Extracranial Germ Cell Tumour

Defenition: No evidence of a primary tumor in the testes or ovaries

  • Typically arise in midline
  • Adults
    • Anterior mediastinum(most common)
    • Retroperitoneum
    • Pineal and suprasellar regions
  • Infants and young children
    • Sacrococcygeal and intracranial GCTs(most common)

Histology

  • Seminoma
  • Nonseminomatous GCTs
    • Yolk sac tumors
    • Choriocarcinomas
    • Embryonal carcinomas
    • Mixed tumors
  • In women —> Dysgerminomas & nondysgerminomas
  • In children —> Germinomas & nongerminomas.
  • Klinefelter syndrome can be a risk factor
  • Extranodal GCT ==> Increase metachronus testicular GCT
    • Particularly among those with retroperitoneal location and nonseminomatous histology( x75-100)
    • Cumulative risk of developing a metachronous testicular cancer: 1-5 at 10yrs

Histogenesis

Two hypothesis:

  • From germ cells that fail to complete the normal migration along the urogenital ridge to the gonadal ridges during embryonal development.
    • This may be due to:
      • Abnormality in the primordial germ cell itself
      • Abnormality in their microenvironment
  • Germ cells transformed in the testes undergo reverse migration

DIAGNOSIS —

  • R/O primary testicular tumour
    • Ph/E and US in all patients
    • Primary mediastinal GCTs —> in the anterior mediastinum
    • Testicular GCTs rarely metastasize to the anterior mediastinum.
  • Tumor markers
  • AFP
  • beta-HCG
    • one or both are high in 85%

Mediastinal nonseminomatous GCTs are more likely to result in pronounced elevations of serum AFP and less likely to result in elevations of beta-hCG compared to gonadal and retroperitoneal nonseminomatous GCTs.

Chance of high marker

AFP beta-HCG
Mediatinal NSGCT 75% 40%
retroperitoneal NSGCT 50% 75%
Extragonadal Seminoma None 30%*
  • small rise!

Association with other malignancies

  • Mediastinal nonseminomatous GCTs —> can transform to sarcoma and carcinoma!
    • Particularly those with teratomatous elements
    • Highly resistant to Chemo and RT
  • High incidence of a number of hematologic disorders
    • x250!
    • 6% over 3years!
    • Acute megakaryoblastic
    • AML
    • Myelodysplasia
    • Malignant mastocytosis
    • Malignant histiocytosis
  • Mediastinal seminomas are not associated with transformation into non-germ cell malignancies

Teratoma

MATURE TERATOMAS

  • Well-differentiated histologic elements
  • From at least two of the three embryonic cell layers (also known as the germinal layers)
    • Ectoderm, mesoderm, and endoderm
  • If in testis
    • Considered malignant —> treated the same as NSGCT ( have potential to mets)
  • In mediastinum
    • Generally benign —> malignant potential
    • Ususally asymptomatic
    • Grow slowly
    • Local resp symptoms
      • Chest pain, cough, SOB
  • Treatment
    • Surgical resection
      • Almost always curative!
    • Mature teratomas are relatively insensitive to both chemotherapy and radiation therapy (RT).

IMMATURE TERATOMAS

  • Rare
  • Mature elements from all three germinal layers, which are mixed with immature tissue
    • Macroscopically, immature teratomas form cystic masses with areas of hemorrhage and necrosis
  • Treatment
    • Radical resection
    • Neoadj chemo —> Four cycles of bleomycin, etoposide, and cisplatin

Mediastinal Seminoma

  • 1/3 of malignant mediastinal GCTs
  • 2 to 4 percent of mediastinal masses
  • Men
    • decade 2-4
  • Mediastinal dysgerminomas (the female counterpart to seminomas) are rare in women with histologically normal ovaries.
  • Slow growing
  • Can be very bulky
  • 75% are symptomatic
  • SVCO —> 12%
  • Rise in beta-HCG —> ~30%
  • Majority metastatic
    • Lungs, bone, and/or liver
    • Nonpulmunary mets —> poor prognosis
  • CT Chest
  • If no mets —> Good risk GCT —> OS 5yr: 90%

Chemotherapy

  • 3 cycles of cisplatin, etoposide, plus bleomycin
  • 4 cycles of etoposide plus cisplatin
    • Specially in thos who have received RT to the chest or mediastinum
      • RT ==> increases the risk of bleomycin lung toxicity
      • Or those lung disease

Radiation therapy

  • If primary chemo not tolerable
  • — In those rare patients who are not candidates for chemotherapy, primary RT (35 to 50 Gy) is an acceptable alternative strategy in the absence of bulky or metastatic disease [33]. If RT is used, the radiation portals should include the mediastinum and bilateral supraclavicular fossae. Careful treatment planning is essential to avoid unnecessary toxicity to the lungs, heart, and other surrounding tissues. Mediastinal radiation has been associated with coronary artery disease, valvular disease, diastolic dysfunction, and constrictive pericarditis. In addition, an increased frequency of late breast, esophageal, and lung cancers, as well as other malignancies, has been reported. (See "Cardiotoxicity of radiation therapy for malignancy".)

