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Primary mediastinal germ cell tumors
Seminars in Oncology 46 (2019) 107–111
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Seminars in Oncology journal homepage: www.elsevier.com/locate/seminoncol
Primary mediastinal germ cell tumors Giovanni Rosti a,∗, Simona Secondino a, Andrea Necchi b, Giuseppe Fornarini c, Paolo Pedrazzoli a,d a
Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Italy Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Department of Medical Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy d Cellular Therapy and Immunobiology Working Party, EBMT b c
a r t i c l e
i n f o
Article history: Received 22 January 2018 Revised 5 April 2019 Accepted 11 April 2019
Keywords: Primary mediastinal germ cell tumors (PMGCT) Extragonadal Germ Cell Tumor Rare diseases
a b s t r a c t Backgroud: Germ cell tumors (GCTs) are a group of neoplasms usually arising in the gonads, and very rarely in sites outside the gonads, mainly in the retroperitoneum, the anterior mediastinum, and pineal gland or the coccyx (mainly in childhood). The prognosis of nonseminoma primary mediastinal GCTs (PMGCTs), is considered to be poorer compared to its retroperitoneal or gonadal counterparts and, according to the International Germ Cell Cancer Collaborative Group, it is considered by definition as a “poor risk” disease. Material and Methods: Our review highlights the clinical features, prognostic factors, and therapeutic strategies in PMGCTs, as described in medical literature. So far available data were obtained through a Medline search of English-language papers. Results: Due to the rarity of the disease, there are no prospective studies comparing different treatment strategies. For this reason, oncology societies recommend treating PMGCTs like other GCTs, according to general risk categories. Conclusion: Because of the rarity of the disease, poor categorization, and the lack of novel therapeutic strategies, an International database is required to obtain more information on these tumors. Additional efforts should be done, with the aims to find effective novel therapeutic agents. © 2019 Elsevier Inc. All rights reserved.
Introduction Germ cell tumors (GCTs) are a group of neoplasms usually arising in the gonads (testes or more rarely in the ovaries). They are the most frequent tumors in the adolescent/young adult age group, with less than 2% being diagnosed above 55–60 years of age [1]. They represent a unique example of solid tumors highly sensitive to chemotherapy (CT) and, in the case of seminoma, to radiotherapy (RT). Consequently, they show an elevated cure rate even in advanced disease and respond well to subsequent therapy for recurrent disease. Nearly 80% of metastatic patients are cured with CT and/or RT and surgery [1] with few late relapses. Even patients with extensive disease, show similarly good survival rates beyond 2 years [2]. GCTs arise very rarely in sites outside the gonads, mainly in the retroperitoneum (although it is unclear how many of these are true primaries) [3] and in other areas such as the anterior mediastinum and pineal gland or the coccyx (mainly in childhood). ∗ Corresponding author. Division of Medical Oncology Fondazione IRCCS Policlinico San Matteo, Piazzale Ospedale 3, 27100 Pavia, Italy. E-mail address: [email protected] (G. Rosti).
https://doi.org/10.1053/j.seminoncol.2019.04.001 0093-7754/© 2019 Elsevier Inc. All rights reserved.
Primary mediastinal GCT (PMGCT) account for 15% of adult anterior mediastinal cancers [4], constituting 1%–3% of all germ cell malignancies. Mean age at diagnosis is 25–35 years and, in contrast to testicular cancer, no increase in incidence has been recently reported [5]. Germinal epithelium forms in the yolk sac during embryologic development and primordial germ cells migrate from the proximal epiblast along the midline to the dorsal mesentery of the hindgut, thence to the urogenital ridge, and finally form the testes in the scrotum. According to the most accepted hypothesis, PMGCTs arise because germ cells stop their descent, despite the presence of otherwise normal testes, and remain in the anterior mediastinum, becoming malignant [6]. Similarities exist between gonadal and mediastinal GCTs: they share a common cytogenetic abnormality, that is, isochromosome 12p, the same histologic and biochemical features (nonseminoma or seminoma with mixed histologies and the same tumor marker expression – alfa-fetoprotein, beta hCG), and LDH as a “mass” marker. Two aspects are peculiar to PMGCT, that is, associations with Klinefelter’s syndrome and hematologic malignancies [7,8].
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Table 1 Clinical features of gonadal GCT and PMGCT. Age at diagnosis (yr)
Hystology
Cytogenetic abnormalities
Genetic syndrome
Prognosis in advanced disease (IGCCCG)
Overall Survival according to IGCCCG (%)
Gonadal GCT
15–40
60% Nonseminoma
isochromosome 12p
–
PMGCT
25–35
70%–80% Nonseminoma
isochromosome 12p
Klinifelter; hematologic malignancies
Good Intermediate Poor Poor
86%–92% 72%–80% 48% 40%–45%
References
PMGCT = primary mediastinal germ cell tumor; IGCCCG = International Germ Cell Cancer Consensus Group.
Fig. 1. Radiological imaging of a patient with PMGCT. (A) CT scan axial plane. (B) CT scan coronal plane.
The prognosis of nonseminoma PMGCT is considered to be poorer compared to its retroperitoneal or gonadal counterparts and, according to the International Germ Cell Cancer Collaborative Group [9], it is considered by definition as a “poor risk” disease. Clinical features of GCT are described on Table 1. The aim of this paper is to review the clinical aspects of this particular disease, the treatment results achieved so far, and future approaches. Disease presentation Mediastinal primary tumors are nonseminomatous in the majority of cases, with pure seminoma accounting for no more than 20%–30% of patients; this is in contrast with the gonadal counterpart where seminomas slightly outnumber nonseminomas. The reason for this difference is not clearly understood. In general, the first symptoms are chest pain, dyspnea, and cough due to the enlargement of the mediastinum, sometimes with the appearance of supraclavicular nodes [10]. Clinically, nonseminoma PMGCTs are more aggressive with a 2-fold increase of such symptoms compared to seminoma. Superior vena cava syndrome presents infrequently, accounting for no more than 10% of the cases; PMGCTs are very rarely asymptomatic at diagnosis. Possible alternative diagnoses are mediastinal lymphoma, thymoma or thymic carcinoma, and also sarcomas which may occasionally arise in the posterior mediastinum; a mass in the anterior mediastinum in a young male is highly suggestive of a PMGCT (Fig. 1). Elevated LDH does not distinguish between the different diseases, whereas the determination of “germ cell markers” such as alfa-fetoprotein and beta-hCG strongly suggests PMGCT, even in the absence of histologic evidence.
