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Extragonadal Germinal Cell Tumour- Mediastinal Seminoma & Non-Seminoma

Extragonadal Germinal Cell Tumour- Mediastinal Seminoma & Non-Seminoma

Extragonadal germ cell tumor is uncommon. Less than 5-7% of germ cells occur outside the gonads, but of the extragonadal sites, the mediastinum is the most common location for germ cell tumors. These tumors can be found anywhere on the midline, particularly the retroperitoneum, 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 exact mechanism whereby germ cell tumors originate in the mediastinum remains unknown. 

The first theory on Extragonadal germ cell tumor postulated that the tumors developed from primitive in the endoderm of the yolk sac or from the urogenital ridge. These cells normally move into the scrotum during development, but when this migration fails, the cells may remain localized to either the mediastinum or the retroperitoneum. Others have hypothesized that these totipotent cells become detached during embryogenesis and result in primitive masses, which may develop into tumors.

Epidemiology

Malignant germ cell tumors of the mediastinum are rare, accounting for approximately 10% of all mediastinal tumors. These tumors occur almost exclusively in males, and the age at presentation is generally 20-35 years.

All types of malignant germ cell masses are more prevalent in males, and most of these males are symptomatic. Benign germ cell tumors, on the other hand, are distributed equally between the sexes, and most develop in the third decade of life. In children, these tumors can occur at any age and are equally divided between boys and girls. 

Mortality / Morbidity

For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported. Extragonadal seminomas carry the best survival rates. Mortality due to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal germ cell tumors (NS-EGGCTs).

Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) account for 60-70%. Nonseminomatous germ cell tumors include yolk-sac tumors, embryonal carcinomas, choriocarcinomas, teratomas, and nonteratomatous combined germ cell tumors. The most common site of extragonadal germ cell tumors (EGGCTs) is the mediastinum (50-70%) followed by the retroperitoneum (30-40%), the pineal gland (5%), and the sacrococcygeal area (less than 5%). 

Presentation

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.

1. 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. 

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

3. Patients with mediastinal germ cell tumors may present with (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, and hoarseness. In one third of patients the anterior mediastinal mass is an incidental finding of a routine chest radiograph (in most of these cases, a benign tumor is found). 

4. 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.

5. Mature teratoma rupture, teratoma with malignant transformation, and hematologic malignancies may complicate mediastinal germ cell tumors. 

6. 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.
Tumour Markers

Tumor markers serum alpha fetoprotein (AFP) and/or the beta subunit of human chorionic gonadotropin (beta-hCG) are elevated in extragonadal nonseminomatous germ cell tumors. These tumor markers provide diagnostic, staging, and prognostic information. These levels should be checked before and then at regular intervals after therapy. AFP, b-hCG, or both are elevated in approximately 85% of extragonadal nonseminomatous germ cell tumors. Small increases in serum beta-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 i(12p) copies. 

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. 

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

Imaging Studies

A benign tumor may not be visible on a plain chest radiograph as a mediastinal mass. Usually, the tumor must be sufficiently large in order to show any evidence of mediastinal widening. In 30% of cases, seminomas manifest as coincidental findings. These tumors tend to become quite large before they cause symptoms, yet they do not demonstrate pathognomonic radiographic findings. 

Diagnostic Procedures

Needle biopsy 
In general, tissue diagnosis is necessary even if typical radiologic features are noted or if serum levels of markers are elevated. Percutaneously performed aspiration needle biopsy is the first step. If the tumor is encroaching the trachea or a bronchus, transbronchial biopsy can be performed.A CT-guided needle biopsy is performed if the diagnosis cannot be confirmed with the aspiration needle or transbronchial biopsy.Cytologic diagnosis is not always sensitive; tissue biopsy is preferred because mediastinal tumors have been diagnosed as lymphomas, which also manifest as bulky lesions in the anterior mediastinum and in persons of the same age range. 

Open biopsy 

Occasionally, a percutaneous technique cannot yield adequate tissue or the mass is in a difficult area; in such cases, an open biopsy is required. Open biopsy is best performed as a small anterior thoracotomy. The procedure is generally accomplished with the patient under GA, and a small parasternal incision is adequate for most patients.Strict airway maintenance is required because large anterior mediastinal tumors can compress the trachea and make intubation difficult. A rigid bronchoscopy cart should always be available during this procedure. 

The biopsy can also be performed using thoracoscopy. The thoracoscopic procedure facilitates better evaluation of the tumor and allows for biopsy specimens to be taken from multiple, otherwise inaccessible sites. 

Treatment

Treatment modality is determined by the site and the histologic type of the primary tumor.

Mediastinal germ cell tumors (MGCTs): Cisplatin-based chemotherapy has made a significant improvement in treatment of seminoma of the mediastinum. Treatment with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy can be used after chemotherapy in bulky mediastinal seminomas. 

In nonseminomatous mediastinal germ cell tumors (NS-MGCT), 4 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 2 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.

Combination Therapy with Radiation and Chemotherapy

Recent clinical trials have demonstrated excellent results when multimodality chemotherapy is combined with radiation for large, localized mediastinal seminomas or extensive residual disease. In these cases, the patient is administered chemotherapy consisting of cisplatin, bleomycin, and etoposide. After the patient has recovered (4-6 wk), radiation is administered at a dose of 40-60 Gy for 4-6 weeks. A CT scan is then obtained to assess the response of the tumor to treatment. If only a small mass remains, it is excised. 

Surgery

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. 

Mediastinal germ cell tumors - 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. 

Outcome And Prognosis

In the last decade, the general trend has been to refer all patients with seminomas, regardless of size, for radiation therapy and chemotherapy. In current practice, seminomas are curable with aggressive treatment. The treatment of pure seminomas today is nonsurgical; only the small, resectable tumors in asymptomatic patients should be completely excised and managed with postoperative radiation, with dose of 40-50 Gy. 

If distant metastases are detected at the time of diagnosis, the patient should be treated with intensive cisplatin-based combination chemotherapy. Even though these tumors are very sensitive to radiation, remissions are observed in only 50-70% of patients; therefore, combination chemotherapy is recommended for bulky disease and radiation is recommended for localized disease. 

For bulky tumors, induction chemotherapy is administered and any residual disease revealed on a CT scan is then resected to determine if a viable tumor remains. A finding positive for a tumor may dictate further therapy. If no lesion is observed on the CT scan, no further therapy is warranted and the patient can be monitored with serial CT scans every 6-12 months. Current treatment regimens provide remission in more than 80% of individuals, and the 5-year survival rate is reported to be approximately 60-80%. 
CT scans and MRIs are useful for determining the precise anatomic relationship and morphologic features.CT scans are usually adequate, but consider MRIs if surgery is a possibility. MRIs have better resolution of nearby tissue and vascular invasion. 
CT scan features of seminomas include the following: 

1. Benign tumors tend to be round masses that grow slowly. They are most commonly located in the superior mediastinum. Calcification may be present but is usually of no help in the diagnosis because calcification is also observed in other anterior mediastinal tumors, including thymomas and thyroid goiters. 
2. In general, malignant tumors tend to be larger than benign ones, to be lobulated, and to grow faster.

3. CT scanning may also reveal evidence of mediastinal invasion, adenopathy, and metastatic disease in the lungs.


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