Although most patients treated with primary RT are cured, the distant relapse rate is high and the five-year disease-free survival rate is only 60 to 67 percent [19,48]. By comparison, long-term disease-free survival is achieved in roughly 90 percent of patients treated with chemotherapy [19]. Most patients who relapse following primary RT can be salvaged with chemotherapy, but there is some evidence that the overall survival rate may be higher with initial chemotherapy [49].

Surgery — In the unusual case in which a mediastinal seminoma is discovered when very small and localized, complete surgical excision may be performed, followed by adjuvant chemotherapy. In general, however, surgical resection or debulking plays no role in the initial management of seminomas because of the typical presence of bulky and/or metastatic disease [19].

Residual mass — Following chemotherapy, many patients are left with a residual mass. Most of these masses consist of necrosis or a scirrhous or desmoplastic reaction. Residual masses should not be treated with chemotherapy or RT without histologic confirmation of residual disease [50,51].

The optimal treatment of a residual mass is a subject of contention. Surgical resection is often technically difficult and may be unnecessary for masses <3 cm. As a result, many recommend surveillance for such cases [52-54]. However, residual masses ≥3 cm in diameter contain residual malignancy in up to 30 percent of cases [52-54], although not all studies have found a relationship between the size of a mass and the probability of viable seminoma [50].

Alternative approaches for masses ≥3 cm include careful monitoring with periodic CT scans and open biopsy of the mass [52,54]. One surveillance regimen that has been used is CT scan every three months the first year and every six months the second year or until normal. Further therapeutic intervention is performed only for progressive disease [52].

One study reported that positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) performed after chemotherapy is highly accurate in distinguishing benign from malignant residual masses [54], but this has not yet been confirmed, and a subsequent study reported a high false-positive rate [55]. If a PET scan is utilized, it should be obtained about two months after completion of chemotherapy. Masses showing increased FDG uptake should be completely resected, if possible, or else extensively biopsied. A positive PET scan alone is not strong enough evidence to justify additional treatment with chemotherapy or radiation therapy due to a significant false positive rate. On the other hand, the false negative rate in masses over 3 cm in size has been reported to be zero [55,56]. Thus, in a patient with a residual mass larger than 3 cm for whom a resection or open biopsy is planned, a negative PET scan provides a reasonable basis for foregoing the operation unless the mass is increasing in size.

Patients who have histologically confirmed residual viable malignancy or who develop progressive disease should generally be treated with salvage chemotherapy, but RT represents an alternative approach for selected patients.

MEDIASTINAL NONSEMINOMATOUS GCT — Nonseminomatous GCTs of the mediastinum may contain yolk sac tumor, choriocarcinoma, or embryonal carcinoma. Mixed GCTs may contain more than one cell type, as well as elements of teratoma and/or seminoma.

In contrast to gonadal nonseminomatous GCTs, mediastinal nonseminomatous GCTs infrequently contain embryonal carcinoma, whereas yolk sac tumors (either pure or mixed with other histologies) are common (picture 4). In one series of 64 cases, 60 percent were pure yolk sac tumors, 12 percent were pure choriocarcinomas, and 9 percent were pure embryonal carcinomas. (See "Pathology of mediastinal tumors".)

Mediastinal nonseminomatous GCTs are less common than seminomas or teratomas, and they carry a distinctly worse prognosis with a five year overall survival of about 40 to 45 percent [19,45]. Mediastinal nonseminomatous GCTs are always considered poor-risk GCTs. They occur far more often in men than women and usually are diagnosed between the ages of 20 and 40 years. (See "Risk stratification of metastatic testicular germ cell tumors".)

Patients with mediastinal GCTs are at risk for developing fatal hematologic disorders, which typically display a megakaryocytic lineage and share cytogenetic abnormalities with nonseminomatous GCTs. (See 'Association with other malignancies' above.)

Clinical manifestations — Most patients with mediastinal nonseminomatous GCTs are symptomatic at presentation [57,58]. Signs and symptoms may include fever, chills, weight loss, chest pain, dyspnea, and/or superior vena cava syndrome. Gynecomastia can be seen in tumors with foci of choriocarcinoma that secrete large amounts of human chorionic gonadotropin. (See "Causes and evaluation of gynecomastia".)