Therefore alfa-fetoprotein and beta-hCG should always be performed when an anterior mediastinal mass is diagnosed and may guide treatment, especially important in patients requiring urgent therapy for a severe mediastinal syndrome. Elevated alfa-fetoprotein and/or beta-hCG at diagnosis is seen in 70%–80% of the patients, although alfa-fetoprotein is not expressed in cases of pure seminoma. Gynecomastia may be present, usually in cases with elevated beta-hCG production. Usually the testes are normal, the association of primary mediastinal and synchronous testicular tumor being mainly based on anecdotal evidence. Prognostic factors All data regarding prognostic factors in extragonadal GCTs mainly come from single-center retrospective series and the results of an international appraisal [11,12]. In a collaborative effort involving 11 centers in USA and Europe over a 21-year period, data from 635 extragonadal patients, 341 with primary mediastinal disease, were retrospectively collected [11,12]. Fifty-one were mediastinal seminoma with an excellent 5year survival of nearly 90%; no difference in progression-free and overall survival (PFS, OS) was noted between these mediastinal patients and 52 patients with retroperitoneal disease. In this retrospective analysis 286 nonseminoma PMGCTs were evaluated, with an overall long-term survival of only 45%. There was a striking difference among mediastinal nonseminoma and 226 retroperitoneal disease patients, with the latter experiencing a long-term survival of nearly 65%. This study showed considerable variability among nonseminoma PMGCTs patients: those of younger age (<30 years) who had localized mediastinal disease without elevation of beta-
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hCG, had a more favorable outcome compared to older patients with beta-hCG elevation or visceral or lung disease. Indeed, this study represents the first attempt to identify risk factors among this heterogeneous group of diseases. In the final analysis over all 635 extragonadal disease patients included in this study, a mediastinal origin of the disease was the worst prognostic factor for response to standard therapy [12]. In particular, in the absence of visceral disease, 2-year OS was 60%, compared to only 34% for those patients with extramediastinal spread; the “best” prognosis group being patients <29 years old, with nonvisceral/lung disease, and normal beta-hCG, who had a 2year survival of 84%. In a more recent retrospective study [13], 61 patients with PMGCTs have been analyzed. All patients received CT (27 BEP and 34 TBEP/CBOP) and 46% underwent surgery on residual disease. In a multivariate analysis on these 61 patients, only age (>24 years) and tumor dimension (>19 cm) were significant (hazard ratio 2.0 and 3.6, respectively) negative prognostic factors. An analysis conducted at MD Anderson Cancer Center showed that beta-hCG levels > 10 0 0 IU/L, histology other than yolk sac tumor and extramediastinal disease, were found to be significantly associated with poorer PFS [14]. In an Italian database including 86 patients [15] from a single referring center, the presence of lung metastases at diagnosis was a significant predictor for worst OS in multivariate analysis. Patients who could undergo radical surgery did better, but only 13/86 patients underwent surgery. At 2 years 66% of patients with no adverse prognostic factor were alive compared to only 40% in those with at least one factor, the authors suggesting the possible existence of two different subpopulations of patients classified as having good or poor prognosis, based on histology, presence of lung metastases and feasibility of surgery. Several CT regimes were employed in this series, so it was not possible to define the most effective CT schedule. Therapeutic strategies Due to the rarity of the disease, there are no prospective studies comparing different treatment strategies or CT schedules, as is the case for primary gonadal tumors. For this reason, oncology societies recommend treating PMGCTs like other GCTs, according to general risk categories. First line treatment No conclusive data regarding a potential benefit of primary surgery are available and this approach is usually not feasible at presentation, mainly because the disease is rarely diagnosed as a small mediastinal mass with non-extramediastinal invasion. An exception might be mature teratoma (no other malignant components, nor marker elevation) for which surgery may be considered as a first therapeutic attempt. Recommended first line CT consists of the combination of bleomycin, etoposide, and cisplatin. (BEP) for three or four courses, depending on whether the PMGCT falls into the good/ intermediate (seminoma) or poor-risk (nonseminoma) category according to the International Germ Cell Cancer Collaborative Group [9]. Because of concerns about possible lung damage induced by bleomycin in patients with bulky thoracic involvement, some groups prefer to avoid such a drug, substituting ifosfamide. In the Indiana University experience there were 11/221 deaths after surgery post-CT and all occurred in patients who received BEP, while none was observed after the ifosfamide-containing regimen [16]. More recently, a phase 2 study of first-line paclitaxel, ifosfamide, and cisplatin (TIP) has been conducted in patients with intermediate and poor risk GCT, including 16 patients with PMGCT [17] (Table 2).
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Table 2 First line therapies and outcomes for PMGCT. Trial
N
First line therapy Outcomes
IGCCC, J Clin Oncol 135 (41 Seminoma) Various standard 1997 [9] regimens Feldman, J Clin 16 TIP Oncol 2016 [17] Kollmannsberger, Ann Oncol 20 0 0 [39] Bokemeyer, BJC 2003 [19]
72
BEP
28
HD-VIP
TIP = taxol, ifosfamide, cisplatin; BEP = bleomycin, VIP = high-dose etoposide, ifosfamide, cisplatin.
