR)

PC-RMR for nonseminomatous EGCT represents an integral and fundamental part of the multimodality treatment of these tumors [24, 25]. Adequate PC-RMR in EGCT is even more important than in metastatic testicular nonseminomas, reflecting the high probability of impaired chemosensitivity, the presence of vital and chemoresistant germ cell tumor elements as well as the high likelihood of teratomatous residual masses and the presence of malignant somatic transformation. With regard to presurgical imaging procedures, FDG-PET/CT does not play an important role since it is not sensitive enough to differentiate between teratoma and fibrosis/necrosis. Surgery is usually performed about 4 weeks after completion of chemotherapy and in the presence of negative or plateauing tumor markers. Every visible residual lesion which can be detected on CT scans or MRI scans needs to be resected completely. Larger residual masses often require the resection and sometimes replacement of adjacent structures such as the superior vena cava, the pericardium, the pleura, lung, bronchus, etc. Complete resection is mandatory for overall survival; incomplete resection is always associated with a high relapse rate and inferior overall survival. Therefore, centralization of the surgical treatment is mandatory, and it is one of the most important steps of first-line treatment.

For patients with seminomatous extragonadal germ cell tumors, residual tumor resection is rarely necessary due to the high chemosensitivity and the very good prognosis of the tumor. In patients with small residual lesions, repetitive imaging studies with therapeutic intervention at the time of proven progression might be sufficient. In patients with large residual masses, it still difficult to distinguish viable cancer from necrosis and fibrosis. FDG-PET/CT examinations might be performed about 6–8 weeks after completion of systemic chemotherapy, which has a high negative predictive value but a poor positive predictive value [26]. Whereas patients with negative scans can be monitored, patients with positive scans either need to undergo a biopsy of the mass or they have to receive a follow-up PET/CT about 3 months after the initial imaging study.

Radiation therapy to small-volume residual masses might be an option in pure seminomatous extragonadal germ cell tumors, although the data are scarce in the literature [27]. In addition, the long-term toxicities with regard to development of secondary neoplasms and the risk of cardiovascular disease needs to be taken into consideration [28]. Therefore, surgical resection of residual masses with viable cancer represents the treatment of choice.

Salvage treatment options

As outlined above, the relapse rate for nonseminomatous EGCT is much higher than for testicular nonseminomas. Patients with relapsing mediastinal nonseminomas have a poor prognosis with a long-term survival of only 11% as compared to 30% for extragonadal nonseminomas located in the retroperitoneum [29]. In this retrospective study of 142 patients with relapsing extragonadal GCT, 48 (34%) patients received high-dose chemotherapy with autologous bone marrow transplant and 10 of these patients remained disease free at a median follow-up 45 months. Second-line high-dose chemotherapy followed by peripheral blood stem cell transplantation has been evaluated in various clinical trials and resulted in disappointing response and survival rates. The European Group for Blood and Bone Marrow Transplantation evaluated the therapeutic efficacy of mainly high-dose carboplatin/etoposide, which resulted in a 3-year overall survival rate of only 14% for mediastinal EGCT [30]. Similar data have been presented by the Indiana group, who reported on a 2-year progression-free survival rate of only 23% as compared to 63% for relapsing testicular GCT [31].

Targeted and immuno-oncological therapy with various compounds has not been successful in mediastinal EGCT [32,33,34]. The studies enrolled chemorefractory GCT patients and only achieved a response rate < 10%. In addition, a negative effect of checkpoint inhibitors was documented, with development of hyper-progression in one third and three quarters of patients treated with durvalumab and tremelimumab and pembrolizumab, respectively.

The identification of druggable mutations in GCT has been disappointing due to the low tumor mutational burden and the low frequency of driving mutations. However, an NGS-based approach has been used in few cases of chemorefractory GCT and resulted in the detection of druggable targets, which prolonged survival [35]. The chance of targeted therapy in mediastinal GCT, however, seems to be quite low based on a recent genomic profiling study in 44 patients, which identified a high frequency of TP53 mutations responsible for the chemoresistance of the tumors. Furthermore, a higher frequency of PIK3CA pathway gene alterations was detected, whereas single genomic alterations were found in 2.3% to 6.3% of the patients [36]. Similar data were reported in a different study on 180 advanced GCT patients performed in order to detect the genomic background of cisplatin resistance [37]. TP53 mutations and deletions were exclusively identified in chemorefractory patients and in 72% of mediastinal EGCT. However, 55% of patients with cisplatin resistance harbored actionable mutations such as RAC1. Based on these data, NGS profiling of relapsing mediastinal EGCT might be helpful to identify the few patients who might benefit from a targeted approach.

Centralization of treatment

Based on the data described above, systemic second-line salvage therapy has limited oncological efficacy independent of the cytotoxic regime used. The first therapeutic approach using a combination of risk-adapted systemic chemotherapy and aggressive surgical resection of residual masses is the most important step of treatment. Therefore, all patients with poor-risk features should be managed in highly experienced tertiary care centers, which will result in an improved survival outcome. Case volume was shown to be associated with significant differences in survival outcomes when a total of 33,417 patients treated in 1239 institutions were analyzed [38]. Despite the fact that high-volume centers treated patients with worse disease characteristics, hospital volume was associated with a significantly better outcome. High-volume centers were defined by a case volume of more than 26 patients, whereas intermediate-high-, intermediate-, intermediate-low-, and low-volume hospitals were defined by 14–26, 6–14, 2–6, and < 2 cases/year respectively. Compared to high-volume centers, the hazard ratio for overall mortality was 1.28, 1.45, 1.48, and 1.83 (p < 0.05) for intermediate-high-, intermediate-, intermediate-low-, and low-volume hospitals, respectively.