Extragonadal Germ Cell Tumors 

Updated: Sep 10, 2018
Author: Kush Sachdeva, MD; Chief Editor: E Jason Abel, MD 

Overview

Practice Essentials

Extragonadal germinal cell tumors (EGGCTs) are rare tumors that predominantly affect young males. Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) account for 60-70%. Nonseminomatous germ cell tumors include the following:

  • Yolk-sac tumors
  • Embryonal carcinomas
  • Choriocarcinomas
  • Teratomas
  • Nonteratomatous combined germ cell tumors

The most common site of extragonadal germ cell tumors is the mediastinum (50-70%) followed by the retroperitoneum (30-40%), the pineal gland (5%), and the sacrococcygeal area (less than 5%).

Pathology of postchemotherapy residual masses reveals necrosis in 24%, teratoma in 45%, sarcoma in 5%, and viable germ cell cancer in 26%. However, the smaller the residual mass, the lower the chance that it harbors viable tumor cells.

The only known risk factor for extragonadal germ cell tumors is Klinefelter syndrome (47XXY), which is associated with mediastinal nonseminomatous germ cell tumors, which are characterized by their location on the midline from the pineal gland to the coccyx.[1, 2] In extragonadal germ cell tumors, no evidence of a primary malignancy is present in either the testes or ovaries by radiologic imaging or physical examination.

Extragonadal germ cell tumors can produce a wide range of clinical manifestations; on the other hand, they may attain large volumes if they arise in silent areas. Histologically, they mirror their gonadal counterparts, with which they share the same chemosensitivity and radiosensitivity. Modern approaches to diagnosis and treatment can result in high rates of long-term survival and even cure.

Pathophysiology

Controversy remains regarding the origin of extragonadal germ cell tumors. These tumors can be found anywhere on the midline, particularly the retroperitoneum, the anterior mediastinum, the sacrococcyx, and the pineal gland. Other less common sites include the orbit, suprasellar area, palate, thyroid, submandibular region, anterior abdominal wall, stomach, liver, vagina, and prostate. The classic theory suggests that germ cell tumors (GCTs) in these areas are derived from local transformation of primordial germ cells misplaced during embryogenesis.

A recent alternative theory suggests that primary mediastinal presentations represent reverse migration of occult carcinoma in situ (CIS) lesions in the gonad; hence, they may be gonadal in origin. According to this theory, the differences in phenotypes expressed by mediastinal germ cell tumors (MGCTs) and gonadal germ cell tumors may be explained by differences in the cellular environment between the gonad and the anterior mediastinum. Some retroperitoneal extragonadal germ cell tumors may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the primary tumor.

To explain the origin of occult carcinoma in situ cells, 2 models have been proposed. The first suggests that fetal gonocytes whose development into spermatogonia is blocked may undergo abnormal cell division and then invasive growth mediated by postnatal and pubertal gonadotrophin stimulation.

 The second model postulates that the most likely target cell for transformation is the zygotene-pachytene spermatocyte. During this stage of germ cell development, aberrant chromatid exchange events associated with crossing over can occur. Normally, these cells are eliminated by apoptosis. In occasional cells, this crossing over may lead to increased 12p copy number and overexpression of cyclin D2. The cell carrying this abnormality is relatively protected against apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of cell cycle and genomic instability.

Malignant transformation of germ cells is the result of a multistep process of genetic changes. One of the earliest events is the increased copy number of 12p, either as 1 or more copies of i(12p)—an isochromosome of the short arm of chromosome 12—or as tandem duplications of chromosome arm 12p.[3] This abnormality is found in occult carcinoma in situ lesions as well as more advanced disease. Further studies indicate that the CCND2 gene is present at chromosome band 12p13 and CCND2 is overexpressed in most GCTs, including CIS. Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S checkpoint.

Hematologic malignancies are frequently associated with mediastinal germ cell tumors.[4] Embryologically, hematopoietic stem cells arise in the yolk sac. Highly differentiated yolk-sac tumors make up 30% of mediastinal germ cell tumors, providing a possible basis for this association.

The balance of the p53-mdm2 interaction has been shown to be disrupted in intracranial germ cell tumors (ICGCTs), in which mdm2 sequesters p53 and inhibits its function as G1-S checkpoint controller and apoptosis inducer. In normal cells, mdm2 availability is controlled by ARF, the product of the p14ARF gene located on INK4a/ARF locus, which binds with mdm2 and induces its degradation.[5] Mutation of ARF, reported in 71% of intracranial germ cell tumors, results in mdm2 accumulation and functional impairment of p53. This abnormality was reported in 90% of seminomatous and 55% of nonseminomatous intracranial germ cell tumors (NS-ICGCTs) examined.