40% 5-year overall survival 62% 3-year estimated survival 60% 3-year overall survival 68% 2-year estimated survival 64% 5-year estimated survival
etoposide,
cisplatin;
HD-
Among studies that have looked at the role of high dose CT (HDCT) requiring stem cell support for “poor prognosis” patients, PMGCTs usually represent a small subpopulation that is rarely discussed or evaluated separately [18]. In 2003 Bokemeyer et al [19] reported a subgroup analysis of 28 patients with nonseminoma PMGCTs, who were treated up-front with HDCT. These patients showed 2-year PFS and OS rates of 64% and 68%, respectively, which compared favourably with historical controls of the International Extragonadal Germ Cell Tumor Study Group. According to this retrospective comparison, the authors suggested that HDCT may produce a 15%–20% absolute improvement in survival. More recently Fizazi et al [20] reported an advantage, over conventional BEP (Bleomycin, Etoposide, Cisplatin), of a dose-dense schedule with G-CSF support, in poor risk GCT, including PMGCT, showing an inadequate marker decline following the first course of CT. While data available on intensified first line CT with hematopoietic stem cell or G-CSG support are not sufficient to propose this therapeutic modality as a routine treatment, this approach could be considered in selected well-informed patients with nonseminoma PMGCT with negative prognostic features. The role of surgery on mediastinal residual disease following CT, is as vital as in gonadal or retroperitoneal disease. Every effort should be made in order to achieve complete resection in residual mass(es) [21], because of the possibility of persistent viable cells, teratoma, and/or teratoma with malignant transformation. Surgery for residual disease is therefore recommended both as a diagnostic and as a therapeutic procedure. It should be kept in mind that residual teratoma tissue may generate the so called “growing teratoma syndrome” [22] with possible secondary cardiopulmonary deterioration. Prompt recognition of this syndrome and surgical intervention, can result in cure [23]. Additionally, there are a very few cases who develop somatic malignant tumors within residual masses. These cases are usually referred to as “teratoma with malignant transformation” and successful treatment is highly dependent upon the possibility radical resection of tumor masses [24]. Surgery may also have an impact on diagnosis and prognosis (Table 3). In a large single-center experience including 158 patients with PMGCT undergoing surgery after CT, complete necrosis was found in 25% and teratoma in 33%, while the remainder showed the presence of malignancy in the form of persistent germ cell cancer as well as nongerm cell elements, often including teratoma—either mature or immature [23]. Five-year PFS in patients with viable cells in the specimen was 47%, compared to 84% in patients with necrosis or teratoma, without viable cells [15]. Unfortunately, the majority of primary nonseminoma PMGCTs are not cured despite standard CT and optimal surgery of residual disease, with long-term survival ranging from 40% to 50% [24].
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Table 3 Surgery after first-line chemotherapy for PMGCT and outcomes. Trial
N
Timing of surgery
Necchi, Clin Genitour Cancer 2015 [15] Walsh, Ann Thor Surg 20 0 0 [21]
68 20
Surgery was performed after first line therapy Eleven patients at first-line therapy Nine patients at salvage therapy
Outcomes
Kesler, Ann Thor Surg 2008 [24] Sarkaria, J Thorac Oncol 2011 [40]
148 57
Surgery was performed after first line therapy Fifty-four patients received preoperative standard chemotherapy
58% 58% 73% 42% 60% 56%
4-year 2-year 2-year 2-year 3-year 2-year
overall survival survival; survival for first line group; survival for salvage group disease-free survival overall survival
Table 4 Subsequent treatment after first-line therapies, and outcomes for PMGCT. Trial
N
Subsequent-line therapy
Hartman, J Clin Oncol 2001 [27]
79
Adra, J Clin Oncol 2017 [30] De Giorgi, Ann Oncol 2005 [31]
20 22
Various regimens (HDCT; cisplatin, ifosfamide; cisplatin, taxol) HDCT HDCT
Outcomes 11% long-term overall survival (standard regimen); 12% long-term overall survival (HDCT) 23% progression-free survival at 24 months 14% disease-free survival at 36 months
HDCT = high-dose chemotherapy.
Mediastinal seminoma, as mentioned earlier, has a much better prognosis, with survival rates similar to the gonadal counterpart. The recommended therapeutic approach is therefore similar to the nonseminoma tumors, but RT can be added in cases of active residual disease.
Beyond first line treatment Usually relapse occurs rather early after completing treatment. The results of second line therapy in testicular cancer are better than those achieved in other solid tumors, as a significant proportion of GCTs can still be cured with either conventional or HDCT [25], or local treatments. However the results of second line CT for PMGCT are at present dismal, with only approximately 5%–10% of patients being cured in the salvage setting irrespective of the regime used [25,26]. Due to the rarity of this tumor and the paucity of such patients in retrospective series of extragonadal germ cell cancer, no clear data emerge from the literature regarding a possible preferred therapeutic option. In a wide international retrospective series of 142 patients with extragonadal disease [27], 79 cases of PMGCT have been evaluated. Only 11% of such patients were longterm disease free compared to 30% of those with retroperitoneal disease. No preferred treatment was suggested, with only a slightly better (not significant) outcome after HDCT. Primary mediastinal disease together with inadequate response to cisplatin, were the strongest negative prognostic factors [27]. HDCT data on PMGCTS are mainly based on the carboplatinetoposide doublet proved to be an effective treatment modality in second and subsequent lines of treatment in GCTs [17,28–30], with a survival curve plateauing at 40% in the large Indiana series [28]. However the data are largely insufficient to draw any firm conclusions [18]. The European Group for Blood and Marrow Transplantation published, in 2005, the registry based experience in 59 patients treated with HDCT as second line therapy in extragonadal disease [31]. Twenty-two patients had primary mediastinal disease and carboplatin/etoposide combination (with or without alkylators) was the most employed regimen; nearly half of these patients received single-dose HDCT [31]. Toxic death rate was 7%. Twentythree percent of these patients obtained complete remission which was long lasting in 14% of cases. With the information available today on patient selection and safety of multiple courses of HDCT, including in the setting of recurrent disease, this approach can be proposed for selected patients still harboring chemosensitive disease (Table 4).
