Chemotherapy in Patients with Teratoma with Malignant Transformation

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1 european urology 51 (2007) available at journal homepage: Testis Cancer Chemotherapy in Patients with Teratoma with Malignant Transformation Omar El Mesbahi a, Marie-Josée Terrier-Lacombe b, Christine Rebischung a, Christine Theodore a, Daniel Vanel c, Karim Fizazi a, * a Department of Medicine, Institut Gustave Roussy, Villejuif, France b Department of Pathology, Institut Gustave Roussy, Villejuif, France c Department of Radiology, Institut Gustave Roussy, Villejuif, France Article info Article history: Accepted October 16, 2006 Published online ahead of print on October 25, 2006 Keywords: Teratoma with malignant transformation Germ-cell tumour Chemotherapy Surgery Abstract Objective: Germ-cell tumours (GCTs) with a non-gct malignant component are a unique and rare phenomenon called teratoma with malignant transformation (TMT). The only published series of patients with TMT treated with chemotherapy comprised 10 patients. We report here our experience in treating 14 patients with TMT. Patients and methods: Sarcoma was identified in 10 of 14 patients, with rhabdomyosarcoma ranking first (n = 4). Other histological types included adenocarcinoma (n = 3) and bronchoalveolar carcinoma (n = 1). Immunohistochemistry was performed to help in identifying the malignant non-gct component. Results: Primary treatment consisted of surgery alone in 4 patients. The remaining 10 patients received first-line cisplatin-based chemotherapy with resection of residual masses (n = 5): 4 patients had a complete response and 5 had a partial response. Overall, 9 patients developed a relapse with a median time of 84 mo (range: 6 168). At relapse, 8 patients received a chemotherapy regimen directed to the non-gct component. Four of these patients achieved a partial response. With a median followup of 59 mo (range: 3 180), 4 of 14 patients are alive, including 3 who are disease-free. Conclusion: To our knowledge, this is by far the largest reported European series of chemotherapy in TMT. Although TMT has a poor prognosis compared to GCT, its management may be improved by adapted chemotherapy associated with surgical resection of residual masses. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Medicine, Institut Gustave-Roussy, 39 rue Camille Desmoulins, Villejuif, France. Tel ; Fax: address: fizazi@igr.fr (K. Fizazi) /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 51 (2007) Introduction Germ-cell tumours (GCTs) are the most common solid tumour in young men. The prognosis of this malignancy has dramatically changed with the advent of cisplatin-containing chemotherapy: more than 80% of patients with a disseminated GCT achieve a cure [1,2]. GCTs are composed of a variety of histologic subtypes usually classified as pure seminoma or nonseminomatous germ-cell tumours (NSGCTs). On rare occasions, teratomas may undergo malignant transformation in which nongerm-cell malignancies emerge. This entity, designated teratoma with malignant transformation (TMT), arises in up to 6% of patients with GCT [3 5]. The prognosis of patients with TMT is poorer than that of patients without malignant nongerm-cell elements [3 9]. Several reports suggested that chemotherapy has a limited role, but only one recently reported series [9] described its use in these patients. In this study, we retrospectively reviewed our clinical experience with patients presenting TMT and treated with chemotherapy. 