Germ Cell Tumor

Oncology

August 29, 2023

≈9 min

Introduction

The anterior mediastinal compartment is the space bounded by the thoracic inlet superiorly, the diaphragm inferiorly, the sternum anteriorly and the brachiocephalic vessels, ascending aorta and pericardium posteriorly ^[1].

The contents of the anterior mediastinum include the thymus, lymph nodes, adipose tissue, and the mediastinal branches of the internal thoracic vessels. Most of the mediastinal masses develop in the anterior mediastinum, adding up to around 50% of all mediastinal masses ^[2,3].

Anterior mediastinal tumors include thymoma and thymic cyst, lymphoma (Hodgkin’s and non-Hodgkin’s), germ cell tumors and thyroid masses. The most common masses are thymic masses (35%) and lymphoma (25%) ^[3].

This chapter will focus on the presentation, diagnosis, and treatment of the mediastinal germ cell tumors. Germ cell tumors (GCTs) comprise a group of neoplasms that usually arise in gonadal tissue. The anterior mediastinum is the most common extragonadal location for GCTs, and accounts for 15% to 20% of all anterior mediastinal masses. These tumors are divided into benign and malignant lesions (Table 1) ^[4].

Benign mediastinal teratoma accounts for 60% of mediastinal GCTs. Malignant mediastinal GCTs are divided into seminomatous and nonseminomatous tumors, with seminomas accounting for 40% of these tumors and nonseminomas accounting for 60%. Nonseminomas include embryonal cell carcinoma, choriocarcinoma, yolk sac tumors, and teratocarcinomas^[5].

Table 1. Histology in GCTs

I. Benign teratomas

Mature teratoma

Grade 0 – All component tissues appear well differentiated

Grade 1 – Occasional microscopic foci contain incompletely differentiated tissues, not exceeding 10% of the sampled surface

Immature teratoma, benign

Grade 2 – Immature tissues make up between 10-50% of sampled tumor surface

Grade 3 – Over half of the surface examined is composed of undifferentiated tissues of uncertain metastatic potential

II. Malignant teratomas

With areas of germ cell tumor

Germinoma (seminoma, dysgerminoma)

Emberyonal carcinoma

Choriocarcinoma

Yolk salc tumor

Mixed (any combination of the above)

With nongerminal malignant tumor pattern

carcinoma

sarcoma

Malignant embryonal tumor

Mixed

Immature teratomas, malignant

Metastatic teratoma

Symptoms

Primary mediastinal seminomas are typically slow growing and can be very bulky by the time they cause discomfort. The majority (75%) are symptomatic at the time of diagnosis.

The common presenting symptoms with mediastinal seminoma are ^[10]:

Chest pain – 39%
Dyspnea – 29%
Cough – 22%
Weight loss – 19%
Superior vena cava syndrome – 12%
Fever – 6%
Nausea – 6%

The majority of mediastinal seminomas have metastasized by the time they are detected, most often to the lymph nodes and less commonly to lungs, bone, and/or liver.

Most patients with mediastinal nonseminomatous GCTs are symptomatic at presentation ^[8].

Presenting symptoms of the nonseminomatous GCTs include ^[10]:

Chest pain – 52%
Dyspnea – 47%
Cough/hemoptysis – 28%
Hoarsenes – 14%
Superior Vena Cava Syndrome – 14%
Pleural effusion – 14%
Fever – 9%

Other symptoms of GCTs include paraneoplastic syndromes such as:

Paraneoplastic autoimmune encephalitis (anti N-methyl-D-aspartate (NMDA) and anti Ma2 antibodies)^[11]
Gynecomastia can be seen in tumors with foci of choriocarcinoma that secrete large amounts of hCG.
Precocious puberty ^[12]
Paraneoplastic inflammatory myopathies (dermatomyositis and polymyositis)^[13]

Diagnostic Workup

The initial diagnostic workup may vary, but most patients usually present with a symptom that leads to chest imaging. Chest radiographs will demonstrate the silhouette of an anterior mediastinal mass. However, in the current era the vast majority of patients will have undergone imaging with computed tomography. Serum α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-HCG) may both be increased in cases of non-seminomatous germ cell tumors. Lactate dehydrogenase (LDH) is less specific. Patients with pure seminoma have normal AFP and usually a mild elevation of β-hCG. A pure nonseminomatous GCT may have elevated AFP (in 50%) and/or β-hCG (also in approximately 50%). Elevated AFP is most closely associated with yolk sac tumors, whereas elevation of hCG is more closely associated with choriocarcinomas (Table 2) ^[5].