Novel (targeted) therapies Poor prognosis and refractory CGTs are tumors of young patients, and reduce life expectancy more than any other adult solid tumor type. This underscores the need to identify new active agents against CGT [32]. Progress has not been swift. In a review of the characteristics and outcome in 90 patients undergoing treatment with new drugs within sequential phase 2 trials at Memorial Sloan Kettering Cancer Center, median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8–1.3) and 4.7 months (95% CI, 3.5– 6.4), respectively with the 12- and 16- week PFS rates standing at 9% (95% Cl, 3%–15%) and 6% (95% Cl, 1%–11%), respectively. Eightysix of the 90 patients have died [33]. Clearly, we need to redouble our efforts to find effective novel therapeutic agents. Angiogenesis inhibitors have been extensively studied in GCT patients, including PMGCT. However, the objective response rate achieved with any of the evaluated compounds was poor. Pazopanib represents the last, and perhaps most noteworthy, chapter in the story of antiangiogenesis in GCT. In an openlabel, single-arm, phase 2 study pazopanib was administered in 43 patients with refractory GCTs [34]. Although only two partial responses were observed (4.7%), most patients experienced serum tumor marker decline, assessed after the first 4 weeks of treatment, but it was generally short-lived. Therefore, antiangiogenic agents have failed to provide substantial improvements in this field when used as single agents. However, they have yet to be combined with other compounds. Regarding immunotherapy, CD30expressing mediastinal GCT may be suitable for inclusion in clinical trials with anti-CD30 compounds. In a small, proof-of-concept study of brentuximab vedotin, an anti-CD30 antibody drug conjugate, two patients out of nine CT-resistant GCT patients, achieved a complete or partial response to treatment. Again, responses were short lived in almost all cases, despite initial serum tumor marker decline. Programmed cell-death-1/ligand-1 (PD-1/L1) immunohistochemical expression has been documented in the majority of cases of both seminoma and nonseminoma from large retrospective studies [35,36]. Most interestingly, pure seminoma displayed an inflammatory tumor microenvironment in a study, making these patients the most likely to respond to immune checkpoint inhibitor therapy [37]. Disappointingly, though, early results from a United States single-arm, phase 2 study with pembrolizumab, an anti-PD-L1 monoclonal antibody, did not show any clinical response among the first 12 patients enrolled [38].
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Additional phase 2 trials are currently evaluating the role of single agent immune checkpoint inhibitors as well as their combination with anti-CTLA4 antibodies in GCT, and results are awaited (NCT03081923, NCT03158064). Conclusions Seminoma and nonseminoma PMGCTs account for 15% of adult anterior mediastinal cancers and for 1% to 3% of all germ cell malignancies. Diagnosis is aimed mainly at differentiating the condition from lymphoid malignancies and cancers of the thymus. In cases with elevated alfa-fetoprotein and beta-hCG a diagnosis of a PMGCT is likely, even in the absence of histologic confirmation. Outcome of seminoma is similar to its gonadal counterpart while nonseminoma has a dismal prognosis requiring a multimodality approach, including cisplatin/ etoposide-containing CT followed by surgery of residual disease. Radical surgery, in addition to improving cure rates, provides histopathologic information (presence of viable tumor cells and/or teratoma with/without malignant transformation) which has important prognostic and therapeutic impact. The results of second line CT for PMGCT are at present very poor, with only approximately 5%–10% of patients being cured in the salvage setting, irrespective of the regime used. The role of intensified therapies with/without stem cell rescue in PMGCTs, is a matter of debate as insufficient data are available to permit any conclusions. Because of the rarity of the disease, poor categorization, and the lack of novel therapeutic strategies, an International database is required to obtain more information on these tumors, and possibly launch a wide multinational study. Patients with PMGCT should be referred to Centers with experience in this rare disease. Disclosure This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. References [1] Rajpert-De Meyt E, McGlynn KA, Okamoto K, et al. Testicular germ cell tumours. Lancet 2016;387:1762–74. [2] Ko JJ, Bernard B, Tran B, et al. Conditioning survival of patients with metastatic testicular germ cell tumors treated with first-line curative therapy. J Clin Oncol 2016;34:714–20. [3] Scholz M, Zehender M, Thalmann GN. Etragonadal retroperitoneal germ cell tumor: evidence of origin in the tetis. Ann Oncol 2002;13:121–4. [4] Den Bakkel MA, Marx A, Mukai K, Stroebel P. Mesenchymal tumors of the mediastinum Part 1. Virchow Arch 2015;467(5):487–501. [5] Rusner C, Trabert B, Katalinic A, et al. Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998-2008. Cancer Epidem 2013;37:370–3. [6] Chaganti RS, Rodriguez E, Mathew S. Origin of adult male mediastinal germ– cell tumours. Lancet 1994;343:1130–2. [7] Nichols CR, Herema NA, Palmer C, et al. Klinefelter’s syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 1987;5:1290–4. [8] John S, Adnan MAM, Khalil MO, et al. Mediastinal germ cell tumor and acute megacaryoblatic leukemia- a systematic review of cases reported in the literature. Blood 2014;124(abs):3694. [9] International Germ Cell Consensus Classification A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997;15:594–603. [10] Liu Y, Wang Z, Peng ZM, Yu Y. Management of the primary malignant mediastinal germ cell tumors: experience with 54 patients. Diagn Pathol 2014;9:33–7. [11] Bokemeyer C, Nichols CR, Broz J-P, et al. Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an International analysis. J Clin Oncol 2002;20:1864–73. [12] Hartmann JT, Nichols CR, Droz J-P, et al. Prognostic variables for response and outcome in patients with extragonadal tumors. Ann Oncol 2002;13:11017–28. [13] Fedaynin M, Tryakin A, Mosyakova Y, et al. Prognostic factors and efficacy of different chemotherapeutic regimens in patients with mediastinal nonseminomatous germ cell tumors. J Cancer Res Clin Oncol 2014;140:311–18.
