Kaohsiung J Med Sci September 2005 • Vol 21 • No 9 395
Extragonadal germ cell tumors are rare and are usually located in the anterior mediastinum [1,2]. The most common germ cell tumors are teratomas [3]. Malignant germ cell tumors are extremely rare, comprising less than 1% of all mediastinal tumors. These germ cell tumors have different clinical presentations, histologic features, serologic markers, and immunohistochemical stain patterns [4–10]. Over the last decade, the prognosis of these malignant germ cell tumors, except for seminomas, has improved significantly because of the introduction of platinum-based chemotherapy [11].
P
RIMARY
G
ERM
C
ELL
T
UMORS
OF
THE
M
EDIASTINUM
:
10 Y
EARS
OF
E
XPERIENCE
IN
A
T
ERTIARY
T
EACHING
H
OSPITAL
Chih-Jen Yang, Meng-Shuan Cheng, Shah-Hwa Chou,1 Kun-Bow Tsai,2 and Ming-Shyan Huang Division of Chest Medicine, Department of Internal Medicine, 1Department of Chest
Surgery, and 2Department of Pathology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Germ cell tumors occur mostly in the gonad. Extragonadal germ cell tumors are rare, and most occur in the retroperitoneum and mediastinum. Primary mediastinal germ cell tumors are often found in the anterior portion of the mediastinum and include teratomas and non-teratomatous tumors. Non-teratomatous tumors include seminomas and malignant non-seminomatous germ cell tumors (MNSGCTs). MNSGCTs include yolk sac tumors, choriocarcinomas, embryonal carcinomas, and mixed type germ cell tumors. Teratomas are the most common germ cell tumors of the mediastinum, and seminomas are the most common non-teratomatous germ cell tumors of the mediastinum. Cases of primary mediastinal MNSGCT reported in the literature are rare. In this report, we review all primary mediastinal germ cell tumors from a 10-year period at the Chung-Ho Memorial Hospital of Kaohsiung Medical University. A total of 14 cases were reviewed, including 11 patients with mature teratomas, two with yolk sac tumors, and one with seminoma. We discuss the differences in clinical presentation, histopathologic characteristics, treatment, and prognosis.
Key Words: germ cell tumor, mediastinal mass
(Kaohsiung J Med Sci 2005;21:395–400)
Received: July 6, 2004 Accepted: May 27, 2005 Address correspondence and reprint requests to: Dr. Ming-Shyan Huang, Division of Chest Medicine, Department of Internal Medicine, Kaohsiung Medical University, 100 Tzyou 1st Road, Kaohsiung 807,
Taiwan.
E-mail: [email protected]
We reviewed all primary mediastinal germ cell tumors from the past 10 years at Chung-Ho Memorial Hospital of Kaohsiung Medical University. We present these primary mediastinal germ cell tumor cases and discuss the differences in clinical presentation, histopathologic characteristics, and prognosis.
PATIENTS AND METHODS
We retrospectively reviewed primary germ cell tumors covering a period from 1993 to 2003. Case definition and diagnosis were identified from the files of the Department of Pathology. All cases were diagnosed by surgical resection.
Clinical findings were recorded separately for each patient. The data analyzed included gender and age at diagnosis, clinical findings, histologic findings, radiologic findings, therapeutic approaches, and follow-up regimen.
R
ESULTSThere were 14 primary mediastinal germ cell tumors at Chung-Ho Memorial Hospital, occurring with equal frequency in male and female patients. The median age was 27 years (range, 1–44 years). Eleven patients had mature teratomas (Figures 1 and 2), one had seminoma, and two had yolk sac tumors (Table 1 and Figure 3). None of these
patients had a history of testicular neoplasm or tumors elsewhere.
The most common symptoms were dry cough (5 cases), chest pain (3 cases), fever (3 cases), and shortness of breath (3 cases) (Table 1). One patient with teratoma had massive left pleural effusion. Four patients were asymptomatic, with tumors encountered accidentally during health examinations. All asymptomatic patients had teratomas.
Table 1. Primary germ-cell tumors of the mediastinum at Chung-Ho Memorial Hospital, Kaohsiung Medical University, from 1993 to 2003
Case Gender Age (yr) Initial presentation Diagnosis
1 F 37 Chest pain for 1 year Mature teratoma
2 F 1 Asymptomatic Mature teratoma
3 M 5 Cough, fever for 2 weeks Mature teratoma
4 M 28 Chest pain, cough Mature teratoma
5 F 36 Asymptomatic Mature teratoma
6 F 2 Fever, cough for 1 week Mature teratoma
7 F 20 Cough for 3 months Mature teratoma
8 F 30 Exertional dyspnea, pleural effusion Mature teratoma
9 M 20 Asymptomatic Mature teratoma
10 M 44 Asymptomatic Mature teratoma
11 F 19 Cough, hemoptysis Mature teratoma
12 M 30 Sudden chest pain Seminoma
13 M 23 Fever, dry cough, weight loss Yolk sac tumor
14 M 24 Intermittent chest pain, cough, weight loss Yolk sac tumor
Figure 2. Case 4: chest computed tomography revealing an anterior mediastinal mass with a fat-containing soft-tissue mass.