 

Epidemiology

Frequency

United States

Extra-gonadal germ cell tumors (EGGCTs) represent 5-10% of all germ cell tumor (GCTs) with an incidence around 1/ in 1,000,000 population.[6]

International

In Norway, a study by Dueland et al estimated the incidence of extra-gonadal germ cell tumor (EGGCTs) at 0.5 per 100,000 population per year.[7] This represents about 2% of the number of testicular cancers reported for the same period. Intracranial germ cell tumors represent 0.3-3.4% of primary intracranial tumors in Western countries and 2.1-12.7% in Japan.[8] In Germany, Rusner et al studied more than 16,000 patients with malignant GCTs from 1998-2008. They concluded that differences in age-specific and age-standardized incidence rates may be the result of different etiologies.[9]

Sex

In children, benign and malignant extragonadal germ cell tumors (EGGCTs) occur equally in males and females. In adults, only benign extragonadal germ cell tumors (teratomas) occur at equal frequency in both sexes; more than 90% of malignant extragonadal germ cell tumors occur in males.

Age

Extragonadal germinal cell syndromes are rare tumors that predominantly affect young males. Pediatric germ cell tumors (GCTs) account for approximately 3.5 % of cancers in children under the age of 15 years and increase in frequency to 16 % among 15- to 19-year-olds. Up to one-third are extragonadal neoplasms and the most common sites are the sacrococcygeal or retroperitoneal region, and the pineal gland.[10]  

 

Prognosis

A classification system developed by the International Germ Cell Collaborative Group (IGCCG) categorizes germ cell tumor (GCT) risk on the basis of the following11:

  • Histologic type (seminomas have a better prognosis than nonseminomas)
  • Localization of metastases (retroperitoneal and testicular portend better prognosis than mediastinal and intracranial)
  • Initial serum alpha fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH) levels (the higher the tumor marker levels, the worse the effect on survival)

For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported. Extragonadal seminomas carry the best survival rates.[6]  Overall survival of patients with seminomatous extragonadal GCTs has been reported to range from 88%-100%, whereas suvival of patients with mediastinal nonseminomatous extragonadal GCTs is 40-45%.[11, 12]  

Patients with mediastinal GCTs have a poor prognosis owing to at least the following 3 factors: mediastinal germ cell tumors are not as sensitive as other germ cell tumors to chemotherapy, bulky disease increases the risk of poor outcome in the short term owing to respiratory failure, and hematologic malignancies are linked to a very unfavorable prognosis.

Mortality due to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal germ cell tumors (NS-EGGCTs).

Nonseminoma

Ganjoo analyzed the data from 75 patients treated at Indiana University for nonseminomatous mediastinal germ cell tumors (NS-MGCTs) with chemotherapy followed by surgery. Tumor marker elevation prior to or after chemotherapy was not found to be an independent prognostic variable for survival. However, the presence of visceral metastases and especially postchemotherapy pathology were the most important predictors of survival.[13]

Good prognosis is indicated by all of the following:

  • Testis/retroperitoneal primary

  • No nonpulmonary visceral metastases

  • Good tumor marker levels - AFP < 1000 ng/mL, β-hCG < 1000 IU/L, and LDH < 1.5 times the upper limit of normal

These features are found in 56% of nonseminomas, which have a 5-year progression-free survival rate (PFS) of 89% and 5-year survival rate of 92%.

Intermediate prognosis is indicated by all of the following:

  • Testis/retroperitoneal primary

  • No nonpulmonary visceral metastases

  • AFP between 1000 and 10,000 ng/mL, β-hCG between 5000 and 50,000 IU/L, or LDH between 1.5 and 10 times the upper limit of normal

These features are found in 28% of nonseminomas, which have a 5-year PFS of 75% and 5-year survival rate of 92%.

Poor prognosis is indicated by any of the following:

  • Mediastinal primary

  • Nonpulmonary visceral metastases

  • Poor markers -  AFP >10,000 ng/mL, β-hCG >50,000 IU/L, or LDH >10 times the upper limit of normal

These features are found in 16% of nonseminomas, which have a 5-year PFS of 41% and 5-year survival rate of 48%

Seminoma

No patients with seminoma are classified as having a poor prognosis. Good prognosis is indicated by the following:

  • Any primary site

  • No nonpulmonary visceral metastases

  • Normal AFP, any β-hCG, any LDH

These features are found in 90% of seminomas, which have a 5-year PFS of 92% and 5-year survival rate of 88%

Intermediate prognosis is indicated by the following:

  • Any primary site

  • Nonpulmonary visceral metastases

  • Normal AFP, any β-hCG, any LDH

These features are found in 10% of seminomas, which have a 5-year PFS of 67% and 5-year survival rate of 72%

 

 

Presentation

History

Symptoms vary depending on the site and the size of the tumor. Those arising in nonvital organs can reach large sizes before becoming symptomatic, but small tumors may result in significant symptoms if they obstruct, compress, or rupture into important structures.[14]

Mediastinal germ cell tumors

The mediastinum is the most common site of extragonadal germ cell tumors. Mediastinal germ cell tumors account for only 2-5% of all germinal tumors, but they constitute 50-70% of all extragonadal tumors. Mediastinal germ cell tumors account for 1-15% of adult anterior mediastinal tumors. Mature teratomas represent 60-70% of mediastinal germ cell tumors.