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Seminars in Oncology journal homepage: www.elsevier.com/locate/seminoncol
Primary mediastinal germ cell tumors Giovanni Rosti a,∗, Simona Secondino a, Andrea Necchi b, Giuseppe Fornarini c, Paolo Pedrazzoli a,d a
Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Italy Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Department of Medical Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy d Cellular Therapy and Immunobiology Working Party, EBMT b c
a r t i c l e
i n f o
Article history: Received 22 January 2018 Revised 5 April 2019 Accepted 11 April 2019
Keywords: Primary mediastinal germ cell tumors (PMGCT) Extragonadal Germ Cell Tumor Rare diseases
a b s t r a c t Backgroud: Germ cell tumors (GCTs) are a group of neoplasms usually arising in the gonads, and very rarely in sites outside the gonads, mainly in the retroperitoneum, the anterior mediastinum, and pineal gland or the coccyx (mainly in childhood). The prognosis of nonseminoma primary mediastinal GCTs (PMGCTs), is considered to be poorer compared to its retroperitoneal or gonadal counterparts and, according to the International Germ Cell Cancer Collaborative Group, it is considered by definition as a “poor risk” disease. Material and Methods: Our review highlights the clinical features, prognostic factors, and therapeutic strategies in PMGCTs, as described in medical literature. So far available data were obtained through a Medline search of English-language papers. Results: Due to the rarity of the disease, there are no prospective studies comparing different treatment strategies. For this reason, oncology societies recommend treating PMGCTs like other GCTs, according to general risk categories. Conclusion: Because of the rarity of the disease, poor categorization, and the lack of novel therapeutic strategies, an International database is required to obtain more information on these tumors. Additional efforts should be done, with the aims to find effective novel therapeutic agents. © 2019 Elsevier Inc. All rights reserved.
Introduction Germ cell tumors (GCTs) are a group of neoplasms usually arising in the gonads (testes or more rarely in the ovaries). They are the most frequent tumors in the adolescent/young adult age group, with less than 2% being diagnosed above 55–60 years of age [1]. They represent a unique example of solid tumors highly sensitive to chemotherapy (CT) and, in the case of seminoma, to radiotherapy (RT). Consequently, they show an elevated cure rate even in advanced disease and respond well to subsequent therapy for recurrent disease. Nearly 80% of metastatic patients are cured with CT and/or RT and surgery [1] with few late relapses. Even patients with extensive disease, show similarly good survival rates beyond 2 years [2]. GCTs arise very rarely in sites outside the gonads, mainly in the retroperitoneum (although it is unclear how many of these are true primaries) [3] and in other areas such as the anterior mediastinum and pineal gland or the coccyx (mainly in childhood). ∗ Corresponding author. Division of Medical Oncology Fondazione IRCCS Policlinico San Matteo, Piazzale Ospedale 3, 27100 Pavia, Italy. E-mail address: [email protected] (G. Rosti).
https://doi.org/10.1053/j.seminoncol.2019.04.001 0093-7754/© 2019 Elsevier Inc. All rights reserved.
Primary mediastinal GCT (PMGCT) account for 15% of adult anterior mediastinal cancers [4], constituting 1%–3% of all germ cell malignancies. Mean age at diagnosis is 25–35 years and, in contrast to testicular cancer, no increase in incidence has been recently reported [5]. Germinal epithelium forms in the yolk sac during embryologic development and primordial germ cells migrate from the proximal epiblast along the midline to the dorsal mesentery of the hindgut, thence to the urogenital ridge, and finally form the testes in the scrotum. According to the most accepted hypothesis, PMGCTs arise because germ cells stop their descent, despite the presence of otherwise normal testes, and remain in the anterior mediastinum, becoming malignant [6]. Similarities exist between gonadal and mediastinal GCTs: they share a common cytogenetic abnormality, that is, isochromosome 12p, the same histologic and biochemical features (nonseminoma or seminoma with mixed histologies and the same tumor marker expression – alfa-fetoprotein, beta hCG), and LDH as a “mass” marker. Two aspects are peculiar to PMGCT, that is, associations with Klinefelter’s syndrome and hematologic malignancies [7,8].
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Table 1 Clinical features of gonadal GCT and PMGCT. Age at diagnosis (yr)
Hystology
Cytogenetic abnormalities
Genetic syndrome
Prognosis in advanced disease (IGCCCG)
Overall Survival according to IGCCCG (%)
Gonadal GCT
15–40
60% Nonseminoma
isochromosome 12p
–
PMGCT
25–35
70%–80% Nonseminoma
isochromosome 12p
Klinifelter; hematologic malignancies
Good Intermediate Poor Poor
86%–92% 72%–80% 48% 40%–45%
References
PMGCT = primary mediastinal germ cell tumor; IGCCCG = International Germ Cell Cancer Consensus Group.
Fig. 1. Radiological imaging of a patient with PMGCT. (A) CT scan axial plane. (B) CT scan coronal plane.
The prognosis of nonseminoma PMGCT is considered to be poorer compared to its retroperitoneal or gonadal counterparts and, according to the International Germ Cell Cancer Collaborative Group [9], it is considered by definition as a “poor risk” disease. Clinical features of GCT are described on Table 1. The aim of this paper is to review the clinical aspects of this particular disease, the treatment results achieved so far, and future approaches. Disease presentation Mediastinal primary tumors are nonseminomatous in the majority of cases, with pure seminoma accounting for no more than 20%–30% of patients; this is in contrast with the gonadal counterpart where seminomas slightly outnumber nonseminomas. The reason for this difference is not clearly understood. In general, the first symptoms are chest pain, dyspnea, and cough due to the enlargement of the mediastinum, sometimes with the appearance of supraclavicular nodes [10]. Clinically, nonseminoma PMGCTs are more aggressive with a 2-fold increase of such symptoms compared to seminoma. Superior vena cava syndrome presents infrequently, accounting for no more than 10% of the cases; PMGCTs are very rarely asymptomatic at diagnosis. Possible alternative diagnoses are mediastinal lymphoma, thymoma or thymic carcinoma, and also sarcomas which may occasionally arise in the posterior mediastinum; a mass in the anterior mediastinum in a young male is highly suggestive of a PMGCT (Fig. 1). Elevated LDH does not distinguish between the different diseases, whereas the determination of “germ cell markers” such as alfa-fetoprotein and beta-hCG strongly suggests PMGCT, even in the absence of histologic evidence.
