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© 2003 American Society for Clinical Oncology Chemotherapy for Teratoma With Malignant TransformationFrom the Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to George J. Bosl, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: boslg{at}mskcc.org.
Purpose: Teratoma with malignant transformation (MT) is a well-described entity that refers to the MT of a somatic teratomatous component in a germ cell tumor (GCT) to a histology that is identical to a somatic malignancy (eg, rhabdomyosarcoma [RMS]). Surgical resection has been the mainstay of therapy for localized transformed disease because these tumors are thought to be resistant to standard treatment. We report that chemotherapy has a role in selected patients with MT, determined by cell type. Patients and Methods: Chemotherapy was administered to 12 patients with MT of GCT limited to a single cell type (two patients with primitive neuroectodermal tumors, five with undifferentiated RMS, one with anaplastic small-cell tumor, two with adenocarcinoma, and two with leukemia); 10 patients had measurable disease. GCT origin was confirmed by molecular cytogenetics in five patients. Each patient received chemotherapy regimens based on the specific malignant cell observed in the transformed histology. Results: Seven patients with measurable disease achieved a partial response, with the duration of response ranging between 1 month and 7 years. Three of those patients are alive. Three patients did not respond to treatment, and all of those patients died as a result of their disease. Conclusion: Chemotherapy for MT limited to a single cell type may result in major responses and long-term survival in selected patients. Local therapy after chemotherapy is an important component of treatment to achieve maximum response.
THOUGH GERM cell tumors (GCTs) account for only 2% of all human malignancies, they are the most common tumors diagnosed in men ages 15 to 35 years. Typically, these tumors are highly treatable malignancies, with more than 90% of newly diagnosed patients being cured, including 70% to 80% of patients with metastatic disease at presentation. The biology of GCTs is unique in that GCTs have the capacity to display totipotential differentiation ranging from pluripotential embryonal carcinoma to extraembryonic cell types (ie, yolk sac tumor or choriocarcinoma) or to somatic cell types (ie, teratoma, mature or immature). Mature teratoma displays fully differentiated somatic elements, such as nerve, skin, or cartilage. Immature teratoma is a tumor with somatic differentiation that has been arrested at the fetal stage of development. On rare occasions, these mature and immature teratomas undergo malignant transformation (MT). Teratoma with MT is a well-described entity that refers to the MT of a somatic teratomatous component in a nonseminomatous GCT (NSGCT) to a histology that is indistinguishable from a somatic malignancy. Examples of histologic transformed cell types include rhabdomyosarcoma (RMS), primitive neuroectodermal tumor (PNET), enteric adenocarcinoma, and leukemia. MTs can occur in GCTs from any primary site, but they arise more commonly in mediastinal NSGCTs than from gonadal or retroperitoneal primary tumors. Acute leukemia has been reported to arise only in mediastinal NSGCTs, whereas carcinomas and sarcomas may be observed in teratomas arising at any site. A short latent interval may be more common with leukemia, sarcoma, or PNET, and a long latent interval seems to be more common with epithelial differentiation. Genetic markers to determine lineage are key to identifying the origin of MT in GCTs. An isochromosome of chromosome 12, i(12p), is a specific marker of GCTs. Excess 12p genetic material with aberrant banding of marker chromosomes or repetitive 12p segments resulting from insertion of 12p chromosomal material occurs in GCTs without i(12p).1 i(12p) or other evidence of excess 12p copy number is identified in all histologic subtypes of GCT, including intratubular germ cell neoplasia. Therefore, the identification of i(12p) or excess 12p copy number in these tumors has established the clonal GCT origin of these malignant cell types and has been identified in acute leukemias associated with mediastinal NSGCT, as well as in somatic malignancies arising from teratoma.2,3 The treatment of MT has been problematic. Surgical resection has been the mainstay of therapy when MT is localized to a single site. Because MTs have been considered resistant to standard chemotherapy, complete resection, particularly of a solitary site, has been the only approach associated with reasonably good outcome. However, the presence of MT at metastatic sites implies a poor prognosis, with a median survival time of 28 months.4 The role of chemotherapy has been limited by the prevailing opinion that these tumors are resistant to chemotherapy. More than 60 patients with MT of teratoma were treated at our institution from 1988 to 2002. The majority was treated with surgery, with the results of this treatment published in a previous series. We review our experience with 12 patients with MT from teratoma treated with chemotherapy, 10 of whom had measurable disease. Our observations suggest that chemotherapy has a role in selected cases of malignant metastatic transformation and that treatment is determined by cell type.