Malignant mediastinal germ cell tumors (30-40%) are divided between seminomas (40%) and nonseminomatous germ cell tumors (60%). Although 90-100% of malignant germ cell tumors are symptomatic, only 50% of teratomas produce symptoms. Nonseminomatous mediastinal germ cell tumors (NS-MGCTs) are faster growing and metastasize earlier than mediastinal seminomas.

Although their incidence peaks in the third decade, several cases have been reported in patients older than 60 years.

Patients with mediastinal germ cell tumors may present with the following (in decreasing order):

  • Chest pain (39%)
  • Dyspnea (29%)
  • Cough (22%)
  • Weight loss (19%)
  • Superior vena cava syndrome (12%)
  • Nausea (6%)
  • Fever (6%)
  • Postobstructive pneumonia
  • Weight loss
  • Night sweats
  • Dysphagia
  • Shoulder or arm pain
  • Vocal cord paralysis
  • Hoarseness

In one third of patients the anterior mediastinal mass is an incidental finding on a routine chest radiograph (in most of these cases, a benign tumor is found).

Metastases to locoregional lymph nodes or to distant sites, such as the lungs, liver, or bone, may be present in 20-50% of cases on presentation. Distant metastases are seen only in malignant mediastinal germ cell tumors.

Mature teratoma rupture, teratoma with malignant transformation, and hematologic malignancies may complicate mediastinal germ cell tumors (see Complications).

Retroperitoneal germ cell tumors

The retroperitoneum is the second most common site of extragonadal germ cell tumors (30-40%), after the mediastinum. Retroperitoneal germ cell tumors (RGCTs) represent 10% of all malignant primary retroperitoneal tumors.

Many patients with retroperitoneal germ cell tumors present late, after their tumors have reached large dimensions. Presenting symptoms are abdominal mass with or without pain, backache, and weight loss. Loss of ejaculation was reported in one case.

Intracranial germ cell tumors

Very rare tumors of the adolescent and young adult, intracranial germ cell tumors (ICGCTs) are localized preferentially to the pineal and suprasellar regions. However, other midline structures can be involved. Although seminomas (60% of intracranial germ cell tumors) have a predilection for the suprasellar region, embryonal carcinomas, yolk-sac tumors, and choriocarcinomas mainly occur in the pineal region.

Patients with pineal tumors present with headache, nausea, and vomiting because of increased intracranial pressure; they require early ventriculoperitoneal (VP) shunting. Deterioration of intellectual functions, gait abnormalities with frequent falls, and sphincteric incontinence are common. Choreic movements and ataxia of the limbs with spastic weakness appear in later stages of Parinaud syndrome.

In suprasellar tumors, precocious pseudopuberty, diabetes insipidus with or without anterior pituitary dysfunctions (eg, adrenocorticotropic hormone [ACTH] deficiency), central hypothyroidism, growth hormone (GH) deficiency, and hypogonadism may be seen. Decreased visual acuity, visual field defect, diplopia, obesity, psychosis, and obsessive-compulsive symptoms have also been reported.

A case of primary spinal seminoma has been reported in a patient with Klinefelter syndrome.[15]

Sacrococcygeal germ cell tumors

In the literature to date, 17 cases have been reported. Pain and bowel habit change are the main symptoms. Severe arthropathy of peripheral joints and evidence of hypertrophic osteoarthropathy were reported in one case.

Extragonadal germ cell cancer syndrome

Midline fast-growing tumors (eg, of the mediastinum, retroperitoneum) occur in young males. Histologically, these tumors are poorly differentiated carcinomas with atypical features.

The germ cell origin of these tumors is suggested by the typical abnormalities of chromosome 12 and the elevation of beta human chorionic gonadotropin (bhCG) and/or alpha-fetoprotein (AFP).

Physical Examination

Mediastinal germ cell tumors (MGCTs) may be silent. Dullness caused by atelectasis or pleural effusion and localized wheezes because of airway compression may be present. A large abdominal mass may be palpated in retroperitoneal germ cell tumors (RGCTs).

In suprasellar intracranial germ cell tumors (ICGCTs), decreased visual acuity and visual field defects, obesity, or signs of endocrine deficiencies may be present.

In pineal tumors, Parinaud syndrome (ie, paralysis of conjugate upward gaze, slightly dilated pupils that react on accommodation but not to light, with a lesion at the level of the superior colliculi) can be present. Gait abnormalities, papilledema, and grasp reflex because of hydrocephalus are present variably. Plantar reflexes are sometimes extensor.

Assess neuropsychologic status in children before they undergo cranial radiation and at regular intervals thereafter.

Perform formal visual examination in patients with suprasellar/hypothalamic tumors.