2. Patients and methods Table 1 Patient characteristics Characteristics Patients (n = 14) Age (yr) Median 29.5 Range Primary site Testis 9 Retroperitoneum 1 Mediastinum 4 Stage I 3 II 2 III 9 IGCCCG risk stratification Good 8 Intermediate 0 Poor 6 Histology Rhabdomyosarcomas 4 Adenocarcinoma 3 Osteosarcoma 2 Undifferentiated sarcoma 1 Neurosarcoma 1 Myxoid sarcoma 1 Fusiform cell sarcoma 1 Bronchoalveolar carcinoma 1 IGCCCG, International Germ Cell Cancer Consensus Group. The records of patients with GCT and a non-germ-cell histological component (TMT) diagnosed between 1986 and 2004 at Institut Gustave Roussy, Villejuif, France, were retrospectively reviewed. Patients with a primary mediastinal NSGCT who developed a hematologic malignancy were described elsewhere [10]. In patients with a testicular primary tumour, stage I was defined as disease limited to the testis, epididymis, or spermatic cord; stage II was defined as retroperitoneal lymph node involvement; and stage III was defined as metastatic spread above the diaphragm or to visceral sites. International Germ-Cell Cancer Consensus Group risk stratification [11] was determined in patients with metastases. The same pathologist (MJTL) reviewed the histologic slides. Treatment, follow-up, and survival were analyzed. Immunohistochemistry was performed to help identifying the malignant non-gct component. For example, in patient 1, the pathologic study revealed osteosarcoma (Figs. 1 and 2). In patient 9 the pathologic analysis of a lymph node showed evidence of an endometroid adenocarcinoma component (Fig. 3). Immunostaining for CK AE1/AE3 revealed numerous cells with intense cytoplasmic 3. Results During an 18-yr period, 14 male patients were diagnosed as having a TMT. Patient characteristics are described in Table 1. All patients had a mixed NSGCT in their primary tumour, containing embryonal carcinoma (n = 10), mature or immature teratoma (n = 8), seminoma (n = 6), yolk sac elements (n = 3), and choriocarcinoma (n = 1). Malignant nongerm-cell elements were identified within the primary tumour in 6 of 14 patients and at the time of relapse after first-line chemotherapy in the remaining 8 patients. Sarcoma was the most frequent histologic type and was identified in 10 patients (Table 1). Fig. 1 Computed tomography scan depicting retroperitoneal calcified mass related to a TMT-containing osteosarcoma.

3 1308 european urology 51 (2007) Fig. 2 Osteosarcomatous component in the TMT, characterized by the production of osteoid by unequivocally anaplastic cells (H & E, G: T400). Fig. 3 Well-differentiated endometrioid adenocarcinoma in TMT; the neoplastic glands are lined by columnar cells with relatively uniform nuclei (H & E, G: T400). reactivity, and negative staining for PLAP, a-feto protein, S 100 protein, synaptophysin, and chromogranin. The sites of TMT and the periods from the initial diagnosis of GCT to the diagnosis of TMT are summarized in Table Treatment Primary treatment of 4 patients consisted of surgery alone followed by surveillance (orchiectomy: n = 2), resection of the mediastinal primary tumour (n = 1), and orchiectomy followed by retroperitoneal lymph node dissection (n = 1). The remaining 10 patients received first-line cisplatin-based chemotherapy. Postchemotherapy resection of residual masses was performed in 5 of these patients. After initial treatment, 4 patients were considered in complete remission, 5 achieved a partial response, and 1 had a lethal progression. Table 3 lists the histology of TMT, site of disease, disease-specific therapy (including surgery or radiation therapy), response to therapy, and current status for all 14 patients. The median time to Table 2 Interval between diagnosis of germ-cell tumour and teratoma with diagnosis of the malignant transformation Patient Histology Interval between GCT and MT diagnosis Presence of MT histology of primary site of GCT Site of MT at time of treatment 1 Osteosarcoma 7 yr no Retroperitoneum 2 Adenocarcinoma 14 yr no Pleura and mediastinum 3 Fusiform cell sarcomas Simultaneous yes Testis 4 Undifferentiated sarcoma 21 mo no Retroperitoneum 5 Neurosarcoma Simultaneous yes Testis 6 Rhabdomyosarcomas Simultaneous yes Testis 7 Rhabdomyosarcomas Simultaneous yes Mediastinum 8 Rhabdomyosarcomas Simultaneous yes Mediastinum 9 Adenocarcinoma 10 yr no Retroperitoneum 10 Myxoid sarcoma 7 yr no Pleura and retroperitoneum 11 Osteosarcoma 4 yr no Retroperitoneum and supraclavicular lymph node 12 Adenocarcinoma 10 yr no Retroperitoneum 13 Rhabdomyosarcomas Simultaneous yes Retroperitoneum 14 Bronchoalveolar carcinoma 12 yr no Lung GCT, germ-cell tumour; MT, malignant transformation