Therefore alfa-fetoprotein and beta-hCG should always be performed when an anterior mediastinal mass is diagnosed and may guide treatment, especially important in patients requiring urgent therapy for a severe mediastinal syndrome. Elevated alfa-fetoprotein and/or beta-hCG at diagnosis is seen in 70%–80% of the patients, although alfa-fetoprotein is not expressed in cases of pure seminoma. Gynecomastia may be present, usually in cases with elevated beta-hCG production. Usually the testes are normal, the association of primary mediastinal and synchronous testicular tumor being mainly based on anecdotal evidence. Prognostic factors All data regarding prognostic factors in extragonadal GCTs mainly come from single-center retrospective series and the results of an international appraisal [11,12]. In a collaborative effort involving 11 centers in USA and Europe over a 21-year period, data from 635 extragonadal patients, 341 with primary mediastinal disease, were retrospectively collected [11,12]. Fifty-one were mediastinal seminoma with an excellent 5year survival of nearly 90%; no difference in progression-free and overall survival (PFS, OS) was noted between these mediastinal patients and 52 patients with retroperitoneal disease. In this retrospective analysis 286 nonseminoma PMGCTs were evaluated, with an overall long-term survival of only 45%. There was a striking difference among mediastinal nonseminoma and 226 retroperitoneal disease patients, with the latter experiencing a long-term survival of nearly 65%. This study showed considerable variability among nonseminoma PMGCTs patients: those of younger age (<30 years) who had localized mediastinal disease without elevation of beta-
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hCG, had a more favorable outcome compared to older patients with beta-hCG elevation or visceral or lung disease. Indeed, this study represents the first attempt to identify risk factors among this heterogeneous group of diseases. In the final analysis over all 635 extragonadal disease patients included in this study, a mediastinal origin of the disease was the worst prognostic factor for response to standard therapy [12]. In particular, in the absence of visceral disease, 2-year OS was 60%, compared to only 34% for those patients with extramediastinal spread; the “best” prognosis group being patients <29 years old, with nonvisceral/lung disease, and normal beta-hCG, who had a 2year survival of 84%. In a more recent retrospective study [13], 61 patients with PMGCTs have been analyzed. All patients received CT (27 BEP and 34 TBEP/CBOP) and 46% underwent surgery on residual disease. In a multivariate analysis on these 61 patients, only age (>24 years) and tumor dimension (>19 cm) were significant (hazard ratio 2.0 and 3.6, respectively) negative prognostic factors. An analysis conducted at MD Anderson Cancer Center showed that beta-hCG levels > 10 0 0 IU/L, histology other than yolk sac tumor and extramediastinal disease, were found to be significantly associated with poorer PFS [14]. In an Italian database including 86 patients [15] from a single referring center, the presence of lung metastases at diagnosis was a significant predictor for worst OS in multivariate analysis. Patients who could undergo radical surgery did better, but only 13/86 patients underwent surgery. At 2 years 66% of patients with no adverse prognostic factor were alive compared to only 40% in those with at least one factor, the authors suggesting the possible existence of two different subpopulations of patients classified as having good or poor prognosis, based on histology, presence of lung metastases and feasibility of surgery. Several CT regimes were employed in this series, so it was not possible to define the most effective CT schedule. Therapeutic strategies Due to the rarity of the disease, there are no prospective studies comparing different treatment strategies or CT schedules, as is the case for primary gonadal tumors. For this reason, oncology societies recommend treating PMGCTs like other GCTs, according to general risk categories. First line treatment No conclusive data regarding a potential benefit of primary surgery are available and this approach is usually not feasible at presentation, mainly because the disease is rarely diagnosed as a small mediastinal mass with non-extramediastinal invasion. An exception might be mature teratoma (no other malignant components, nor marker elevation) for which surgery may be considered as a first therapeutic attempt. Recommended first line CT consists of the combination of bleomycin, etoposide, and cisplatin. (BEP) for three or four courses, depending on whether the PMGCT falls into the good/ intermediate (seminoma) or poor-risk (nonseminoma) category according to the International Germ Cell Cancer Collaborative Group [9]. Because of concerns about possible lung damage induced by bleomycin in patients with bulky thoracic involvement, some groups prefer to avoid such a drug, substituting ifosfamide. In the Indiana University experience there were 11/221 deaths after surgery post-CT and all occurred in patients who received BEP, while none was observed after the ifosfamide-containing regimen [16]. More recently, a phase 2 study of first-line paclitaxel, ifosfamide, and cisplatin (TIP) has been conducted in patients with intermediate and poor risk GCT, including 16 patients with PMGCT [17] (Table 2).
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Table 2 First line therapies and outcomes for PMGCT. Trial
N
First line therapy Outcomes
IGCCC, J Clin Oncol 135 (41 Seminoma) Various standard 1997 [9] regimens Feldman, J Clin 16 TIP Oncol 2016 [17] Kollmannsberger, Ann Oncol 20 0 0 [39] Bokemeyer, BJC 2003 [19]
72
BEP
28
HD-VIP
TIP = taxol, ifosfamide, cisplatin; BEP = bleomycin, VIP = high-dose etoposide, ifosfamide, cisplatin.