Complications

Growing teratoma syndrome is the increase in tumor size during or after chemotherapy for mediastinal germ cell tumors (MGCT) or retroperitoneal germ cell tumors (RGCT) in which histologic analysis of the resected tumor specimen shows only mature teratoma.[16]  A mature teratoma component is present in the majority of the primary tumors (86%). The major risk factor for this complication is the completeness of the surgical resection of the primary tumor because it was seen in only 4% of the patients who underwent complete resection compared to 83% of those patients who had partial resection. Complete surgical resection is the treatment of choice.

Rupture of a mature teratoma as a result of the digestive enzymes secreted by intestinal mucosa or pancreatic tissue into the bronchi or lung may result in hemoptysis[17]  or expectoration of hair or sebum. Rupture into the pleura or pericardium leads to pericardial or pleural effusion.

Teratoma with malignant transformation is a rare complication of mediastinal germ cell tumors. The most common transformations are into different kinds of sarcomas, glioblastomas, nephroblastomas, neuroblastomas, adenocarcinomas, and hematologic malignancies.

The incidence of hematologic malignancies in patients with nonseminomatous mediastinal germ cell tumors (NS-MGCTs) is 200- to 300-fold higher than in matched controls. The median time from the diagnosis of the germ cell tumors (GCTs) to the diagnosis of the hematologic malignancy is 6 months (range 0-47 mo). Acute myelogenous leukemia and myelodysplasia with megakaryocyte lineage abnormalities are the most common disorders.

Patients present with pancytopenia, isolated thrombocytopenia, splenomegaly, and/or hepatomegaly. Flushing and syncope are suggestive of systemic mastocytosis, another unusual hematologic malignancy complicating mediastinal germ cell tumors.

The clinical course is very aggressive, with a median survival of 5 months. Predictors of the subsequent occurrence of leukemia are mediastinal localization of the germ cell tumors and endodermal sinus tumor and teratocarcinoma histologic types. Bone marrow biopsy should not be delayed if cytopenia persists or recurs after the initial chemotherapy period.

 

DDx

Diagnostic Considerations

The differential diagnosis includes the following:

  • Mediastinal germ cell tumors
  • Thymic tumors
  • Mesenchymal tumors
  • Lymphomas
  • Neurogenic tumors
  • Retroperitoneal germ cell tumors
  • Soft tissue sarcoma
  • Poorly differentiated carcinoma
  • Intracranial germ cell tumors
  • Pinealoma (pinealocytoma and pinealoblastoma)
  • Glioma

Differential Diagnoses

 

Workup

Laboratory Studies

The tumor markers serum alpha fetoprotein (AFP) and/or the beta subunit of human chorionic gonadotropin (β-hCG) are elevated in extragonadal nonseminomatous germ cell tumors. These tumor markers provide diagnostic, staging, and prognostic information. Check these levels before and then at regular intervals after therapy.

Choriocarcinoma, embryonal carcinoma, and a minority of seminomas (< 10%) produce β-hCG. Neoplasms with which β-hCG elevation can be seen are prostate, bladder, ureteral, and renal cancers. The levels of β-hCG in the cerebrospinal fluid of patients with primary intracranial germ cell tumors (ICGCT) are elevated more frequently than in the plasma before treatment and become detectable prior to any increase of the serum values in case of relapse.

Serum AFP elevations are seen in yolk-sac tumors and embryonal carcinoma. Pure seminomas and pure choriocarcinomas do not produce AFP. Pregnancy, hepatocellular carcinoma, cirrhosis, and hepatitis also may be associated with increased levels of serum AFP.

The half-life of β-hCG is 24 hours, and that of AFP is 4-6 days.

AFP, β-hCG, or both are elevated in approximately 85% of extragonadal nonseminomatous germ cell tumors. Small increases in serum β-hCG can be seen in up to 50% of patients with disseminated seminoma.

Lactate dehydrogenase (LDH) is a nonspecific marker. Its level correlates well with the tumor burden and with the number of copies of the i(12p) isochromosome of the short arm of chromosome 12.

Placental alkaline phosphatase is used in some centers as a marker and is useful in the immunohistochemical characterization of midline tumors.

Cytogenetic analysis of patients with mediastinal germ cell tumors (MGCTs) reveals trisomy 8 in 16% of cases and Klinefelter syndrome (XXY) in 14-20% of cases. However, the most common karyotype abnormality is i(12p), present in 38% of patients. The presence of this abnormality helps identify midline germ cell tumors presenting as poorly differentiated carcinomas with atypical features.

Obtain baseline evaluation of pituitary function (ie, thyroid-stimulating hormone, cortisol, growth hormone, follicle-stimulating hormone, luteinizing hormone, prolactin) before treatment and then at regular intervals in patients with intracranial germ cell tumors.

Evaluation of blood counts, liver function, and kidney function before therapy and after recovery is necessary.