Patients with MT from 1988 to 2002 were identified from the review of recorded diagnoses in the GCT database at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY). All patients had the diagnosis of GCT of the testis or an extragonadal site and MT distinct from any GCT cell type (eg, leukemia, RMS, or PNET). No patient had a history of a non-GCT malignancy before diagnosis. Among all patients identified with MT, 12 patients were identified who received chemotherapy specifically for MT, 10 of whom had measurable disease. All patients were participants in a protocol of treatment or tissue acquisition approved by the Institutional Review Board. Teratoma with MT was defined morphologically as an expansile growth of a somatic malignancy in association with conventional GCT elements, usually teratoma. The cells constituting this expansile growth were cytologically malignant (hyperchromatic, pleomorphic, and mitotically active) and histologically consistent with non-GCT types, such as RMS or colonic-type adenocarcinoma. All pathology was reviewed at MSKCC. The case records of these 12 patients were reviewed and patient characteristics and outcomes recorded. All patients had normal levels of alpha-fetoprotein and human chorionic gonadotropin. The stage of disease at diagnosis was also recorded. Stage I disease was defined as disease limited to the testis. Stage II disease involved metastatic disease to retroperitoneal lymph nodes and stage III disease included metastatic disease to other nodal and/or visceral sites. International Germ Cell Cancer Consensus Group (IGCCCG) risk stratification was determined at the time of initial diagnosis and recorded.5 Specific chemotherapy was selected according to the patient’s transformed histology. The response to therapy was recorded according to previously defined criteria. A complete response (CR) to chemotherapy alone was defined as a complete disappearance of all evidence of disease for at least 1 month. Patients who underwent surgical resection without evidence of viable tumor were also considered to have achieved a CR to chemotherapy alone. A CR to chemotherapy plus surgery was defined as complete resection of all masses, any one of which contained viable malignant tumor. Response categories that were less than complete (partial response [PR]) and no response [NR]) were considered as an incomplete response. Survival time was calculated from the date of diagnosis to the date of last contact for follow-up or death. Genetic studies were performed on tumor samples from five patients, four with measurable disease and one treated with chemotherapy after resection of all visible sites of disease. These studies were performed on tumor specimens obtained at the time of diagnostic procedures for routine histopathology under a tissue acquisition protocol approved by the Institutional Review Board at MSKCC. Genetic analyses included karyotype analysis after short-term culture and molecular cytogenetic analysis by fluorescence in situ hybridization for the identification of i(12p) and chromosome 12 aneuploidy.
Clinical Characteristics The clinical presentation of 10 men with measurable disease at initial diagnosis of GCT is shown in Table 1  . Median age at the time of diagnosis of GCT in these 10 patients was 30 years (range, 19 to 55 years). The primary site of GCT at the time of diagnosis was testis in six patients and mediastinum in four patients. No patients presented with retroperitoneal disease as the sole site of disease. Two patients had stage I disease at the time of diagnosis, two had stage II disease, and the remainder had stage III disease (including patients with mediastinal primary tumors). Patients were characterized at original diagnosis according to IGCCCG risk stratification criteria into good-, intermediate-, and poor-risk groups; four patients had good risk, two patients had intermediate risk, and four patients had poor risk. The observed malignant transformed histologies included four RMSs, one PNET, two adenocarcinomas, two leukemias, and one anaplastic small-cell tumor.
The time from initial diagnosis of GCT to diagnosis of MT was determined and classified according to histology of transformed disease (Table 2 ). Only patients with MT to adenocarcinoma developed their disease 20 or more years after their initial GCT diagnosis. All other transformed histologies occurred 5 years or less from their initial GCT diagnosis. The malignant transformed histology was diagnosed contemporaneously with the diagnosis of GCT in three patients with the malignantly transformed histology coexisting within the tumor in the testis in two patients (patients 4 and 5) and in the mediastinum in one patient (patient 7). Patient 6 developed embryonal RMS (ERMS) in the mediastinum 18 months after his initial diagnosis and treatment for mediastinal GCT; all other patients developed evidence of MT at metastatic sites (Table 2). The site of MT at the time of treatment and the presence or absence of the malignant transformed cell type at the primary site of GCT are noted in Table 2.
