Germ-cell tumors (GCTs) are neoplasms that can arise within the gonads (i.e., testicles and ovaries) or at extragonadal sites, where they are referred as extragonadal germ-cell tumors (EGCTs). Among the latter, midline areas of the body are typically affected (1), especially the mediastinum (2). This tendency could be explained by considering EGCTs as derived from primordial germ cells deposited during migration from the epiblast to the genital ridge during embryogenesis (3). Still, extra-midline cases have been reported [e.g., lungs (2) and kidneys (4)] and some challenge the existence of bona fide EGCTs which they consider to be metastases. The debate is fueled by the presence of non-random chromosomal changes essentially identical to the ones present in gonadal GCTs (5). Abnormalities of 12p chromosome are the most specific both at gonadal and extragonadal sites (6). By some authors this could suggest a gonadal origin of EGCTs, with an early migration of neoplastic cells to extragonadal sites (5). Still, despite the presence of some biological overlaps with gonadal GCTs, mediastinal EGCTs (MEGCTs) not only stand out for their peculiar location. They as well have distinct epidemiological features, worth-noting histological patterns and factors of aggressiveness related to their growth within specific anatomical site and the structures therein present. We present the following article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-21-22/rc) and on the base of a literature search of case reports, epidemiological surveys, clinical and pathological studies written in English with no specific time-frame considered.
EGCTs are rare neoplasms whose total crude incident rate is 1.27/1,000,000 person-years, peaking between 15 and 24 years of age at 2.2/1,000,000 person-years (2). Such increased amount of cases around the onset of puberty is considered to reflect a hormone-related growth boost of neoplastic germ-cells (3). The mediastinum is the most frequent location of EGCTs (2,3), especially in the anterior compartment, although involvement of the middle mediastinum has also been reported (7,8). Still, MEGCTs constitute only 1–3% of germ cell malignancies (7) and 16% of mediastinal tumors (9). MEGCTs predominantly affect males (3) and patients have a 10% chance of developing metachronous testicular cancer over a 10-year period (10,11). Individuals affected from Klinefelter syndrome are especially at risk and the presence of this syndrome should be investigated among young patients with MEGCTs (12). Women are instead less frequently affected by MEGCTs and they usually, but not exclusively, present with yolk sac tumors (YSTs) or mature teratomas (MTs) (13-16). The latter are actually the most frequent type of MEGCTs in men as well. In fact, non-seminomatous neoplasms represent up to 85% of MEGCT, prevailing over mediastinal seminomas (3,10,17). This picture also applies to individuals suffering from Klinefelter syndrome (12) and it contrasts with testicular pathology, where seminomas outnumber non-seminomatous neoplasms.
Histological patterns and factors of aggressiveness
MEGCTs have in general a worse prognosis compared to their gonadal counterparts (18). Nevertheless, not all MEGCTs are equal and different features can be identified in the modulation of aggressiveness.
Type of MEGCT
According to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification of prognostic groups for patients with GCTs, MEGCTs are classified in the poor-prognosis class (i.e., 50% 5-year survival rate) (18). Nevertheless, this projection can be considered accurate for non-seminomatous MEGCTs, whereas mediastinal seminomas have a much better prognosis which parallels intermediate- and good-prognosis IGCCCG classes (18,19). Also, mediastinal seminomas respond very well to chemotherapy and radiotherapy with excellent long-term chances of cure (19), while non-seminomatous MEGCTs require chemotherapy followed by surgical resection of the residual tumor (20). It must be also remembered that MEGCTs can feature more than one type of germ-cell neoplasia within a single tumor (i.e., mixed MEGCT). Acknowledgment of each present entity is of paramount importance for patient management and cannot be overstressed.
Mediastinal seminomas show discohesive epithelioid cells with clear cytoplasm, distinct cellular membranes and nucleoli. These cells have a CD117+ immunohistochemical phenotype, which could be a potential diagnostic pitfall in the differential diagnosis with thymic carcinoma. Intratumoral lymphocytic infiltrates and granulomatous reactions can become very prominent, up to the point of significantly obscuring the underlying neoplasia. Scattered multinucleated syncytiotrophoblast can be found within seminomas, without implying a diagnosis of choriocarcinoma. The latter would require the concomitant presence of multinucleated syncytiotrophoblast and mononucleated cytotrophoblast. YSTs can have different pattern of growth, the most frequent being microcystic/reticular, with or without Schiller-Duval bodies. However, choriocarcinoma and YST can be diagnosed even without performing a tumoral biopsy by detecting high blood levels of human chorionic gonadotrophin (hCG) and a-fetoprotein (AFP), respectively (20).