Most patients have an elevated serum AFP at presentation, and a sizable minority have an elevated serum beta-hCG. This pattern is so characteristic that some institutions accept an elevated AFP and beta-hCG in a young adult male with an anterior mediastinal mass as de facto evidence of an extragonadal nonseminomatous GCT, and chemotherapy is sometimes started without a tissue diagnosis. We recommend histologic confirmation in all patients if it can be safely accomplished unless the clinical scenario demands immediate treatment. Histologic confirmation is clearly required in the roughly 10 percent of patients with normal serum tumor markers.

Serial monitoring of serum AFP and beta-hCG is helpful in monitoring the response to therapy and detecting early recurrence. The suggested schedule is similar to that used in testicular nonseminomatous GCTs. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)

Treatment — Mediastinal nonseminomatous GCTs are aggressive tumors that are often metastatic at presentation [57,59]. A multimodality approach is generally used, utilizing chemotherapy initially followed by surgery to resect any residual masses.

Systemic chemotherapy — Standard initial treatment consists of four cycles of chemotherapy, as is used in patients with advanced testicular intermediate- or poor-risk GCTs. (See "Initial chemotherapy for advanced testicular germ cell tumors", section on 'Intermediate- and poor-risk advanced disease'.)

Four cycles of VIP is preferred by some oncologists for mediastinal nonseminomas because these patients will typically undergo a thoracotomy or sternotomy for resection of residual disease and may require prolonged exposure to high partial pressures of oxygen during surgery, which can provoke bleomycin-related pneumonitis. Four cycles of BEP is an alternative. Indiana University reported that among 158 men undergoing postchemotherapy operations for mediastinal nonseminomas, 19 (13 percent) developed postoperative respiratory failure, of whom nine died. All 19 had received bleomycin, whereas respiratory failure occurred in none of the 17 patients who received VIP chemotherapy [60]. The efficacy and toxicity of VIP as an alternative to BEP and the results of trials comparing these regimens in patients with advanced nonseminomatous GCTs are discussed separately but the two regimens appear to have similar efficacy against nonseminomatous germ cell tumors and different toxicity profiles. (See "Initial chemotherapy for advanced testicular germ cell tumors", section on 'Intermediate- and poor-risk advanced disease'.)

Surgery for residual mass — Most patients with mediastinal nonseminomatous GCTs have residual masses at the conclusion of chemotherapy. Radical resection of all residual masses following chemotherapy plays an integral role in the treatment of these tumors and should be completed whenever technically feasible, even if serum tumor markers are rising at the completion of chemotherapy given the poor results with salvage chemotherapy [19,61-64]. These masses should be completely resected if possible. Aggressive surgery is required, and these operations are often complex. Referral to thoracic surgeon with substantial experience with mediastinal nonseminomas is advisable when possible.

Following post-chemotherapy surgery, no further therapy is necessary if the residual masses contain teratoma or necrosis. If viable malignancy is identified, two additional cycles of VIP chemotherapy should be given.

Salvage chemotherapy — Salvage chemotherapy (using either standard- or high-dose chemotherapy regimens) for mediastinal nonseminomatous GCTs has been minimally effective, with a long-term disease-free survival rates ranging from 0 to 11 percent [19,59,63,65-68]. The series with the most favorable results involved a retrospective review of 79 patients treated at 11 centers, who had relapsed after receiving cisplatin-based therapy [19,68]. Only 8 percent were long-term disease-free survivors compared to 30 percent of those with primary retroperitoneal disease. Of the 25 patients with primary mediastinal tumors who received high-dose chemotherapy with autologous stem cell transplantation at relapse, only three (12 percent) were long-term survivors.

Prognosis — The effectiveness of this combined modality approach as the initial approach to treating mediastinal nonseminomatous GCTs was illustrated in a retrospective multicenter study that included 287 patients with mediastinal nonseminomatous GCTs, in which 278 patients (97 percent) were initially treated with chemotherapy [19]. The complete response rate to chemotherapy was 19 percent, and tumor markers normalized during a partial response in 45 percent. Surgery was used to resect a residual mass in 143 patients (50 percent). The five-year progression-free and overall survival rates were 44 and 45 percent, respectively.

RETROPERITONEAL TUMORS — Retroperitoneal GCTs are generally bulky at the time of diagnosis. Their clinical behavior, prognosis, and management are similar to disseminated testicular GCTs [16].

Retroperitoneal seminoma — For patients with a retroperitoneal seminoma, systemic chemotherapy with a cisplatin-based regimen is the preferred approach, using the same regimens as for patients with advanced testicular seminoma. (See "Treatment of stage II seminoma", section on 'Bulky (stage IIB/IIC) seminoma'.)

The results with this approach are similar to those for advanced testicular seminoma. In a multinational series that included 52 patients with retroperitoneal seminoma and 51 with mediastinal seminoma, the progression-free and overall five-year survival rates for the entire cohort were 87 and 90 percent, respectively [19,46]. In this series, 75 percent of patients were treated with chemotherapy alone. (See "Treatment of stage II seminoma".)

