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Diagnostic and Therapeutic Quandaries in a Patient With a Germ Cell Tumor

Indiana University, Indianapolis, IN

To the Editor:We report the case of a 19-year-old male with gynecomastia, a serum beta-human chorionic gonadotropin (b-hCG) level greater than 940,000 mIU/mL, and an alpha-fetoprotein level of 199 ng/mL. A chest x-ray revealed innumerable pulmonary nodules and a 4- to 6-cm anterior mediastinal mass. A scrotal ultrasound, abdominal computed tomography, and brain magnetic resonance imaging were unrevealing for malignancy. A fine-needle aspirate of the mediastinal mass revealed choriocarcinoma. He was treated with bleomycin, etoposide, and cisplatin beginning in July 1990. The b-hCG decreased to 298 mIU/mL before cycle 4 but did not normalize after four cycles of bleomycin, etoposide, and cisplatin. Radiographic abnormalities in the chest decreased in size from baseline but persisted. During the first cycle of salvage treatment with vinblastine, ifosfamide, and cisplatin, the patient was discovered to have a brain metastasis and received whole-brain radiotherapy. The b-hCG slowly decreased but never normalized after four cycles of vinblastine, ifosfamide, and cisplatin, but subsequently normalized without further treatment over the next 6 months. There was no change in radiographic abnormalities of the lung or mediastinum over the next 9 years. In February 2001, right hilar adenopathy became radiographically apparent. The b-hCG and alpha-fetoprotein levels remained normal. He underwent a right hilar lymph node dissection and excision of the stable anterior mediastinal mass. Pathologic analysis revealed noncaseating granulomas from the enlarging hilar adenopathy and mature teratoma from the anterior mediastinal mass.

Patients with primary mediastinal nonseminomatous germ cell tumor (NSGCT) or patients with NSGCT of testicular origin with either brain metastasis or a b-hCG level greater than 50,000 mIU/mL have 5-year survival rates of 40%, 33%, and 51%, respectively.¹ The survival of this patient, who had all three of these features, is remarkable. Furthermore, this case highlights several important points about GCTs.

• First, patients with GCT require life-long follow up. For patients with GCT who achieve a complete remission, relapse beyond 2 years is considered rare but will occur in 2% to 3% of patients. Late-relapse tumors are chemosensitive but, unlike early relapsed disease, are rarely cured with chemotherapy alone and surgery should be considered the definitive treatment for patients with late relapse.² Therefore, life-long follow-up is necessary.
  
• After chemotherapy for GCT, patients may continue to have residual radiographic abnormalities. For patients with NSGCT treated with first-line chemotherapy, these abnormalities may represent teratoma (45%), necrosis (45%), or residual germ cell cancer (10%). We therefore advocate the resection of residual radiographic abnormalities, if feasible.
  
• There is an association between GCT and sarcoid, which may lead to diagnostic confusion in some patients.^3-7 Histologic confirmation with either biopsy or excisional biopsy is needed to establish this diagnosis in light of the patient’s history of NSGCT. The causal relationship between testicular cancer and sarcoid-like granulomas remains unclear.
  
• Patients with b-hCG levels greater than 50,000 mIU/mL at presentation will usually experience a plateau after an initial rapid descent of b-hCG. It is common to have elevated levels 1 month after completion of therapy, even in patients who were cured with their initial chemotherapy.⁸ Therefore, monthly observation and treatment only at the time of serologic progression should be undertaken for these patients.
  
• Primary mediastinal NSGCTs represent a distinct clinical entity, with a clinical behavior that suggests that these are biologically distinct from testicular GCTs. If tumor markers have not normalized after chemotherapy for primary mediastinal NSGCT, surgery may still be undertaken if the mass can be completely resected. In a series reported by Kesler et al,⁹ seven of 24 patients with persistent GCT in a completely resected residual mass remain alive and disease-free.
  
• Finally, teratoma may behave in a biologically indolent manner. Many patients present with mixed tumors composed of teratoma and other GCT elements. The nonteratoma germ cell components respond to platinum-based chemotherapy; however, teratoma is chemoresistant. Therefore, these patients may have an enlarging mass, which represents teratoma, during or shortly after chemotherapy is completed. Surgical resection is the only effective treatment for teratoma. This case, with pathologic confirmation, reveals that teratoma can behave in a biologically inert fashion, with no growth over a 10-year period.
  

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2. Baniel J, Foster R, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13: 1170-1176, 1995[Abstract]

3. Horwich A: Sarcoid-like lymphadenopathy in malignant teratoma. Post Grad Med J 59: 108-110, 1983[Abstract]

4. Fossa S, Abeler V, Marton P, et al: Sarcoid reaction of hilar and paratracheal lymph nodes in patients treated for testicular cancer. Cancer 56: 2212-2216, 1985[Medline]

5. Urbanski S, Alison R, Jewett M, et al: Association of germ cell tumours of the testis and intrathoracic sarcoid-like lesions. CMAJ 137: 416-417, 1987[Medline]

6. Kok T, Haasjes J, Splinter T, et al: Sarcoid-like lymphadenopathy mimicking metastatic testicular cancer. Cancer 68: 1845-1847, 1991[Medline]

7. Heffner J, Milam M: Sarcoid-like hilar and mediastinal lymphadenopathy in a patient with metastatic testicular cancer. 60: 1545-1547, 1987

8. Zon R, Nichols C, Einhorn L: Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels. J Clin Oncol 16: 1294-1297, 1998[Abstract/Free Full Text]

9. Kesler K, Rieger K, Ganjoo K, et al: Primary mediastinal nonseminomatous germ cell tumors: The influence of postchemotherapy pathology on long-term survival after surgery. J Thorac Cardiovasc Surg 118: 692-701, 1999[Abstract/Free Full Text]

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