MTs don’t feature elevated tumoral markers instead and they therefore require a biopsy to be diagnosed (20). Moreover, they are chemo-resistant and they require a surgical approach (20). Histologically, mature forms show only phenotypically—developed tissues derived from one of the three germinal layers (e.g., skin with cutaneous adnexa, teeth, bone and cartilage). MTs often have cystic areas that can be so prominent to radiologically imitate pleural and pericardial effusions (21,22). Three major factors of aggressiveness can be present in teratomas: digestive tract tissue, neuroectodermal immature cells and somatic malignant transformation (SMT). Digestive tract tissue capable of secreting proteolytic enzymes (e.g., pancreatic glands) not only makes MTs more prone to rupture, but it can also erode mediastinal structures (23). Neuroectodermal immature components are identifiable as small blue cells with S100+ immunophenotype. As they can be focal (24), collection can be missed in biopsies. Not only the presence or absence of immature tissue could be important, as a grading system has been developed in the ovary on the basis of the quantity of immature neuroepithelium (25). According to it, the larger the amount of immature neuroepithelium, the worse the prognosis (25), but this has not been validated in the mediastinum (24). Moreover, some authors suggested that immature teratomas, if radically resected, could still be associated to a prognosis which is equivalent to that of a MTs (26).
SMT is defined as the presence within GCTs of non-germinal malignant tumors (i.e., carcinomas and sarcomas). These can include adenocarcinoma, rhabdomyosarcoma, neuroblastoma as well as many other phenotypes which retain their proper morphological and immunophenotypical features (27,28). Nevertheless, differently from the corresponding neoplasms outside the context of GCTs, somatic malignant components often carry 12p chromosomal alterations, paralleling germinal neoplastic cells and aiding in the differential diagnosis with metastases (29). SMT in the form of adenocarcinoma must also be distinguished from embryonal carcinoma, which is the least frequent MEGCT and it can be made of glandular structures with atypical epithelioid cells (30). Ancillary immunohistochemical staining would prove positive for CD30 and OCT3/4 in the case of embryonal carcinoma, while NST would mark positive for different markers according to the phenotype (e.g., CDX2 in colonic-type adenocarcinoma). In contrast with cases of gonadal GCTs, patients suffering from MEGCTs have also an increased risk of developing hematological neoplastic diseases, especially acute megakaryoblastic leukemia (AMKL) (31). Malignant hematological cells have indeed been found within MEGCTs (32) and the source of hematopoietic malignancies might be represented by precursor cells within YST components (33). Still, AMKL usually presents as a bone-marrow involvement. Nevertheless, MEGCTs with concomitant AMKL have been found to share mutations in p53 and PTEN genes, as well as the presence of isochromosome 12p (i12p) (34-36). These data supports that these tumors share a common founding clone, as well as the importance of such genetic alterations in the pathogenesis of these associated tumors that might represent a unique biological entity when they co-occur (34-36).
Compression and infiltration of mediastinal structures
MEGCTs can become clinically worrisome by means of their growth patterns. Even when they do not have infiltrative margins, but rather an expansive profile, they can get big enough to compress on mediastinal structures leading to a variety of possible clinical presentations. Pressure on major vessels can impair blood flow. If the superior vena cava is involved and compression develops quickly, a superior vena cava syndrome can ensue, bringing to a medical emergency (37,38). If the process is slower, flows through the azygos system or the inferior vena cava can (at least temporarily) compensate for the obstruction (37). Pressure on the microvasculature can instead bring to tissue necrosis. For instance, ischemic death of the bronchial wall would lead to perforation of the airway with hemoptysis (39-41). Rupture of a teratoma within the airways has been also reported to cause the expectoration of tumoral hair (trichoptysis) even in the absence of blood (23). Other reported presentations are dyspnea, Horner syndrome and cardiac arrythmia following pulmonary, nervous and right atrial compression, respectively (21,30,42,43).