Nonbulky retroperitoneal seminomas can also be treated with primary RT in a manner similar to stage II testicular seminoma. However, there is insufficient published experience to determine the complete remission and cure rates using this approach. (See "Treatment of stage II seminoma".)

Retroperitoneal nonseminomatous GCTs — The initial therapy of patients with retroperitoneal nonseminomatous GCTs consists of either three or four cycles of cisplatin-based chemotherapy, depending upon whether the patient falls into the good or intermediate/poor prognosis group. (See "Initial chemotherapy for advanced testicular germ cell tumors".)

The results with this approach are illustrated by a multicenter series of 227 patients with retroperitoneal nonseminomatous GCTs, of which 98 percent were treated with chemotherapy initially [19]. Of these, 101 (45 percent) underwent surgery for resection of a residual mass. The five-year progression-free and overall survival rates were 42 and 65 percent, respectively.

For those who relapse following first-line chemotherapy, salvage cisplatin-based chemotherapy is identical to that for gonadal nonseminomatous GCTs. In one large review, 30 percent of patients with relapsed retroperitoneal nonseminomatous GCTs achieved long-term disease-free survival [68]. (See "Treatment of relapsed and refractory testicular germ cell tumors".)

SUMMARY AND RECOMMENDATIONS — Extragonadal germ cell tumors (GCTs) are rare tumors that most frequently arise in the mediastinum and retroperitoneum in adult males.

There are no randomized trials to guide treatment in patients with mediastinal or retroperitoneal GCTs. The evidence supporting therapeutic recommendations are based upon observational series and experience with gonadal GCTs.

Mature mediastinal teratomas

For patients with a mature teratoma of the mediastinum, we recommend complete surgical resection (Grade 1A). 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 (RT). (See 'Mature teratomas' above.)
Immature mediastinal teratomas

For patients with immature teratomas of the mediastinum, we recommend four cycles of preoperative VIP chemotherapy followed by complete surgical resection if technically feasible (Grade 1B). Neither chemotherapy alone nor surgery alone has consistently resulted in long-term survival. (See 'Immature teratomas' above and "Initial chemotherapy for advanced testicular germ cell tumors".)
Mediastinal seminomas

For patients with a mediastinal seminoma, we suggest cisplatin-based chemotherapy rather than radiation therapy or surgery (Grade 2B). Good risk patients should receive four cycles of etoposide and cisplatin (EP) or three cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. Intermediate risk patients (ie, those with nonpulmonary visceral metastases) should receive four cycles of BEP chemotherapy or etoposide, ifosfamide, and cisplatin (VIP) chemotherapy. Radiation therapy is an alternative for patients who do not have bulky or metastatic disease. (See 'Mediastinal seminoma' above and "Initial chemotherapy for advanced testicular germ cell tumors".)
Residual masses larger than 3 cm should be evaluated with a PET scan or an open biopsy or should be closely observed. Residual masses smaller than 3 cm should be closely observed or evaluated with a PET scan. PET-negative lesions should be observed. (See 'Residual mass' above.) PET-positive lesions should not be treated with chemotherapy or radiation unless a biopsy or resection provides histopathological documentation of residual cancer.
Mediastinal seminomas with elements of other cell types or with an elevation of serum alpha fetoprotein (AFP) should be treated like a nonseminomatous GCT. (See 'Mediastinal nonseminomatous GCT' above.)
Mediastinal nonseminomatous germ cell tumors

For patients with a mediastinal nonseminomatous GCT, we recommend four cycles of etoposide, ifosfamide and cisplatin (VIP) chemotherapy as the initial therapy, rather than surgery or radiation therapy (Grade 1A). (See 'Mediastinal nonseminomatous GCT' above and "Initial chemotherapy for advanced testicular germ cell tumors".)
For patients with a residual mediastinal mass following initial chemotherapy, we recommend complete surgical resection if technically feasible (Grade 1A). If viable malignancy is identified, two additional cycles of VIP chemotherapy should be given. (See 'Surgery for residual mass' above.)
Retroperitoneal seminoma

For patients with a retroperitoneal seminoma, we recommend cisplatin-based chemotherapy (Grade 1B). Radiation therapy may be an alternative for patients with nonbulky disease. (See 'Retroperitoneal seminoma' above and "Treatment of stage II seminoma".)
Retroperitoneal nonseminomatous GCTs

For patients with a retroperitoneal nonseminomatous GCT, we recommend cisplatin-based chemotherapy, as would be used for a testicular nonseminomatous GCT, rather than radiation therapy or surgery (Grade 1B). Depending upon whether the patient falls into the good or intermediate/poor prognosis group, this would include three or four cycles of treatment. This should be followed by surgical resection of any residual mass. (See "Retroperitoneal lymph node dissection in testicular germ cell tumors" and "Initial chemotherapy for advanced testicular germ cell tumors".)