Magnetic Resonance Imaging (MRI) may be helpful to further elucidate great vessel involvement. Positron emission tomography with computed tomography (PET-CT) is also often performed on a case by case basis ^[6]. The vast majority of patients are diagnosed between a combination of imaging and serum markers. Biopsy (either CT-guided or surgical in rare cases where percutaneous biopsy is not feasible) may be obtained to secure cytologic diagnosis.

Table 2. Serum markers in GCTs

	AFP	ß-HCG
Seminoma	–	+/-
Yolk sac	↑	–
Choriocarcinoma	–	↑
Teratocarcinoma	↑	↑

Management

The treatment of mature mediastinal teratomas is surgical excision, and this is almost always curative since mature teratomas are relatively insensitive to both chemotherapy and radiotherapy. For patients with immature teratomas, recommended treatment is cisplatin-based chemotherapy followed by complete surgical resection ^[15].

The differentiation between the seminomatous and nonseminomatous germ cell tumors has important prognostic and therapeutic implications. The primary treatment for mediastinal seminomas is cisplatin-based chemotherapy. Response rates are higher with approximately 80% of patients cured with chemotherapy. Residual masses with PET activity and histopathologic residual cancer after treatment of seminoma may be surgically resected if possible in preference to radiation therapy. The optimal treatment of a residual mass remains debatable^[8].

Nonseminomas are treated with three-drug chemotherapy (etoposide, ifosfamide, and cisplatin). Surgical resection was reserved for a residual mass after treatment that was associated with normalization of serum markers. Researchers at Indiana University reviewed their 25-year experience with treated mediastinal nonseminomatous germ cell tumors in 158 patients. With a median follow-up of 34 months, they reported a 62% overall survival^[9].

Surgical resection of residual disease is typically planned 4 to 6 weeks following chemotherapy. Common surgical approaches are median sternotomy, clamshell with transverse sternotomy, anterolateral thoracotomy, or sternotomy combined with separate thoracotomy, to optimize exposure of technically difficult areas anticipated during surgery. Surgical removal involves en bloc dissection of the residual mass and surrounding involved structure with an ultimate goal of obtaining an R0 resection. Patients with extensive great vessels, middle mediastinal involvement may be precluded from safe surgical resection^[14].

Controversies/limitations

Treatment approach for the seminomatous and nonseminomatous germ cell tumors has been debatable in the past recent years especially for residual tumor cases. The advancement in new radiotherapy and chemotherapy augmented the controversy.

Recent studies have suggested surgical resection for residual nonseminomatous germ cell tumors appear to be improved with the use of chemotherapy regimens even in patients with poor but possible long-term survival, which justifies an aggressive surgical approach in patients who are deemed operable. Such studies have limitations such as small study size or complicated metastatic disease that poorly responded to chemotherapy.

Summary

Extragonadal germ cell tumors (GCTs) are rare tumors that most frequently arise in the mediastinum and retroperitoneum, most commonly in adult males.
Mediastinal GCTs include mature teratomas, immature teratomas, seminomas, and nonseminomatous GCTs.
Common presenting symptoms are chest pain, dyspnea, cough, weight loss, superior vena cava syndrome, fever, or nausea.
Most patients will have undergone imaging with computed tomography.
There are no randomized trials to guide treatment in patients with mediastinal or retroperitoneal GCTs. The evidence supporting therapeutic recommendations is based upon observational series and experience.
In patients with a mature teratoma of the mediastinum, complete surgical resection is indicated. Partial resection should be limited to patients in whom a complete resection is not technically feasible. Mature teratomas are relatively insensitive to both chemotherapy and radiation therapy.
For patients with a mediastinal seminoma, it is suggested to treat with cisplatin-based chemotherapy rather than radiotherapy or surgery as a first line treatment.
For patients with a mediastinal nonseminomatous, the current recommended first line treatment is chemotherapy and surgery is reserved for residual tumors.

References

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