Contact between MEGCTs and mediastinal structures can be furtherly complicated by fibrotic bands which create adherence or by an infiltrating growth pattern of neoplastic cells. In such cases, radical surgical treatment is either reached by en-bloc removal of encroached organs along with the tumor, or not possible altogether, considering the unresectable vital anatomical structures present in the mediastinum (8,37,38,40,44).
Response to treatment
As previously mentioned, patients with MTs can be successfully treated with surgery, if feasible. Nevertheless, this also reflects the resistance of MTs to chemotherapies. Such biological feature can become problematic after a patient have received systemic therapy for a non-seminomatous MEGCT with a teratomatous component. The latter can be selected, surviving to the treatment and starting to grow. This leads to the so-called growing-teratoma syndrome (GTS). GTS is clinical phenomenon set before or immediately after the fourth cycle of cisplatin-based chemotherapy with a paradoxical enlargement of the tumor, concomitant normalization of previously elevated serum tumoral markers and cardiopulmonary deterioration caused by compression of the great vessels/heart/lungs (45). GTS therefore requires a prompt surgical approach (45,46). Pathology reports usually tell of teratomatous elements in a setting of inflammation and necrosis (46). Although the prognosis of GTS is considered to be excellent after the excision of the tumor (47), there are reports of relapses even after complete resection (i.e., absence of residual masses at the end of the surgical operation and at postoperative CT scan) (48) Further research is therefore needed to optimize an effective therapeutic approach to this complication, a possibility limited by its rarity.
The mediastinum can harbor different kinds of neoplasia, including GCTs. The full spectrum of MEGCTs includes a variety of tumors with different clinical behaviors. Aggressiveness follows the inherent ability of local and systemic spread of each neoplastic type, as well as their distinct responsiveness to therapy.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Margaret Ottaviano and Giovannella Palmieri) for the series “New Treatments and Novel Insights of Thymic Epithelial Tumors and Mediastinal Germ Cell Tumors” published in Mediastinum. The article has undergone external peer review.
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-21-22/rc
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-21-22/coif). The series “New Treatments and Novel Insights of Thymic Epithelial Tumors and Mediastinal Germ Cell Tumors” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
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- Ronchi A, Cozzolino I, Montella M, et al. Extragonadal germ cell tumors: Not just a matter of location. A review about clinical, molecular and pathological features. Cancer Med 2019;8:6832-40. [Crossref] [PubMed]
- Trama A, Mallone S, Nicolai N, et al. Burden of testicular, paratesticular and extragonadal germ cell tumours in Europe. Eur J Cancer 2012;48:159-69. [Crossref] [PubMed]
- 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 Epidemiol 2013;37:370-3. [Crossref] [PubMed]
- Kumar Y, Bhatia A, Kumar V, et al. Intrarenal pure yolk sac tumor: an extremely rare entity. Int J Surg Pathol 2007;15:204-6. [Crossref] [PubMed]
- Chaganti RS, Rodriguez E, Mathew S. Origin of adult male mediastinal germ-cell tumours. Lancet 1994;343:1130-2. [Crossref] [PubMed]
- Sung MT, Maclennan GT, Lopez-Beltran A, et al. Primary mediastinal seminoma: a comprehensive assessment integrated with histology, immunohistochemistry, and fluorescence in situ hybridization for chromosome 12p abnormalities in 23 cases. Am J Surg Pathol 2008;32:146-55. [Crossref] [PubMed]