Imaging Studies

Testicular ultrasound

This should be ordered whenever a malignant germ cell tumor is diagnosed to rule out a gonadal primary site.[18]

Computed tomography of the chest, abdomen, and pelvis

On computed tomography (CT) scans, mature teratomas appear as heterogeneous cystic, well-defined, anterior mediastinal masses with walls of different thicknesses. Calcifications are present in approximately one quarter, with a bone or a tooth rarely identifiable. The combination of fluid, soft tissue, calcium, and/or fat attenuation in an anterior mediastinal mass is highly specific for mature teratoma.

Seminomas present as bulky, lobulated, homogeneous, anterior mediastinal masses. Although invasion of adjacent organs is uncommon, metastases to regional lymph nodes and bone can be seen. Calcifications are rare.

Nonseminomatous mediastinal germ cell tumors (NS-MGCTs) appear as irregular, anterior mediastinal masses, often with extensive, central heterogeneous areas of low attenuation caused by necrosis, hemorrhage, and/or cyst formation. Adjacent organ involvement and metastases to regional lymph nodes as well as to distant sites may occur.

Chest x-ray

Chest x-ray films show enlargement of the mediastinum on the anteroposterior view. The lateral view reveals the anterior location of the mass.

Brain Imaging

CT scan or magnetic resonance imaging (MRI) of the brain shows pineal seminoma as a discrete mass that usually reaches 3-4 cm in diameter. It compresses the superior colliculi and sometimes the superior surface of the cerebellum and narrows the sylvian aqueduct. Obstructive hydrocephalus may be evinced by the presence of dilated ventricles and interstitial edema.

Positron emission tomography (PET)

Early published studies that compared positron emission tomography (PET) with CT for the evaluation of patients with newly diagnosed disease or residual germ cell neoplasms after chemotherapy suggested that PET may be more sensitive than CT, although PET did not detect tumors smaller than 0.5 cm.[19, 20, 21] In patients with nonseminomatous germ cell tumors (NSGCT), PET has not been consistently able to identify residual viable malignant germ cell tumors (GCTs) and also does not detect teratoma. One study has shown that PET is useful in the detection of residual viable seminoma in patients with masses larger than 3 cm in diameter after chemotherapy.[22]

Other Tests

Biopsy of the tumor mass

Histologic confirmation of germ cell tumors (GCTs) may be obtained by open biopsy of an abdominal mass, anterior median sternotomy of a mediastinal mass, and neuroendoscopy of a pineal tumor. Fine-needle aspiration frequently establishes the diagnosis, obviating open biopsy.[23] Pathologic studies help determine the histologic subtype, the presence of non–germ cell elements, or the rare cases of marker-positive non–small cell lung cancer.

Tumor marker elevation in the appropriate clinical setting makes the diagnosis of germ cell tumors highly likely.[24] Chemotherapy can be initiated in these cases without tissue diagnosis if a need for immediate treatment is present.

Histologic Findings

Extra-gonadal germ cell tumor (EGGCTs) show the same histologic features as gonadal germ cell tumors (GCTs).

Staging

Clinical staging of mediastinal germ cell tumors (MGCT) is as follows:

  • Stage I - Well-circumscribed tumor with or without focal adhesions to the pleura or pericardium but without microscopic evidence of invasion into adjacent organ

  • Stage II - Tumor confined to the mediastinum with macroscopic and/or microscopic evidence of infiltration into adjacent structures

  • Stage III - Tumor with metastases; stage IIIA is with metastases to intrathoracic organs, stage IIIB is with extrathoracic metastases

Pediatric Oncology Group/Children's Cancer Group Staging for Malignant Extragonadal Germ Cell Tumors is as follows:

  • Stage I - Complete resection at any site; coccygectomy for sacrococcygeal site; negative tumor margins; tumor markers positive or negative

  • Stage II - Microscopic residual; lymph nodes negative; tumor markers positive or negative

  • Stage III - Gross residual or biopsy only; retroperitoneal nodes negative or positive; tumor markers positive or negative

  • Stage IV - Distant metastases, including liver

 

Treatment

Approach Considerations

Treatment modality is determined by the site and the histologic type of the primary tumor. Seminomas are very sensitive to chemotherapy and radiotherapy. Nonseminomatous germ cell tumors (NS-GCTs) are less sensitive to these modalities and may require surgery for resection of a postchemotherapy residual mass. Prior to the availability of cisplatin-based chemotherapy, cure rates for nonseminomatous germ cell tumors were less than 10%. Mature teratomas are relatively insensitive to both chemotherapy and radiation therapy; therefore surgery is the only treatment.

Medical Care

Mediastinal germ cell tumors (MGCTs)

Cisplatin-based chemotherapy has made a significant improvement in treatment of seminoma of the mediastinum.[25] Treatment with four cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy can be used after chemotherapy in bulky mediastinal seminomas.[26]

In nonseminomatous mediastinal germ cell tumors (NS-MGCT), four cycles of bleomycin, etoposide, and cisplatin also are recommended. If the serum tumor markers remain elevated, give salvage chemotherapy. If the CT scan shows residual disease with or without tumor marker elevation, perform surgical resection followed by two cycles of chemotherapy. The nature of the salvage and postsurgical chemotherapy remains debated. Intensive cisplatin-based chemotherapy followed by resection of residual tumor was shown to yield survival rates of 48-73% in nonseminomatous mediastinal germ cell tumors.