Figure 1. Case 4: chest X-ray of a 28-year-old man showing an anterior mediastinal mass.
All cases were diagnosed through surgical resection. Interestingly, both patients with yolk sac tumors presented with elevated _-fetoprotein (AFP). Surgical specimens stained positive for AFP (Figure 4), but had previously been misdiagnosed as having undifferentiated adenocarcinomas by a local hospital. The misdiagnosis was according to fine needle aspiration biopsy (FNAB) and histologic features.
All germ cell tumors were located in the anterior mediastinum and demonstrated typical widened mediastinum on chest X-rays. Malignant non-teratomatous tumors were observed in three cases (Table 2). The patient presenting with seminoma responded well to radiotherapy after completion of surgical resection, showing no evidence of recurrence after 8 years. Both patients with yolk sac tumors underwent radical resection and received postoperative platinum-based chemotherapy. Both patients lived for more than 10 months after surgery.
D
ISCUSSIONGerm cell tumors include teratomatous lesions and non-teratomatous lesions. Teratomatous lesions consist of mature teratomas, immature teratomas (containing fetal tissue), and teratomas combined with other malignant components [1,2]. Non-teratomatous lesions include seminomas and non-seminomatous tumors, such as yolk sac tumors, embryocarcinomas, choriocarcinomas, and mixed types. The most frequent germ cell tumors are teratomas [1–3], and the most common non-teratomatous tumors are seminomas. Eleven cases of teratoma were diagnosed at our hospital over the 10 years, and there were only three cases (21%) of non-seminomatous germ cell tumors. All of the primary mediastinal germ cell tumors were located in the anterior mediastinum.
The most common symptoms among these cases of
Figure 4. Case 13: positive staining with _-fetoprotein supports the diagnosis of yolk sac tumor (_-fetoprotein stain, × 200).
Table 2. Characteristics and prognosis of malignant germ cell tumors
Case (diagnosis) Serum marker Immunohistochemical staining Survival
12 (seminoma) AFP 0 IU/mL; `-hCG 0 IU/L All stains negative Postoperative radiotherapy and no relapse for 8 years 13 (yolk sac tumor) AFP 2,533 IU/mL; `-hCG 0 IU/L; AFP positive, `-hCG negative Alive 10 months after diagnosis
CEA 1.92 ng/mL; LDH 456 U/L
14 (yolk sac tumor) AFP 1,842 IU/mL; `-hCG 0 IU/L; AFP positive, `-hCG negative Alive 9 months after diagnosis CEA 1.31 ng/mL; LDH 268 U/L
Normal range: serum _-fetoprotein (AFP) < 20 IU/mL; serum and urine `-human chorionic gonadotropin (`-hCG) < 0.01 IU/L in males; serum carcinoembryonic antigen (CEA) < 5 ng/mL; serum lactate dehydrogenase (LDH) 289–497 U/L.
Figure 3. Case 13: typical Schiller-Duvall body in a yolk sac tumor (hematoxylin & eosin stain, × 200).
mature teratomas were chest pain, cough, and fever. Interestingly, one case with teratoma showed exertional dyspnea because of massive pleural effusion. Pleural effusion is generally thought to be related to the rupture of teratomatous cysts [3]. Four of our cases (36%) were asymptomatic at the time of presentation, and the tumor was found from abnormal chest X-ray findings during health examinations. All cases showed a well-circumscribed anterior mediastinal mass. Fat, fluid, and calcification on chest computed tomography (CT) are the characteristics of teratomas. Radical surgical removal leads to resolution in all patients with teratomas [3].
Seminomas are the second most common germ cell tumors of the mediastinum and almost exclusively affect men. Approximately 25% of all reported cases are asymptomatic [4,5]. The typical presentations from chest X-rays are well-circumscribed masses extending to one or both lungs. Importantly, seminomas are lobulated with homogeneous attenuation on chest CT. Seminomas are typically composed of uniform polygonal or round cells with distinct cell borders, granular or clear cytoplasm, and centrally located nuclei. The cells may occur in sheets or form small lobules separated by fibrous septa [4,5]. Because seminomas are radiosensitive, radiotherapy is used as the primary postoperative therapy. One of our patients had seminoma. He presented with chest pain and was diagnosed at complete surgical resection, then received postoperative radiotherapy. No evidence of recurrence was noted during 8 years of follow-up.