40% 5-year overall survival 62% 3-year estimated survival 60% 3-year overall survival 68% 2-year estimated survival 64% 5-year estimated survival
etoposide,
cisplatin;
HD-
Among studies that have looked at the role of high dose CT (HDCT) requiring stem cell support for “poor prognosis” patients, PMGCTs usually represent a small subpopulation that is rarely discussed or evaluated separately [18]. In 2003 Bokemeyer et al [19] reported a subgroup analysis of 28 patients with nonseminoma PMGCTs, who were treated up-front with HDCT. These patients showed 2-year PFS and OS rates of 64% and 68%, respectively, which compared favourably with historical controls of the International Extragonadal Germ Cell Tumor Study Group. According to this retrospective comparison, the authors suggested that HDCT may produce a 15%–20% absolute improvement in survival. More recently Fizazi et al [20] reported an advantage, over conventional BEP (Bleomycin, Etoposide, Cisplatin), of a dose-dense schedule with G-CSF support, in poor risk GCT, including PMGCT, showing an inadequate marker decline following the first course of CT. While data available on intensified first line CT with hematopoietic stem cell or G-CSG support are not sufficient to propose this therapeutic modality as a routine treatment, this approach could be considered in selected well-informed patients with nonseminoma PMGCT with negative prognostic features. The role of surgery on mediastinal residual disease following CT, is as vital as in gonadal or retroperitoneal disease. Every effort should be made in order to achieve complete resection in residual mass(es) [21], because of the possibility of persistent viable cells, teratoma, and/or teratoma with malignant transformation. Surgery for residual disease is therefore recommended both as a diagnostic and as a therapeutic procedure. It should be kept in mind that residual teratoma tissue may generate the so called “growing teratoma syndrome” [22] with possible secondary cardiopulmonary deterioration. Prompt recognition of this syndrome and surgical intervention, can result in cure [23]. Additionally, there are a very few cases who develop somatic malignant tumors within residual masses. These cases are usually referred to as “teratoma with malignant transformation” and successful treatment is highly dependent upon the possibility radical resection of tumor masses [24]. Surgery may also have an impact on diagnosis and prognosis (Table 3). In a large single-center experience including 158 patients with PMGCT undergoing surgery after CT, complete necrosis was found in 25% and teratoma in 33%, while the remainder showed the presence of malignancy in the form of persistent germ cell cancer as well as nongerm cell elements, often including teratoma—either mature or immature [23]. Five-year PFS in patients with viable cells in the specimen was 47%, compared to 84% in patients with necrosis or teratoma, without viable cells [15]. Unfortunately, the majority of primary nonseminoma PMGCTs are not cured despite standard CT and optimal surgery of residual disease, with long-term survival ranging from 40% to 50% [24].
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Table 3 Surgery after first-line chemotherapy for PMGCT and outcomes. Trial
N
Timing of surgery
Necchi, Clin Genitour Cancer 2015 [15] Walsh, Ann Thor Surg 20 0 0 [21]
68 20
Surgery was performed after first line therapy Eleven patients at first-line therapy Nine patients at salvage therapy
Outcomes
Kesler, Ann Thor Surg 2008 [24] Sarkaria, J Thorac Oncol 2011 [40]
148 57
Surgery was performed after first line therapy Fifty-four patients received preoperative standard chemotherapy
58% 58% 73% 42% 60% 56%
4-year 2-year 2-year 2-year 3-year 2-year
overall survival survival; survival for first line group; survival for salvage group disease-free survival overall survival
Table 4 Subsequent treatment after first-line therapies, and outcomes for PMGCT. Trial
N
Subsequent-line therapy
Hartman, J Clin Oncol 2001 [27]
79
Adra, J Clin Oncol 2017 [30] De Giorgi, Ann Oncol 2005 [31]
20 22
Various regimens (HDCT; cisplatin, ifosfamide; cisplatin, taxol) HDCT HDCT
Outcomes 11% long-term overall survival (standard regimen); 12% long-term overall survival (HDCT) 23% progression-free survival at 24 months 14% disease-free survival at 36 months
HDCT = high-dose chemotherapy.
Mediastinal seminoma, as mentioned earlier, has a much better prognosis, with survival rates similar to the gonadal counterpart. The recommended therapeutic approach is therefore similar to the nonseminoma tumors, but RT can be added in cases of active residual disease.
Beyond first line treatment Usually relapse occurs rather early after completing treatment. The results of second line therapy in testicular cancer are better than those achieved in other solid tumors, as a significant proportion of GCTs can still be cured with either conventional or HDCT [25], or local treatments. However the results of second line CT for PMGCT are at present dismal, with only approximately 5%–10% of patients being cured in the salvage setting irrespective of the regime used [25,26]. Due to the rarity of this tumor and the paucity of such patients in retrospective series of extragonadal germ cell cancer, no clear data emerge from the literature regarding a possible preferred therapeutic option. In a wide international retrospective series of 142 patients with extragonadal disease [27], 79 cases of PMGCT have been evaluated. Only 11% of such patients were longterm disease free compared to 30% of those with retroperitoneal disease. No preferred treatment was suggested, with only a slightly better (not significant) outcome after HDCT. Primary mediastinal disease together with inadequate response to cisplatin, were the strongest negative prognostic factors [27]. HDCT data on PMGCTS are mainly based on the carboplatinetoposide doublet proved to be an effective treatment modality in second and subsequent lines of treatment in GCTs [17,28–30], with a survival curve plateauing at 40% in the large Indiana series [28]. However the data are largely insufficient to draw any firm conclusions [18]. The European Group for Blood and Marrow Transplantation published, in 2005, the registry based experience in 59 patients treated with HDCT as second line therapy in extragonadal disease [31]. Twenty-two patients had primary mediastinal disease and carboplatin/etoposide combination (with or without alkylators) was the most employed regimen; nearly half of these patients received single-dose HDCT [31]. Toxic death rate was 7%. Twentythree percent of these patients obtained complete remission which was long lasting in 14% of cases. With the information available today on patient selection and safety of multiple courses of HDCT, including in the setting of recurrent disease, this approach can be proposed for selected patients still harboring chemosensitive disease (Table 4).