Walsh et al reported on the experience at M.D. Anderson Cancer Center over 5 years with 20 patients treated for nonseminomatous mediastinal germ cell tumors. Of those treated, 11 patients had received no prior chemotherapy, and 9 patients were referred following treatment at other facilities for salvage therapy after progression of their tumors.[27]

Patients received combination chemotherapy with alternating sequential courses comprising, first, bleomycin, vincristine, and cisplatin (BOP); followed in 7 days by cisplatin, cyclophosphamide, doxorubicin (Adriamycin) (CISCA); followed in 14 days by cisplatin, vincristine, methotrexate, and bleomycin (POMB); followed in 10 days by actinomycin, cyclophosphamide, and etoposide (ACE).

In addition to this regimen, etoposide, ifosfamide, and cisplatin (VIP) were also used in the salvage group. Major toxic effects occurred in all these patients, including neuropathy, ototoxicity, mucositis, cytopenias, and renal toxicity. The 2-year survival rate of the entire group was 58%. However, the 2-year survival rate for the previously untreated group was 72%, whereas it was 39% for the salvage group.

Intensification of the chemotherapy was achieved by decreasing the interval between cycles and by alternating drugs from course to course. This was made possible by the systemic use of hematopoietic growth factors. Stem cell rescue has been used in certain centers to achieve dose intensification.

The 5-year overall survival of patients with seminomatous and non-seminomatous EGCT was 100% and 44%, respectively in a study of patients treated with cisplatin-based combination chemotherapeutic regimens followed by a multimodal strategy that included high-dose chemotherapy, aggressive surgery, and early salvage chemotherapy.[12]

Analysis of data from 75 patients treated at Indiana University for nonseminomatous germ cell tumors showed that of those treated, 48 patients received BEP, 9 patients received VIP, 9 patients received VIP/Velban (vinblastine) and bleomycin (VeB), and the rest were treated with different cisplatin-containing regimens. No significant difference in survival was reported between those who received BEP and those who received VIP.  Of the 62 patients (58%) who underwent surgical resection of a residual mass, 36 are long-term survivors. Overall survival rate for the group is 48%. None of the 17 patients whose disease relapsed after or progressed on first-line chemotherapy and surgery could achieve complete remission despite salvage therapy with cisplatin-based regimens, high-dose chemotherapy, paclitaxel, or oral etoposide.[28]

Intracranial germ cell tumors (ICGCTs)

The standard treatment for intracranial germ cell tumors has been radiotherapy, either alone (seminomas) or in combination with chemotherapy (nonseminomatous germ cell tumors). A wide range of survival rates (37-100%) is reported after radiation. However, because of its long-term toxicity, attempts are made to use lower doses of craniospinal irradiation (CSI) in combination with chemotherapy. Regardless of the type of the initial treatment, combined modality therapy comprising radiation and chemotherapy is the recommended salvage therapy for relapse.

Radiation therapy varies in intensity from craniospinal irradiation (CSI) with boost (the most intense), to whole brain irradiation with boost, ventricular irradiation with boost, and focal irradiation alone (the least intense).

Event-free survival rate (EFS) of 90% for patients with seminomas who received only CSI was reported by Calaminus et al.[29] Chemotherapy alone resulted in an EFS of 53%, although the follow-up period was short and the number of patients was limited in this group. Patients receiving combined modality achieved an EFS of about 92%. In nonseminomas, EFS was affected by the cumulative dose of cisplatin. Patients who received a cumulative dose of 400 mg/m2 had an EFS of 86%. Those who received 200 mg/m2 had a significantly lower EFS, 56%. The two groups were observed for 46 and 65 months, respectively.

Balmaceda and colleagues reported on 71 patients treated by chemotherapy alone for intracranial germ cell tumors (45 seminomas and 26 nonseminomatous germ cell tumors). Diagnosis was established by resection (approximately 50% of patients) or biopsy. Patients were evaluated after four cycles of carboplatin, etoposide, and bleomycin. If complete response (CR) was achieved, two more cycles were given.

Surgery alone resulted in three CR. Of 68 patients, 39 achieved CR after chemotherapy alone. Of the 29 patients with partial response (PR), 10 achieved CR with intensified chemotherapy and 3 more after second surgery, bringing the number of CRs to 55 (78%). Although response to chemotherapy was not affected by the histologic type (81% for nonseminomas vs 82% for seminomas), long-term survival differed significantly by histologic type (84% for seminomas vs 62% for nonseminomas). Treatment mortality rate was 10%.[30]

The optimal role for surgery remains to be defined. Because of the risk of intraspinal metastases related to surgery or even to stereotactic biopsy, a sandwich protocol using preoperative chemotherapy, followed by surgery, then postoperative chemotherapy was suggested. Surgery is indicated only if a residual mass is present after chemotherapy. Such a protocol uses BEP preoperatively and VIP postoperatively. The tumor marker elevation in nonseminomatous germ cell tumors obviates the need for surgical biopsies.