Primary malignant non-seminomatous germ cell tumors (MNSGCTs) are extremely rare. For example, primary mediastinal yolk sac tumors have been reported in only 104 cases in the English literature until 1994. The most common age of patients with MNSGCTs is from the 20s to 40s. Males predominate, and almost all MNSGCTs are located in the anterior mediastinum [1,2,7–9]. MNSGCTs are uniquely associated with hematologic malignancies, and approximately 20% of patients have Klinefelter’s syndrome [10]. The most common symptoms of MNSGCT include chest pain, cough, dyspnea, weight loss, fever, and superior vena cava (SVC) syndrome. Some cases are asymptomatic and are encountered on routine chest X-ray. We had two patients with primary yolk sac tumors, and they both presented with chest pain, weight loss, and cough. One patient also showed signs of SVC syndrome.
Chest X-rays of MNSGCTs often show a large smooth contour or lobulated anterior mediastinal masses, with or without local lung invasion. An inhomogeneous soft-tissue attenuation is frequently noted on chest CT.
Contrast-enhanced chest CT shows Contrast-enhanced margins and central attenuation or diffusely inhomogeneous enhancement [5,6]. In yolk sac tumors, the most pathologic presentations are reticular patterns. A lacelike appearance, Schiller-Duvall bodies, and intra- and extracytoplasmic hyaline globules are the characteristics of the reticular pattern [5,7]. Both our mediastinal yolk sac tumors showed the typical histologic pattern in surgical specimens. Serologic investigations of yolk sac tumor are elevated AFP (often > 20 ng/mL), possi-bly combined with carcinoembryonic antigen or lactate dehydrogenase elevation. The most reliable immuno-histochemical marker of yolk sac tumors is AFP staining, which is often positive to a variable degree. On the other hand, serum `-human chorionic gonadotropin is elevated and stains in choriocarcinoma [1,2,7,8]. Under assisted and immunohistochemical analysis, FNAB for diagnosis of MNSGCT is established with a high degree of accuracy in the literature. Unfortunately, inappropriate sampling and negative results on immunohistochemical staining will lead to misdiagnosis [12]. Both our cases of mediastinal yolk sac tumors were misdiagnosed as undifferentiated adenocarcinomas according solely to CT-guided FNAB at local hospitals. We did not have any primary mediastinal choriocarcinomas or embryonal carcinomas in the 10-year period at Chung-Ho Memorial Hospital.
Cisplatin-based chemotherapy has become the standard therapy for mediastinal MNSGCT. Overall, complete remission rates of 50–70% are obtained in most case series, and 5-year survival is approximately 45% [10]. Combined platinum-based chemotherapy followed by surgical resection for primary germ cell tumors is the best approach for improving results. Radiotherapy produces modest benefits for these MNSGCTs [4,10,11]. Currently, patients receiving platinum-based chemotherapy are still alive 10 months after diagnosis.
REFERENCES
1. Dulmet EM, Macchiarini P, Verley JM. Germ cell tumors of the mediastinum. A 30-year experience. Cancer 1993;72:1894–901. 2. Bichols CR. Mediastinal germ cell tumors – clinical features
and biologic correlates. Chest 1991;99:472–9.
3. Moran CA, Suster S. Primary germ cell tumors of the mediastinum: I. Analysis of 322 cases with special emphasis on teratomatous lesions and a proposal for histopathologic classification and clinical staging. Cancer 1997;80:681–90. 4. Moran CA, Suster S. Primary germ cell tumors of the
mediastinum: II. Mediastinal seminomas—a clinicopathologic and immunohistochemical study of 120 cases. Cancer 1997;80: 691–8.
5. Rosado-de-Christenson ML, Templeton P, Moran CA. Mediastinal germ cell tumors: radiologic and pathologic correlation. Radiographics 1992;12:1013–30.
6. Knapp RH, Hurt RD. Malignant germ cell tumors of the mediastinum. J Thorac Cardiovasc Surg 1985;89:82–9. 7. Moran CA, Suster S. 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;80: 699–707.
8. Moran CA, Suster S. Primary mediastinal choriocarcinomas: a clinicopathologic and immunohistochemical study of eight
cases. Am J Surg Pathol 1997;21:1007–12.
9. Michael WS, Celeste NP. Cytology of germ cell tumors: extragonadal, extracranial masses and intraoperative problems. Cancer 1997;81:220–7.
10. Bokemeyer C, Nichols CR. Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 2002;20:1864–73. 11. Strollo DC, Rosado-de-Christenson ML, Jett JR. Primary
mediastinal tumors. Part 1: tumors of the anterior mediastinum.
Chest 1997;112:511–22.
12. Yang CJ, Huang MS. Primary mediastinal yolk sac tumor— a report of two cases and literature review. Thorac Med 2004; 19:202–8.