Novel (targeted) therapies Poor prognosis and refractory CGTs are tumors of young patients, and reduce life expectancy more than any other adult solid tumor type. This underscores the need to identify new active agents against CGT [32]. Progress has not been swift. In a review of the characteristics and outcome in 90 patients undergoing treatment with new drugs within sequential phase 2 trials at Memorial Sloan Kettering Cancer Center, median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8–1.3) and 4.7 months (95% CI, 3.5– 6.4), respectively with the 12- and 16- week PFS rates standing at 9% (95% Cl, 3%–15%) and 6% (95% Cl, 1%–11%), respectively. Eightysix of the 90 patients have died [33]. Clearly, we need to redouble our efforts to find effective novel therapeutic agents. Angiogenesis inhibitors have been extensively studied in GCT patients, including PMGCT. However, the objective response rate achieved with any of the evaluated compounds was poor. Pazopanib represents the last, and perhaps most noteworthy, chapter in the story of antiangiogenesis in GCT. In an openlabel, single-arm, phase 2 study pazopanib was administered in 43 patients with refractory GCTs [34]. Although only two partial responses were observed (4.7%), most patients experienced serum tumor marker decline, assessed after the first 4 weeks of treatment, but it was generally short-lived. Therefore, antiangiogenic agents have failed to provide substantial improvements in this field when used as single agents. However, they have yet to be combined with other compounds. Regarding immunotherapy, CD30expressing mediastinal GCT may be suitable for inclusion in clinical trials with anti-CD30 compounds. In a small, proof-of-concept study of brentuximab vedotin, an anti-CD30 antibody drug conjugate, two patients out of nine CT-resistant GCT patients, achieved a complete or partial response to treatment. Again, responses were short lived in almost all cases, despite initial serum tumor marker decline. Programmed cell-death-1/ligand-1 (PD-1/L1) immunohistochemical expression has been documented in the majority of cases of both seminoma and nonseminoma from large retrospective studies [35,36]. Most interestingly, pure seminoma displayed an inflammatory tumor microenvironment in a study, making these patients the most likely to respond to immune checkpoint inhibitor therapy [37]. Disappointingly, though, early results from a United States single-arm, phase 2 study with pembrolizumab, an anti-PD-L1 monoclonal antibody, did not show any clinical response among the first 12 patients enrolled [38].
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Additional phase 2 trials are currently evaluating the role of single agent immune checkpoint inhibitors as well as their combination with anti-CTLA4 antibodies in GCT, and results are awaited (NCT03081923, NCT03158064). Conclusions Seminoma and nonseminoma PMGCTs account for 15% of adult anterior mediastinal cancers and for 1% to 3% of all germ cell malignancies. Diagnosis is aimed mainly at differentiating the condition from lymphoid malignancies and cancers of the thymus. In cases with elevated alfa-fetoprotein and beta-hCG a diagnosis of a PMGCT is likely, even in the absence of histologic confirmation. Outcome of seminoma is similar to its gonadal counterpart while nonseminoma has a dismal prognosis requiring a multimodality approach, including cisplatin/ etoposide-containing CT followed by surgery of residual disease. Radical surgery, in addition to improving cure rates, provides histopathologic information (presence of viable tumor cells and/or teratoma with/without malignant transformation) which has important prognostic and therapeutic impact. The results of second line CT for PMGCT are at present very poor, with only approximately 5%–10% of patients being cured in the salvage setting, irrespective of the regime used. The role of intensified therapies with/without stem cell rescue in PMGCTs, is a matter of debate as insufficient data are available to permit any conclusions. Because of the rarity of the disease, poor categorization, and the lack of novel therapeutic strategies, an International database is required to obtain more information on these tumors, and possibly launch a wide multinational study. Patients with PMGCT should be referred to Centers with experience in this rare disease. Disclosure This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. References [1] Rajpert-De Meyt E, McGlynn KA, Okamoto K, et al. Testicular germ cell tumours. Lancet 2016;387:1762–74. [2] Ko JJ, Bernard B, Tran B, et al. Conditioning survival of patients with metastatic testicular germ cell tumors treated with first-line curative therapy. J Clin Oncol 2016;34:714–20. [3] Scholz M, Zehender M, Thalmann GN. Etragonadal retroperitoneal germ cell tumor: evidence of origin in the tetis. Ann Oncol 2002;13:121–4. [4] Den Bakkel MA, Marx A, Mukai K, Stroebel P. Mesenchymal tumors of the mediastinum Part 1. Virchow Arch 2015;467(5):487–501. [5] Rusner C, Trabert B, Katalinic A, et al. Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998-2008. Cancer Epidem 2013;37:370–3. [6] Chaganti RS, Rodriguez E, Mathew S. Origin of adult male mediastinal germ– cell tumours. Lancet 1994;343:1130–2. [7] Nichols CR, Herema NA, Palmer C, et al. Klinefelter’s syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 1987;5:1290–4. [8] John S, Adnan MAM, Khalil MO, et al. Mediastinal germ cell tumor and acute megacaryoblatic leukemia- a systematic review of cases reported in the literature. Blood 2014;124(abs):3694. [9] International Germ Cell Consensus Classification A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997;15:594–603. [10] Liu Y, Wang Z, Peng ZM, Yu Y. Management of the primary malignant mediastinal germ cell tumors: experience with 54 patients. Diagn Pathol 2014;9:33–7. [11] Bokemeyer C, Nichols CR, Broz J-P, et al. Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an International analysis. J Clin Oncol 2002;20:1864–73. [12] Hartmann JT, Nichols CR, Droz J-P, et al. Prognostic variables for response and outcome in patients with extragonadal tumors. Ann Oncol 2002;13:11017–28. [13] Fedaynin M, Tryakin A, Mosyakova Y, et al. Prognostic factors and efficacy of different chemotherapeutic regimens in patients with mediastinal nonseminomatous germ cell tumors. J Cancer Res Clin Oncol 2014;140:311–18.
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