Mediastinal Nonseminoma


Article Author:
Srinath Sundararajan


Article Editor:
Yvonne Carter


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/10/2019 8:10:40 AM

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[1]. 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 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%)[2]. 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[3]. 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[4].

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[5]. 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 include retrosternal thyroid tumors, lymphomas, and thymic tumors. A workup for the anterior mediastinal tumors noted above is recommended, including obtaining serum levels of lactate dehydrogenase (LDH) and thyroid-stimulating hormone (TSH). A tissue diagnosis is needed for a definitive histologic diagnosis and to plan subsequent management.

Treatment / Management

Mediastinal non-seminomatous germ cell tumors are considered poor risk tumors[6]. No standardized staging system exists for mediastinal germ cell tumors. Treatment strategies for mediastinal non-seminomatous germ cell tumors are largely determined by the histology of the tumor. The rare occurence of these tumors lends to the 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, thus surgical resection is the treatment of choice for benign teratomas[7]. 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[8]. 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. Sequential treatment with chemotherapy followed by autologous stem cell transplantation has been shown to improve survival and might be a good strategy in certain patients[9]. 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 mass is recommended to improve overall outcome[10][11] and is recommended even if serum tumor markers remain elevated after chemotherapy for patients who are 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[12]. 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%[13]. 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[14]. Surgical oncologist plays a role in resection of 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).


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Mediastinal Nonseminoma - Questions

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A young male with anterior mediastinal mass has elevated levels of both HCG and AFP. CT scan of the chest reveals a large mass extending into the right chest. The patient was administered multimodality chemotherapy for two months. The levels of HCG and AFP still remain elevated. How do you manage this patient now?



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32 year old male presents to hospital with 4-month history of progressive dyspnea, intermittent chest pain, and 20 lbs. unintentional weight loss. A CT chest done shows 4 cm x 8 cm anterior mediastinal mass. Serum AFP is elevated at 35, beta-HCG, TSH and LDH are normal. Biopsy of the mass shows germ cell tumor with components of choriocarcinoma, teratoma, and yolk-sac tumor. Patient was started on chemotherapy with cisplatin with ifosfamide and etoposide (VIP). After 4 cycles, PET CT scan shows 3.2 x 4 cm residual mass. His AFP level has returned to normal range. Patient undergoes surgical resection of the tumor. Histopathologic exam confirms completely excised mature teratoma with negative margins. What is the best management?



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A 52-year-old male was recently diagnosed with a mediastinal germ cell tumor of embryonal carcinoma type that is infiltrating into his right lung. He has an 80 pack-year history of smoking and Gold Stage III chronic obstructive pulmonary disease. He also has a history of chronic pancreatitis. His performance status is Eastern Cooperative Oncology Group 1. His pulmonary function tests show a predicted forced expiratory volume 1 of 1. 5 liters. What is the appropriate treatment?



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A 35-year-old male was recently diagnosed with mediastinal nonseminoma and has completed chemotherapy with excellent response to treatment. What is the patient at risk for in the future?



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A 40-year-old male was recently diagnosed with a mediastinal mass when he was evaluated for chest pain. CT scan showed 6 cm anterior mediastinal mass with prominent calcification. Serum alpha-fetoprotein and beta-hCG are within normal limits. The patient underwent surgical excision of the mass. Gross cut section of the mass had chalky mass with sebum like material, hair, and tooth. He was diagnosed with mediastinal nonseminoma. What treatment should be offered to this patient next?



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The chest x-ray of a 16-year-old boy with a history of Klinefelter syndrome complaining of cough, dyspnea, and night sweats reveals an opacity in the right lower lung field and a widened mediastinum. Which of the following is most likely to be found on a chest CT scan of the patient?



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Mediastinal Nonseminoma - References

References

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]
[A multi-disciplinary approach to the treatment of germ cell tumors]., Honecker F,Souchon R,Krege S,Bokemeyer C,, Der Internist, 2010 Nov     [PubMed]
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]
[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]
[Results of surgical treatment for pimary germcell tumors of the mediastinum]., Yano M,Fujii Y,, Nihon Geka Gakkai zasshi, 2006 Nov     [PubMed]
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]
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]
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]
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]
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]
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]
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]
COLLINS DH,PUGH RC, CLASSIFICATION AND FREQUENCY OF TESTICULAR TUMOURS. British journal of urology. 1964 Jun;     [PubMed]
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]

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