Mediastinal Nonseminoma

Article Author:
Srinath Sundararajan
Article Editor:
Yvonne Carter
Updated:
3/9/2019 8:38:45 PM
PubMed Link:
Mediastinal Nonseminoma

Introduction

Germ cell tumors are cancers that arise from the reproductive cells of the testis or ovaries.

Etiology

A vast majority of germ cell tumors are gonadal in location. However, germ cell cancers can arise outside the gonads, from the remnants of primordial germ cells along their path of migration and are called extragonadal germ cell tumors. Extragonadal germ cell tumors are rare tumors accounting for 1% to 5 % of all germ cell tumors. The common locations of extragonadal germ cell tumors are mediastinum, retroperitoneal area, pineal gland, and the suprasellar area. Tumors arising in the mediastinum are called as mediastinal germ cell tumors, and they are the most common type of extragonadal germ cell tumors.

Epidemiology

Mediastinal germ cell tumors are very rare and represent 3% to 10% of all mediastinal tumors and are more common in men. Similar to gonadal germ cell tumors, mediastinal germ cell tumors are broadly divided into seminomatous and non-seminomatous germ cell tumors based on the tumor histology. Yolk sac tumor, teratoma, choriocarcinoma, embryonal carcinoma are the common sub-types of mediastinal non-seminomatous germ cell tumors. When the tumor contains more than one cell line, it is referred to as mixed germ cell tumor, and it is considered as a non-seminomatous germ cell tumor even if there is a component of seminoma. Mature teratomas are benign in nature. Among the various subtypes, mediastinal yolk sac tumor is the commonest histological subtype (about 60%). Mediastinal non-seminomatous germ cell tumors most commonly affect children and young adults. However, a few cases have been reported in older adults as well. Mediastinal non-seminomatous germ cell tumors can be associated with genetic disorders such as Klinefelter syndrome and other hematological malignancies such as acute myeloid leukemia, mastocytosis and myelodysplastic syndromes.

History and Physical

Presenting manifestations depend on the histological subtype, the size of the tumor, and the rapidity of growth. Mature teratomas, which are slow growing, can often be diagnosed incidentally. The common clinical symptoms of mediastinal non-seminomatous germ cell tumors are a cough, dyspnea, chest pain, fever, night sweats, and weight loss. Rarely the tumor can compress critical structures such as the superior vena cava in the mediastinum resulting in manifestations of superior vena cava syndrome such as facial plethora, prominent neck veins. Compression of bronchus can result in post-obstructive pneumonia, and hemoptysis can be seen when erosion into bronchus occurs. 

Evaluation

A complete physical exam including genital exam is crucial. Alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (B-HCG), and lactate dehydrogenase (LDH) are the tumor markers that can be elevated in these patients. Patients with benign teratomas do not have elevated b-HCG or AFP. Mediastinal germ cell tumors are noted as an anterior mediastinal mass in an x-ray. Teratomas can manifest with derivatives of more than one germ layer that can be seen in an x-ray including in bones, calcification, and teeth. Although chest x-rays can identify a larger mediastinal mass, a computed tomography (CT) or magnetic resonance imaging (MRI) of the chest is required to define the size, borders, and the location of the mass accurately. Patients with an extragonadal germ cell tumor have a higher risk of harboring a metachronous testicular tumor. A testicular ultrasound is mandatory to rule out a co-existing testicular tumor.

The differential diagnoses of mediastinal non-seminomatous germ cell tumors non-seminomatous germ cell tumors include retrosternal thyroid tumors, lymphomas, and thymic tumors. A workup for the anterior mediastinal tumors noted above is recommended including lactate dehydrogenase (LDH) and thyroid-stimulating hormone (TSH). A tissue diagnosis would be needed to identify the histology and to plan subsequent management.

Treatment / Management

Mediastinal non-seminomatous germ cell tumors are considered poor risk tumors. There is no standardized staging system for mediastinal germ cell tumors. Treatment strategies for mediastinal non-seminomatous germ cell tumors largely depend on the tumor histology. Due to the rarity of the disease, there is a paucity of large randomized controlled studies to guide treatment. Treatment strategies are based on small case series, retrospective data, single-center studies, and the literature from gonadal germ cell tumors. Chemotherapy and surgery are two main modalities that have been evaluated for the treatment of mediastinal germ cell tumors.

Teratomas are refractory to chemotherapy. Surgical resection is the treatment of choice for benign teratomas. The mainstay of treatment for mediastinal non-seminomatous germ cell tumors other than mature teratoma is multi-agent chemotherapy followed by salvage surgery to resect any residual tumors. The chemotherapy regimen includes a combination of cisplatin with bleomycin and etoposide (BEP) or with ifosfamide and etoposide (VIP) for four cycles. In a trial that compared bleomycin and etoposide to ifosfamide and etoposide in 304 patients with advanced or disseminated germ cell tumors, the response rates, complete remission rates, and two-year overall survival were similar between the two groups. Ifosfamide and etoposide are sometimes preferred over the bleomycin-containing regimen in patients with mediastinal non-seminomatous germ cell tumors because of potential pulmonary toxicity with bleomycin and the potential need for salvage surgery after chemotherapy. Tumor markers such as AFP and b-HCG need to be followed to assess response to chemotherapy and early fall in tumor markers would be helpful to plan subsequent treatment. 