Treatment Patients received chemotherapy dictated by the transformed histologies. In the limited literature that does exist on MT of GCT, the consensus has been that MT does not respond to cisplatin-based therapy and that surgery is the mainstay of treatment.4,6,7 Four patients with RMS and the one patient with anaplastic small-cell tumor received doxorubicin- or ifosfamide-based therapy. One patient with PNET received an intensive standard chemotherapy regimen with cyclophosphamide, doxorubicin, vincristine, ifosfamide, and etoposide (P6 regimen),8 typically used to treat this tumor in pediatric patients. Patients with leukemia received standard induction chemotherapy with idarubicin and cytarabine, and those with adenocarcinoma were treated with fluorouracil (FU)-based chemotherapy regimens. Two patients, presumed to have residual NSGCT as a component of active disease at the time of treatment for MT, received a full course of standard cisplatin-based chemotherapy for GCT in addition to treatment for MT (patients 4 and 9). Table 3 lists the histology of MT, site of disease, disease-specific therapy (including surgery or radiation therapy), response to therapy, and current status for patients. Table 4 shows the surgical outcome in those patients (patients 4 to 7, 9, and 10) who underwent surgery as a component of their therapy and lists their chemotherapy course in relation to their surgical interventions. It is notable that among the patients with ERMS, patients 4 and 5 remained with stable disease almost 5 years and almost 2.5 years, respectively, after surgery before experiencing disease progression and requiring salvage chemotherapy. They subsequently achieved PR to their respective therapies (Table 4). Patient 6 had no response to salvage chemotherapy initiated immediately postoperatively for incompletely resected disease, and patient 7 did achieve a significant PR to disease-specific chemotherapy. After resection of residual disease following definitive chemotherapy, patient 7 received consolidative chemotherapy and continues be free of disease. For the two patients with adenocarcinoma, patient 9 was treated over the course of 2 years with several disease-specific chemotherapy regimens. Patient 10 had only a short-lived PR to FU-based therapy once he experienced disease progression.
Among 10 patients receiving chemotherapy for measurable metastatic disease, seven achieved a major response. Figure 1 displays the response of patient 2 (with mast cell leukemia), who achieved a brief cytogenetic CR after standard idarubicin plus cytarabine induction therapy. Figure 2 shows the radiographic response to therapy in patient 1 with PNET, and Figure 3 shows the radiographic response to therapy in patient 7 with RMS.
Adjuvant Chemotherapy Two additional patients (patients 11 and 12) received chemotherapy in the so-called adjuvant setting. Patient 11 had a PNET and was treated with the P6 chemotherapy regimen after complete resection of tumor. Patient 12 had an RMS and received doxorubicin-based therapy after complete resection of all disease. The choice of treatment in these two patients was predicated on the known effectiveness of chemotherapy in the adjuvant treatment of patients with PNET8 and RMS.9 Both patients are alive and remain free of disease.
Cytogenetics
Contrary to most reports on MT, systemic chemotherapy may be effective when the treatment choice is based on the transformed histology. Long-term disease-free survival is possible in some cases when systemic therapy is complemented by locoregional treatment strategies. Among the 10 patients with measurable disease, three are alive and disease free with combined-modality therapy. MT is estimated to occur in 3% to 6% patients with GCT with teratomatous differentiation.6,10 It has been postulated that MT develops from either MT of pre-existing teratomatous elements or by differentiation of totipotential germ cells with concomitant MT.11,12 MT often is found in conjunction with typical germ cell elements. However, MT can exist without evidence of concurrent GCT. The germ cell origin of MT has been confirmed by identification of i(12p) or extra copies of chromosome 12p, as well as by its tendency in many cases to exist in the context of other GCT components. Chromosomal analysis performed on tumor specimens from five of our 12 patients confirmed the characteristic chromosomal abnormalities of GCT origin in these malignant transformed cell types. There are no clinical characteristics that are unique to the diagnosis of teratoma with MT. Typically, this histology is found incidentally at the time of surgery. Occasionally, the clinician may suspect MT in patients who have disease that is not responsive to cisplatin-based chemotherapy or when GCTs with normal tumor markers grow radiographically and/or clinically despite cisplatin-based chemotherapy. As previously reported, we found that MT of adenocarcinoma tends to occur after a long latent interval, whereas other histologies tend to occur with a much shorter latent interval. In addition, patients with a late relapse (> 2 years after treatment) or a mediastinal NSGCT have a disproportionately high likelihood of MT.13,14 MT rarely may also be detected on routine screening blood work as in the cases of MT to acute leukemia. MT