Third ventriculostomy via neuroendoscopy can be performed to drain obstructive hydrocephalus. This procedure prevents peritoneal seeding related to VP shunt.

Retroperitoneal germ cell tumors (RGCTs)

Primary chemotherapy with four cycles of bleomycin, etoposide, and cisplatin (BEP) is recommended for both seminomas and nonseminomas, with excision of residual mass in nonseminomas.

Pectasides reported on 16 patients with retroperitoneal germ cell tumors, 11 with nonseminomatous germ cell tumors, and 5 with seminomatous germ cell tumors.[31] Cisplatin-based (or carboplatin-based) chemotherapy resulted in complete or PR in 14 patients. Ten patients underwent surgery, bringing the number of patients with CR to 14 (87.5%); nine of them are long-term survivors (56.25%).

Nichols recommends primary abdominal radiotherapy for patients with small-volume retroperitoneal seminomas (abdominal mass < 5 cm) and chemotherapy for patients with larger volume disease (abdominal mass >10 cm).[32] Patients with intermediate disease may be treated with either modality.

Sacrococcygeal germ cell tumors

Patients with sacrococcygeal germ cell tumors have a poor prognosis. Long-standing remission is attained in only 31% of patients treated with multiagent chemotherapy.

Surgical Care

Surgery is the primary and only effective modality in teratomas. It is also used as primary or secondary treatment of nonseminomatous germ cell tumors (NS-EGGCTs). The current standard of care is surgery if a residual mass is present after neoadjuvant chemotherapy. Used in this setting, chemotherapy allows translation of partial responses into complete responses and evaluation of the chemosensitivity of the tumor.

However, the size of residual mass for which surgery is indicated remains controversial. In the experience at the Memorial Sloan-Kettering Cancer Center, 5 of 20 patients underwent surgery for residual mass after receiving chemotherapy or radiotherapy for retroperitoneal seminoma. No viable seminoma was found in masses less than 3 cm. Therefore, they recommend surgical resection for residual tumors greater than 3 cm to ascertain the need for subsequent chemotherapy.

No further chemotherapy is recommended if the final pathology is consistent with mature teratoma or necrotic tissue. Additional postoperative chemotherapy is given if the patient is found to have viable tumors. Although the same chemotherapy used preoperatively may be used after surgery, it is reasonable to switch to another drug combination.

The surgical resection should include all gross disease with en bloc resection of all involved structures that can be sacrificed. Orchiectomy or testicular biopsy is not required unless testicular examination and/or ultrasound findings are suggestive or frankly abnormal.

Mediastinal germ cell tumors (MGCT): Midline sternotomy is the most common approach, followed by posterolateral thoracotomy. Partial pericardial resection is required in most cases. Thymectomy is performed routinely because the thymus is often replaced totally by tumor. Dissection of the aorta and sometimes resection of certain veins occasionally are required to achieve complete resection.

Retroperitoneal germ cell tumors (RGCT): Midline, transverse, or oblique transperitoneal approaches have been used to remove retroperitoneal germ cell tumors. Excision via a thoracoabdominal extraperitoneal approach has been suggested recently. The alleged benefits of this approach are more ready removal of the primary tumor and its possible intrathoracic extensions, avoidance of paralytic ileus, and decreased risk of ejaculatory dysfunction.

Pineal germ cell tumors: En bloc resection of the pineal mass is performed via the supracerebellar infratentorial approach.

Complications

Chemotherapy-related complications

Chemotherapy-related complications may be immediate or delayed. Nausea and vomiting became less common with the advent of 5-hydroxytryptamine 3 (5-HT3) antagonists. Postcisplatin delayed emesis is better treated by oral administration of metoclopramide, benzodiazepine, and dexamethasone for 2-4 days. A certain degree of cisplatin-related nephrotoxicity is almost always present and is cumulative. Hypomagnesemia is common, requiring supplementation for prolonged periods in some patients.

Arthralgias, myalgias, peripheral neuropathy, and paralytic ileus are common toxic effects of vinblastine. However, since replacement of vinblastine with etoposide in first-line therapy began, these complications are no longer seen. Auditory toxicity with reduced high-tone hearing may be seen after cisplatin. It rarely requires hearing aids.

Neutropenic fever and severe thrombocytopenia are relatively uncommon with etoposide and cisplatin (EP) as first-line chemotherapy. The addition of bleomycin and salvage chemotherapy results in significant increase of these complications (50%), requiring the prophylactic use of hematopoietic growth factors after the first episode of neutropenic fever.