- Rosti G, Secondino S, Necchi A, et al. Primary mediastinal germ cell tumors. Semin Oncol 2019;46:107-11. [Crossref] [PubMed]
- Xu J, Zhao J, Geng S, et al. Primary seminoma arising in the middle mediastinum: A case report. Oncol Lett 2016;12:348-50. [Crossref] [PubMed]
- Takeda S, Miyoshi S, Ohta M, et al. Primary germ cell tumors in the mediastinum: a 50-year experience at a single Japanese institution. Cancer 2003;97:367-76. [Crossref] [PubMed]
- Schmoll HJ. Extragonadal germ cell tumors. Ann Oncol 2002;13:265-72. [Crossref] [PubMed]
- Hartmann JT, Nichols CR, Droz JP, et al. Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors. Ann Oncol 2002;13:1017-28. [Crossref] [PubMed]
- Bonouvrie K, van der Werff Ten Bosch J, van den Akker M. Klinefelter syndrome and germ cell tumors: review of the literature. Int J Pediatr Endocrinol 2020;2020:18. [Crossref] [PubMed]
- Dulmet EM, Macchiarini P, Suc B, et al. Germ cell tumors of the mediastinum. A 30-year experience. Cancer 1993;72:1894-901. [Crossref] [PubMed]
- Radaideh SM, Cook VC, Kesler KA, et al. Outcome following resection for patients with primary mediastinal nonseminomatous germ-cell tumors and rising serum tumor markers post-chemotherapy. Ann Oncol 2010;21:804-7. [Crossref] [PubMed]
- Schneider DT, Schuster AE, Fritsch MK, et al. Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Chromosomes Cancer 2002;34:115-25. [Crossref] [PubMed]
- Grabski DF, Pappo AS, Krasin MJ, et al. Long-term outcomes of pediatric and adolescent mediastinal germ cell tumors: a single pediatric oncology institutional experience. Pediatr Surg Int 2017;33:235-44. [Crossref] [PubMed]
- Bokemeyer C, Hartmann JT, Fossa SD, et al. Extragonadal germ cell tumors: relation to testicular neoplasia and management options. APMIS 2003;111:49-59; discussion 59-63. [Crossref] [PubMed]
- Schmoll HJ, Souchon R, Krege S, et al. European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004;15:1377-99. [Crossref] [PubMed]
- Bokemeyer C, Nichols CR, Droz JP, et al. Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 2002;20:1864-73. [Crossref] [PubMed]
- Albany C, Einhorn LH. Extragonadal germ cell tumors: clinical presentation and management. Curr Opin Oncol 2013;25:261-5. [Crossref] [PubMed]
- Dorterler ME, Boleken ME, Koçarslan S. A Giant Mature Cystic Teratoma Mimicking a Pleural Effusion. Case Rep Surg 2016;2016:1259175. [Crossref] [PubMed]
- Phan J, Bellinghausen Stewart A, Son A, et al. Unruptured Mediastinal Teratoma Presenting as Pericardial Effusion With Tamponade Symptoms. Chest 2014;146:201A. [Crossref]
- Guibert N, Attias D, Pontier S, et al. Mediastinal teratoma and trichoptysis. Ann Thorac Surg 2011;92:351-3. [Crossref] [PubMed]
- McLeod NP, Vallely MP, Mathur MN. Massive immature mediastinal teratoma extending into the left pleural cavity. Heart Lung Circ 2005;14:45-7. [Crossref] [PubMed]
- Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 1976;37:2359-72. [Crossref] [PubMed]
- Hiroshima K, Toyozaki T, Iyoda A, et al. Apoptosis and proliferative activity in mature and immature teratomas of the mediastinum. Cancer 2001;92:1798-806. [Crossref] [PubMed]
- Rachwalik M, Kosiorowska K, Bochenek M, et al. Mature mediastinal teratoma with somatic type malignancy including neuroblastoma and intestinal type of adenocarcinoma: A Case Report. Int J Surg Case Rep 2021;80:105680. [Crossref] [PubMed]
- Asakura K, Izumi Y, Ikeda T, et al. Mediastinal germ cell tumor with somatic-type malignancy: report of 5 stage I/II cases. Ann Thorac Surg 2010;90:1014-6. [Crossref] [PubMed]
- Fichtner A, Richter A, Filmar S, et al. The detection of isochromosome i(12p) in malignant germ cell tumours and tumours with somatic malignant transformation by the use of quantitative real-time polymerase chain reaction. Histopathology 2021;78:593-606. [Crossref] [PubMed]