Surgical resection of any residual masses is recommended to improve overall outcome. Surgery is recommended in even in patients who have elevated tumor markers post chemotherapy who are otherwise good surgical candidates. In a salvage surgery study that included 32 patients with residual mediastinal non-seminomatous tumor after chemotherapy, 66% of resected tumors were noted to be viable, 22% of tumors were teratoma, and 12% were necrosis. Additional systemic chemotherapy is recommended in patients who had a viable residual tumor.  Unlike mediastinal seminomas, there is no role for radiation therapy in the treatment of mediastinal non-seminomatous germ cell tumors.

Pearls and Other Issues

Mediastinal germ cell tumors have worse outcomes compared to testicular germ cell tumors. The overall prognosis of mediastinal non-seminomatous germ cell tumors is inferior to mediastinal seminomas, teratomas, and gonadal non-seminomatous germ cell tumors. The five-year overall survival ranges between 35% to 45%. Considering most patients with mediastinal non-seminomatous tumors are younger, close surveillance with labs, a physical exam, and imaging is needed for identifying recurrence early. Furthermore, these patients would need to be monitored for long-term, chemotherapy-related complications including metabolic syndrome, pulmonary toxicity, neuropathy, cardiovascular events, infertility and secondary hematological malignancies. Preserving fertility is a major consideration in these young patients and efforts should be made to bank sperm before chemotherapy.

Enhancing Healthcare Team Outcomes

Management of mediastinal nonseminoma comprises a team of providers with surgical oncologists, medical oncologists, and radiologists. Surgical oncologist plays a role in resection of the cancer or for biopsies. After this, a medical oncologist typically carries forward management with chemotherapy. Radiologists play a key role in reading scans pre and post-treatment so that the effectiveness of treatment can be measured. Nursing staff and pharmacist also play a very important role in proper verification of chemotherapy drug doses, administration and side effects management (Level IV).


References

[1] Postchemotherapy surgery for germ cell tumors--what have we learned in 35 years?, Riggs SB,Burgess EF,Gaston KE,Merwarth CA,Raghavan D,, The oncologist, 2014 May     [PubMed PMID: 24718515]
[4] [A multi-disciplinary approach to the treatment of germ cell tumors]., Honecker F,Souchon R,Krege S,Bokemeyer C,, Der Internist, 2010 Nov     [PubMed PMID: 20938625]
[5] American Society of Clinical Oncology Clinical Practice Guideline on uses of serum tumor markers in adult males with germ cell tumors., Gilligan TD,Seidenfeld J,Basch EM,Einhorn LH,Fancher T,Smith DC,Stephenson AJ,Vaughn DJ,Cosby R,Hayes DF,, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2010 Jul 10     [PubMed PMID: 20530278]
[6] [Primary germ cell tumor in the mediastinum-report of 47 cases]., Zhou ZT,Wang JW,Yang L,Wang J,Zhang W,, Zhonghua zhong liu za zhi [Chinese journal of oncology], 2006 Nov     [PubMed PMID: 17416013]
[7] [Results of surgical treatment for pimary germcell tumors of the mediastinum]., Yano M,Fujii Y,, Nihon Geka Gakkai zasshi, 2006 Nov     [PubMed PMID: 17147287]
[8] Poor outcomes in patients with primary malignant mediastinal germ-cell tumors., Hsiao HH,Liu YC,Tsai HJ,Tsai KB,Cheng YJ,Chou SH,Chong IW,Yang WC,Liu TC,Lin SF,, The Kaohsiung journal of medical sciences, 2005 Dec     [PubMed PMID: 16670048]
[9] First-line sequential high-dose VIP chemotherapy with autologous transplantation for patients with primary mediastinal nonseminomatous germ cell tumours: a prospective trial., Bokemeyer C,Schleucher N,Metzner B,Thomas M,Rick O,Schmoll HJ,Kollmannsberger C,Boehlke I,Kanz L,Hartmann JT,, British journal of cancer, 2003 Jul 7     [PubMed PMID: 12838296]
[10] Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis., Bokemeyer C,Nichols CR,Droz JP,Schmoll HJ,Horwich A,Gerl A,Fossa SD,Beyer J,Pont J,Kanz L,Einhorn L,Hartmann JT,, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2002 Apr 1     [PubMed PMID: 11919246]
[11] Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum., Vuky J,Bains M,Bacik J,Higgins G,Bajorin DF,Mazumdar M,Bosl GJ,Motzer RJ,, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2001 Feb 1     [PubMed PMID: 11157018]
[12] The relative risk of second nongerminal malignancies in patients with extragonadal germ cell tumors., Hartmann JT,Nichols CR,Droz JP,Horwich A,Gerl A,Fossa SD,Beyer J,Pont J,Einhorn L,Kanz L,Bokemeyer C,, Cancer, 2000 Jun 1     [PubMed PMID: 10861442]
[14] Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study., Nichols CR,Catalano PJ,Crawford ED,Vogelzang NJ,Einhorn LH,Loehrer PJ,, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1998 Apr     [PubMed PMID: 9552027]
[15] A Rare Case of Primary Anterior Mediastinal Yolk Sac Tumor in an Elderly Adult Male., Nakhla SG,Sundararajan S,, Case reports in oncological medicine, 2016     [PubMed PMID: 27144043]
[16] COLLINS DH,PUGH RC, CLASSIFICATION AND FREQUENCY OF TESTICULAR TUMOURS. British journal of urology. 1964 Jun;     [PubMed PMID: 14184707]
[17] Moran CA,Suster S,Koss MN, Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum--a clinicopathologic and immunohistochemical study of 64 cases. Cancer. 1997 Aug 15;     [PubMed PMID: 9264353]