Pulmonary toxicity from bleomycin is unpredictable and rare (10% of treated patients) and is dose- and age-dependent (rate is higher in patients >70 y and after a cumulative dose >1200 IU or 400 mg). The progression to pulmonary fibrosis is uncommon and occasionally fatal (1%). Although carbon monoxide diffusing capacity may not predict clinically significant lung damage, its use was recommended along with chest x-ray as a screening test in patients treated with bleomycin. If radiographic changes or a decrease of diffusing capacity of lung for carbon monoxide (DLCO) greater than 30% is detected, discontinue the drug. Raynaud phenomenon and, to a lesser degree, stroke and myocardial infarction were reported after use of bleomycin.

Infertility is seen in as many as 50% of patients after chemotherapy. Standard bilateral retroperitoneal lymph node dissection almost always is associated with retrograde ejaculation. Nerve-dissecting, nerve-avoiding, and posterior approaches decrease, but do not abolish, this adverse effect.

The frequency of etoposide-related secondary leukemia is dose dependent. It is seen in less than 0.5% of patients who received a total dose less than 2000 mg/m2 and in about 6% of those who received more than 3000 mg/m2. Abnormalities of chromosome band 11q23 are very common in this setting. Latency period varies from 2-4 years. The incidence of gastrointestinal malignancies, especially gastric cancers, and soft-tissue sarcomas is increased slightly after combined radiation and chemotherapy. Latency period is about 10 years or more.

Weijl et al reported a high rate of thromboembolic events (8.4%) during chemotherapy in 179 patients with germ cell tumors. Liver metastases and high-dose corticosteroids were identified as risk factors for these complications.[33]

Radiotherapy-related complications

Accelerated coronary artery disease is a well-recognized complication of mediastinal radiotherapy. 

With the achievement of prolonged survival for patients with intracranial germ cell tumors (ICGCTs), researchers became increasingly aware of long-term effects of cranial radiation on intellectual and endocrine functions. These complications are correlated with the total dose and fraction sizes of irradiation and are correlated conversely to the patient's age at the time of treatment. Concomitant chemotherapy increases the risk of toxicity.

Verbal IQs and reading skills are affected to a lesser degree than performance IQs or mathematic ability. Personality changes include anxiety, depression, lability, belligerence, hypersexuality, reduced attention span, memory problems, and reduced reasoning ability. GH deficiency with growth retardation and hypothyroidism are much more common than gonadotropin and corticotropin deficiencies. Leukoencephalopathy, hearing loss, and second malignancies (20-y cumulative probability of about 12% for the latter) are increased after cranial irradiation.

Long-Term Monitoring

Detection of late recurrences (>2 y after treatment discontinuation), development of testicular tumors several years after the initial diagnosis of extragonadal germ cell tumors (EGGCTs), and treatment-related complications justify prolonged periods of follow-up care with clinical evaluation, tumor markers, and imaging studies.

In children (and probably in adults) with intracranial germ cell tumors (ICGCTs), obtain baseline intelligence quotient (IQ) and achievement tests before starting radiotherapy. Perform follow-up intellectual assessments at 1 year after completion of radiation, then at 2, 3, and 5 years, and if any intellectual deterioration is noted. Evaluate hearing if intellectual deterioration occurs. Evaluation of thyroid, corticotropin, gonadotropin, prolactin, and GH functions is obtained before and regularly after radiation therapy.

 

Medication

Medication Summary

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Chemotherapeutic agents

Class Summary

Regardless of the tumor location and whenever chemotherapy is considered, a BEP combination (bleomycin, etoposide, and cisplatin) is the treatment of choice (BEP for 4 cycles at 3-wk intervals). VIP (etoposide, ifosfamide, and cisplatin) has been used as salvage therapy for progressive disease or as postoperative therapy following resection of residual mass containing viable tumor. Vinblastine has occasionally replaced etoposide if the latter was used in the initial regimen.

Cisplatin (Platinol)

Platinum-containing compound that exerts antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. Can react with 2 different sites on DNA to produce cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in cell it binds to DNA, resulting in interstrand and intrastrand cross-linking.

Modify dose on basis of creatinine clearance (CrCl). Avoid use if CrCl < 60 mL/min.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle. Prodrug activated by dephosphorylation.

Reduce dose in hepatic (increased total bilirubin [TB]) and renal (decreased CrCl) impairment.

Bleomycin (Blenoxane)

Glycopeptide antibiotic that acts by intercalating and binding to guanosine and cytosine portions of DNA. May induce single- or double-stranded DNA breaks by ability to form oxygen free radicals.

Test dose is optional: 1-2 U IV/IM prior to full dose.

Ifosfamide (Ifex)

Alkylating agent—2 major metabolites are produced after its activation in liver. Ifosfamide mustard, by its ability to cross-link DNA strands, responsible for therapeutic effect. Acrolein related to bladder toxicity.

Vinblastine (Velban)

Vinca alkaloid, inhibits microtubule formation, which in turn disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.

Reduce dose by 50% in patients with TB > 3 mg/dL. Dose reduction not required in impaired renal function.