has traditionally been thought to be unresponsive to chemotherapy. In one review, 46 patients with MT were observed. Patients who had complete resection of MT had significantly better overall survival, and the prognosis for patients with metastatic disease was grim.4 There have been few reports of successful treatment of MT with chemotherapy. Korfel et al10 recently published a case report of a 51-year-old male with a testicular GCT with RMS who was successfully treated with chemotherapy. The primary tumor histology revealed seminoma, immature teratoma, and RMS; serum levels of alpha-fetoprotein and human chorionic gonadotropin were normal. The patient was treated with a retroperitoneal lymph node dissection, and the pathology from his surgery was negative. Three months later, the patient returned with massive RMS involvement of the bone marrow. Chemotherapy with epirubicin, etoposide, ifosfamide, and cisplatin, followed by high-dose etoposide, carboplatin, epirubicin, and melphalan with stem-cell support resulted in a CR that has lasted 4 years.10 Although our number of patients is small, our experience in treating these patients has paralleled an expectation of response based on histology. Surgery clearly plays an essential role in therapy, as indicated by the postsurgical interval of stable disease in patients 4, 5, 9, and 10. In summary, this retrospective study shows that systemic therapy will benefit a minority of patients with MT of teratoma. If a single site of disease is present, surgical resection should always be considered the primary modality. Except for acute leukemia, unresectable or metastatic settings will generally require multimodal therapy including both chemotherapy and locoregional approaches. The choice of chemotherapy should be dictated by the transformed histology. Cisplatin-based therapy has no role in this setting unless residual GCT exists in conjunction with the malignant transformed tumor type demonstrated by biopsy or elevated markers. Adenocarcinoma will generally be treated with FU-based chemotherapy, PNET is treated with an intensive pediatric chemotherapy regimen that is standard for this tumor, RMS is treated with doxorubicin-based regimens, and leukemia is treated with standard induction chemotherapy with idarubicin and cytarabine. PNET and RMS histologies seem to have the best response to chemotherapy. Local therapy plays an integral role in the management of nearly all patients with this disease entity. Rarely, so-called adjuvant therapy after complete resection of disease should be considered as it was in two of our patients. This setting should be restricted to those patients with a single transformed histology that is known to benefit from adjuvant therapy after complete resection in the de novo setting.
The authors indicated no potential conflicts of interest.
1. Rodriguez E, Matthew S, Reuter V, et al: Cytogenetic analysis of 124 prospectively ascertained male germ cell tumors. Cancer Res 52:2285–2291, 1992 2. Chaganti RS, Ladanyi M, Samaniego F, et al: Leukemic differentiation of a mediastinal germ cell tumor. Genes Chromosomes Cancer 1:83–87, 1989[Medline]
3. Ladanyi M, Samaniego F, Reuter VE, et al: Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors. J Natl Cancer Inst 82:221–227, 1990 4. Motzer RJ, Amsterdam A, Prieto V, et al: Teratoma with malignant transformation: Diverse malignant histologies arising in men with germ cell tumors. J Urol 159:133–138, 1998[CrossRef][Medline]
5. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers—International Germ Cell Consensus Collaborative Group. J Clin Oncol 15:594–603, 1997 6. Comiter CV, Kibel AS, Richie JP, et al: Prognostic features of teratomas with malignant transformation: A clinicopathological study of 21 cases. J Urol 159:859–863, 1998[CrossRef][Medline] 7. Ulbright TM, Loehrer PJ, Roth LM, et al: The development of non-germ cell malignancies within germ cell tumors: A clinicopathologic study of 11 cases. Cancer 54:1824–1833, 1984[CrossRef][Medline] 8. Kushner BH, Meyers PA, Gerald WL, et al: Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing’s sarcoma, in children and young adults. J Clin Oncol 13:2796–2804, 1995[Abstract]
9. Crist W, Gehan EA, Ragab AH, et al: The third intergroup rhabdomyosarcoma study. J Clin Oncol 13:610–630, 1995 10. Korfel A, Fischer L, Foss HD, et al: Testicular germ cell tumor with rhabdomyosarcoma successfully treated by disease-adapted chemotherapy including high-dose chemotherapy: Case report and review of the literature. Bone Marrow Transplant 28:787–789, 2001[CrossRef][Medline] 11. Ahmed T, Bosl GJ, Hajdu SI: Teratoma with malignant transformation in germ cell tumors in men. Cancer 56:860–863, 1985[CrossRef][Medline] 12. Little JS Jr, Foster RS, Ulbright TM, et al: Unusual neoplasms detected in testicular cancer patients undergoing postchemotherapy retroperitoneal lymphadenectomy. World J Urol 12:200–206, 1994[Medline]
13. George DW, Foster RS, Hromas RA, et al: Update on late relapse of germ cell tumor: A clinical and molecular analysis. J Clin Oncol 21:113–122, 2003
14. Vuky J, Bains M, Bacik J, et al: Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 19:682–688, 2001 Submitted January 3, 2003; accepted September 17, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
