April 26, 2008
Metastatic Malignant Teratoma Arising From Mediastinal Nonseminomatous Germ Cell Tumor: A Case Report
By Collen, Jacob Carmichael, Mark; Wroblewski, Tanya
ABSTRACT Primary mediastinal nonseminomatous germ cell tumors (NSGCT) have a worse prognosis than gonadal germ cell tumors (GCTs). Malignant transformation of teratomatous components of GCT to a somatic malignancy is rare. We present a case of primary mediastinal NSGCT with malignant transformation of a teratoma in an active duty airman who presented with a 12-cm anterior mediastinal mass and vertebral body lesion. Pathology confirmed NSGCT with yolk sac and teratomatous components. Chemotherapy for GCT normalized serum tumor markers with little effect on the mediastinal mass. Incomplete resection of the residual tumor revealed high-grade mixed sarcoma. Serum tumor markers rose 3 months following resection with metastatic disease to bone and liver. Chemotherapy targeting sarcoma induced a partial response, but the patient developed acute myeloid leukemia refractory to chemotherapy. We discuss our approach to management of this complicated patient. INTRODUCTION
Primary mediastinal germ cell tumors (GCTs) account for 15% of adult anterior mediastinal tumors, and between 5 and 10% of all GCTs.1 Primary mediastinal nonseminomatous GCTs (PMNSGCT), while histologically and serologically identical to gonadal GCT, have a worse prognosis. Nonseminomatous GCTs (NSGCT) may exhibit embryonal, extraembryonal, or somatic histology (teratoma).
Pre- and postchemotherapy serologic markers of disease have not been shown to predict survival. Extent of disease and pathology of the resected tumor are the most important prognostic indicators.1 Malignant transformation of the somatic teratomatous component of GCT to a histologically identical somatic malignancy is a rare but well-described feature of NSGCT.
For localized disease of malignantly transformed teratoma, surgical resection is the mainstay of treatment. Chemotherapy targeting the predominant cell type is of unclear clinical efficacy.2 We present a case of a PMNSGCT with malignant transformation to poorly differentiated sarcoma followed by progression to acute myeloid leukemia (AML).
A 23-year-old active duty male was referred to medical oncology at Walter Reed Army Medical Center following a computed tomography (CT)-guided core-needle biopsy of a primary mediastinal mass performed at an outside facility. He had initially presented with 3 months of fatigue, cough, night sweats, dyspnea on exertion, thoracic back pain, and a 10pound weight loss over the preceding year. His past medical/ surgical history was notable for a hydrocele repair in 1985. He had a smoking history of approximately a half pack per day for
His physical examination was notable for a normal testicular examination. Initial laboratory showed a normal complete blood count and differential, serum electrolytes, an elevated erythrocyte sedimentation rate of 59 mm/hour (4-27 mm/hour), negative human immunodeficiency virus, and normal thyroid function tests.
Evaluation for germ cell serum tumor markers revealed a lactate dehydrogenase that was significantly elevated at 1,265 U/L (313-618 U/L), an alpha-fetoprotein (AFP) of 6,826 ng/mL (0-15 ng/ml), and a mildly elevated ss-human chorionic gonadotropin of 15.5 rnlU/mL (
Testicular ultrasound was normal. A chest radiograph revealed an 11-cm anterior mediastinal mass. CT of the chest, abdomen, and pelvis (Fig. 1) showed a 9-cm heterogeneous left anterior mediastinal mass with local lymph node invasion without evidence of distant metastatic disease. Whole body positron emission tomography (PET) scan (Fig. 2) showed increased metabolic activity in the retrosternal mediastinal mass (8.32 standard uptake value (SUV)), right retrosternal internal mammary lymphadenopathy (5.70 SUV), and a 10th thoracic vertebral body lesion (5.30 SUV). The SUV of normal tissue is expected to be
A core-needle biopsy confirmed NSGCT with benign teratoma and malignant GCT elements with a yolk sac histology. He was clinically staged as pTxNlMlbS2. The Tumor, Nodes, and Metastases Staging System for GCTs is based on a primary testicular mass as well as a degree of elevation of serum tumor markers in addition to the standard criteria. Our patient did not have a testicular primary, hence the pTx designation, and an intermediate level of serum tumor marker elevation, hence the S2 designation. His clinical stage group is IIIc, which represents a poor risk NSGCT category.