- el-Khatib M, Chew FS. Embryonal carcinoma of the anterior mediastinum. AJR Am J Roentgenol 1998;170:722. [Crossref] [PubMed]
- John S, Muqeet Adnan MA, Khalil MO, et al. Mediastinal Germ Cell Tumor and Acute Megakaryoblastic Leukemia– a Systematic Review of Cases Reported in the Literature. Blood 2014;124:3694. [Crossref]
- Saito A, Watanabe K, Kusakabe T, et al. Mediastinal mature teratoma with coexistence of angiosarcoma, granulocytic sarcoma and a hematopoietic region in the tumor: a rare case of association between hematological malignancy and mediastinal germ cell tumor. Pathol Int 1998;48:749-53. [Crossref] [PubMed]
- Orazi A, Neiman RS, Ulbright TM, et al. Hematopoietic precursor cells within the yolk sac tumor component are the source of secondary hematopoietic malignancies in patients with mediastinal germ cell tumors. Cancer 1993;71:3873-81. [Crossref] [PubMed]
- Oshrine BR, Olsen MN, Heneghan M, et al. Acquired isochromosome 12p, somatic TP53 and PTEN mutations, and a germline ATM variant in an adolescent male with concurrent acute megakaryoblastic leukemia and mediastinal germ cell tumor. Cancer Genet 2014;207:153-9. [Crossref] [PubMed]
- Lu C, Riedell P, Miller CA, et al. A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia. Cold Spring Harb Mol Case Stud 2016;2:a000687. [Crossref] [PubMed]
- Akizuki K, Sekine M, Kogure Y, et al. TP53 and PTEN mutations were shared in concurrent germ cell tumor and acute megakaryoblastic leukemia. BMC Cancer 2020;20:5. [Crossref] [PubMed]
- Di Liello R, Sparano F, Iacovino ML, et al. Asymptomatic azygos vein overflow in a young patient with primary mediastinal seminoma. Thorac Cancer 2019;10:2308-11. [Crossref] [PubMed]
- Xu X, Sun C, Zhang L, et al. A case of mediastinal seminoma presenting as superior vena cava syndrome. Intern Med 2012;51:1269-72. [Crossref] [PubMed]
- Gunes S, Varon J, Walsh G. Mediastinal teratoma presenting as massive hemoptysis in an adult. J Emerg Med 1997;15:313-6. [Crossref] [PubMed]
- Jothianandan K, Tibb AS, McLemore M, et al. An adult man presenting with hemoptysis caused by mature teratoma with rupture into the bronchus and pericardium and complicated by Haemophilus influenzae infection. J Thorac Cardiovasc Surg 2010;139:e104-7. [Crossref] [PubMed]
- Chen RF, Chang TH, Chang CC, et al. Mediastinal teratoma with pulmonary involvement presenting as massive hemoptysis in 2 patients. Respir Care 2010;55:1094-6. [PubMed]
- Cates CA, Etchells DE, Dorrell ED, et al. Horner's syndrome in yolk sac tumour of the mediastinum. Br J Ophthalmol 1999;83:1406. [Crossref] [PubMed]
- Ramonfaur D, Josephs M, Shmorhun D, et al. A teenager with recurrent supraventricular tachycardia and a giant mediastinal mass. J Pediatr Surg Case Reports 2021;64:101750. [Crossref]
- Imaniar R, Syahruddin E, Soepandi PZ, et al. Mediastinal yolk sac tumor infiltrating the heart. Exp Oncol 2018;40:82-4. [Crossref] [PubMed]
- Kesler KA, Patel JB, Kruter LE, et al. The “growing teratoma syndrome” in primary mediastinal nonseminomatous germ cell tumors: criteria based on current practice. J Thorac Cardiovasc Surg 2012;144:438-43. [Crossref] [PubMed]
- Zheng R, Devin CL, O'Malley T, et al. Surgical management of growing teratoma syndrome: robotic-assisted thoracoscopic resection of mediastinal teratoma. Surg Endosc 2020;34:1019-23. [Crossref] [PubMed]
- Scavuzzo A, Santana Ríos ZA, Noverón NR, et al. Growing teratoma syndrome. Case Rep Urol 2014;2014:139425. [Crossref] [PubMed]
- André F, Fizazi K, Culine S, et al. The growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients. Eur J Cancer 2000;36:1389-94. [Crossref] [PubMed]
Cite this article as: Pini GM, Colecchia M. Mediastinal germ cell tumors: a narrative review of their traits and aggressiveness features. Mediastinum 2022;6:5.