He was treated with four cycles of bleomycin, etoposide, and cisplatin from October 2005 to January 2006, with a biochemical response documented by rapid normalization of beta-human chorionic gonadotropin, and steady normalization of serum AFP from October 2005 to March 2006 (AFP 2.7 ng/mL; see Fig. 4). The vertebral body lesion resolved by PET scan; however, there was no effect on the size of the mediastinal mass.
Aggressive surgical resection of the residual mediastinal mass was attempted in February 2006. This was technically challenging and incomplete, with residual disease in nodes adjacent to the right phrenic nerve that could not be safely approached due to loss of the left phrenic nerve with removal of the primary tumor.
Pathology of the resected specimen showed a high-grade glioblastoma with mixed sarcoma histology (immature teratoma, undifferentiated sarcoma rhabdomyosarcoma, liposarcoma, chondrosarcoma), and immature glial cells. Postsurgical assessment was high-grade mixed sarcoma with a poorly differentiated histology and a poor prognosis.
In May 2006, the patient's AFP increased and metastatic disease was documented in the mediastinum, vertebrae, and liver on CT and PET scans (Fig. 3). A fine-needle aspiration was performed on one of the liver lesions to establish the predominant histology and to refine chemotherapy. The biopsy showed metastatic GCT consistent with malignant teratoma and immature sarcomatous elements. Doxorubicin, ifosfamide, and mesna was selected to target the sarcoma histology.
After one cycle of doxorubicin, ifosfamide, and mesna, chemotherapy was revised to paclitaxel, ifosfamide, and cisplatin to target the NSGCT component that was felt to be causing the rising AFP. After three cycles of paclitaxel, ifosfamide, and cisplatin, the AFP normalized (Fig. 4). Disease sites showed decreased size and metabolic activity by CT and PET, respectively. Two additional cycles of doxorubicin and dacarbazine were given to target the sarcomatous elements.
The patient's continued response to chemotherapy by CT, PET, and AFP levels was offset by toxicities from treatment that included Raynaud's phenomenon, grade 2 peripheral neuropathy, grade 2 anemia, and thrombocytopenia. In October 2006, he was hospitalized with new leukocytosis, thrombocytopenia, and painful splenomegaly. Peripheral blood evaluation showed a white blood cell count of 22.9 with circulating blasts (43%) and immature myeloid cells, hemoglobin of 8.2 g/dL, and platelet count of 30. Bone marrow aspiration revealed 90% cellularity, with the blast population comprising over 50% of the cells. Immunohistochemistry and flow cytometry were consistent with AML. His leukemia was felt to be treatment related, and he was entered into a protocol using amonafide and cytarabine for secondary AML. He was refractory to induction therapy and subsequently died of multiorgan dysfunction 6 months following the development of leukemia.
We present a rare case of PMNSGCT presenting with transformation of teratomatous elements to a poorly-differentiated malignant sarcoma. This case highlights the importance of keeping PMNSGCT in the differential diagnosis of a young, otherwise healthy, patient presenting with mediastinal mass.
Treatment consisting of a standard regimen of bleomycin, etoposide, and cisplatin chemotherapy followed by surgical resection of residual disease failed to eradicate his disease despite normalization of his tumor markers.3 More unfortunate is the malignant transformation to high-grade mixed sarcoma and lack of response to chemotherapy followed by progression to treatment- related AML.
PMNSGCT have a worse prognosis than their gonadal counterparts due to the potential of residual unresectable disease following chemotherapy, a secondary association with acute leukemia, and rare transformation of a GCT to a somatic malignancy in 3% to 6% of cases.1
Teratoma with malignant transformation occurs when a somatic teratomatous component in a NSGCT transforms to a histology that is indistinguishable from a somatic malignancy. The GCT origin of malignant transformation is based on chromosomal analysis from the resected specimen, with abnormalities in chromosome 12 (isochromosome 12, il2p, or excess 12p copy number via insertion).1
Examples of transformed histologies are rhabdomyosarcoma, primitive neuroectodermal tumor, enteric adenocarcinoma, and acute leukemias. Malignant transformation should be suspected when the patient has primary refractory disease to cisplatin-based therapy, or the mass grows despite normalization of serum tumor markers. Treatment is problematic with malignant transformation to teratoma, as the malignantly transformed cells are often resistant to standard chemotherapy. Primary resection of residual tumor represents the only curative option.4 When chemotherapy is employed in malignant transformation of teratoma, agent selection is based on the predominant cell type in the resected specimen (see Table I).4 Prognosis has been evaluated in previous studies from the standpoint of impact of prechemotherapy tumor markers, extent of disease at diagnosis, postchemotherapy tumor markers, disease progression during induction, and the pathology of the postchemotherapy resected specimen. Prechemotherapy tumor markers have not been found to be predictive of survival. Extrapulmonary disease at diagnosis is a poor prognostic indicator, as is progression of disease postinduction chemotherapy (as evidenced by postchemotherapy tumor markers and/or increase in mass). However, the most important predictor of survival is the pathology of the postchemotherapy resected specimen.1
Patients who achieve normalization of tumor markers following chemotherapy and have necrotic tissue in the resected residual mass have an excellent outcome. On the other hand, residual carcinoma in the resected specimen after chemotherapy has a high relapse rate. It is crucial that PMNSGCT patients receive adequate primary therapy with cisplatincontaining regimens followed by resection of residual mass. Patients who do not respond to primary therapy typically have very poor outcome, and are rarely cured by salvage chemotherapy (in contrast to gonadal GCT).2
Ultimately, PMNSGCT is categorized as a poor risk GCT, and transformation to a high-grade mixed sarcoma portends a grave prognosis. There is no optimal treatment and treatment plans and regimens must be individualized. High-dose chemotherapy regimens and autologous stem cell transplant have been assessed, but this is limited to small case series, in patients with different histologies than ours.3
We selected therapies active in GCT and sarcoma with objective evidence of tumor response by both serum tumor markers and imaging. The progression to AML was refractory to all treatment efforts. The overall survival benefit of this chemotherapy in our patient is unknown. This case highlights the need for chemotherapy that targets the resultant somatic malignancy.
Our findings indicated the following: (1)PMNSGCT may present without a testicular primary; (2) mediastinal and extrapulmonary disease, and elevated serum tumor markers, indicate poorer prognosis; (3) after initial chemotherapy, residual tumor must be resected; and (4) when a GCT malignantly transforms, chemotherapy is directed at the transformed histology (i.e., leukemia, sarcoma, primitive neuroectodermal tumor, enteric adenocarcinoma, GCT, etc.).
1. Ganjoo KN, et al: Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors. Cancer 2000; 88: 1051- 6.
2. Sakurai H, et al: Management of primary malignant germ cell tumor of the mediastinum. Jpn J Clin Oncol 2004; 34: 386-92.
3. Michel M, Pratt JW: Anterior mediastinal nonseminomatous germ cell tumor with malignant transformation: a case report. Curr Surg 2004; 61; 577-9.
4. Donadio AC, et al: Chemotherapy for teratoma with malignant transformation. J Clin Oncol 2003; 21: 4285-91.
5. Jones RH, Vasey PA: Part II: Testicular cancer-management of advanced disease. Lancet Oncol 2003; 4: 738-47.
CPT(P) Jacob Collen, MC USA; MAJ Mark Carmichael, MC USA; MAJ Tanya Wroblewski, MC USA
Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Building 2, Washington, DC 20307.
The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. government.
This manuscript was received for review in June 2007. The revised manuscript was accepted for publication in December 2007.
Reprint & Copyright (c) by Association of Military Surgeons of U.S., 2008.
Copyright Association of Military Surgeons of the United States Apr 2008
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