4 Table 3 Chemotherapy for teratoma with malignant transformation Patient Stage Histology Site of malignant transformation at time of treatment Chemotherapy Response Radiation Surgery Response duration Patient status 1 II Osteosarcoma Retroperitoneum DOX-CDDP-IFM/Paclitaxelepirubicin 2 III Adenocarcinoma Pleura and mediastinum CDDP-5 FU-FOL-BLM/OXL- IRI/MTX SD no Retroperitoneal lymph node dissection (at presentation and in relapse) 10 mo alive PR yes Resection of mediastinal mass 6 mo dead 3 I Fusiform cell sarcoma Testis CR no Orchyectomy 10 yr alive 4 III Undifferentiated Retroperitoneum VP16-IFM-CDDP/DOX- PR no Orchyectomy, retroperitoneal 17 mo dead sarcoma CDDP/IFM high dose 5 III Neurosarcoma Testis DOX no None 0 dead 6 I Rhabdomyosarcomas Testis EPI-CDDP/VP 16-IFM/CBDCA- EPI/VP 16 7 III Rhabdomyosarcomas Mediastinum EPI-CBDCA-VCR/IFM- VCR-ACT D/VP16 PD yes Orchyectomy, retroperitoneal PR yes Resection residual mediastinal mass after chemotherapy 8 III Rhabdomyosarcomas Mediastinum CR no Resection of mediastinal mass without lymph dissection. 9 III Adenocarcinoma Retroperitoneum CR no Orchyectomy removing unique retroperitoneal adenopathy 10 III Myxoid sarcoma Pleura and retroperitoneum 11 III Osteosarcoma Retroperitoneum and supraclavicular lymph node VP16-IFM-CDDP/DOX-CDDP- IFM/OXL-Paclitaxel 12 I Adenocarcinoma Retroperitoneum VP16-IFM-CDDP/VP16- CDDP/DOX-CDDP PR no Orchyectomy, retroperitoneal DOX-CDDP-IFM PR no Resection residual mediastinal mass after chemotherapy PR no Orchyectomy, retroperitoneal (at presentation and at relapse) 13 II Rhabdomyosarcomas Retroperitoneum CR no Orchyectomy, retroperitoneal 14 III Bronchoalveolar carcinoma Lung VP16-IFM-CDDP/DOX- CPM/Paclitaxel-OXL/GEM PR no Orchyectomy, retroperitoneal node dissection, resection of pleural mass 12 mo dead 4 mo dead 6 mo alive 2 yr alive 5 mo dead 4 mo dead 5 mo dead 4 yr dead ACT D, actinomycine D; BLM, bleomycine; CBDCA, carboplatin; CDDP, cisplatin; CPM, cyclophosphamide; DOX, doxorubicine; EPI, epirubicine; 5FU, 5-fluorouracil; FOL, folinic acid; IFM, Ifosfamide; MTX, methotrexate; OXL, oxaliplatine; VBL, vinblastine; VP16, etoposide; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. european urology 51 (2007)

5 1310 european urology 51 (2007) recurrence was 84 mo (range: 6 168). Nine patients developed a relapse. The most frequent site of relapse was the retroperitoneum (n = 5). At relapse, 8 patients received histologically adapted chemotherapy, a regimen directed to the non-gct component identified in the biopsy or operative TMT specimen. Four of these patients achieved a partial response lasting 10, 11, 11, and 24 mo, respectively. One patient had a stable disease; 3 patients had a progression, and 2 of them rapidly died. After a median follow-up of 59 mo (range: 3 180), only 4 of 14 patients are alive, including 3 who are diseasefree. 4. Discussion TMT denotes a GCT containing a malignant somatic element [4]. The transformation of GCT remains rare and poorly understood. Two mechanisms for the development of TMT have been postulated: malignant differentiation of the totipotential embryonal carcinoma cell to a neoplasia of somatic type, or malignant transformation of mature teratoma elements. Some teratomas are malignant because of post-teratomatous malignant transformation; such tumours usually occur in the ovary or the testis and exhibit a spectrum of biologic behaviour. High-grade examples include dermoid cysts with squamous cell carcinoma or various sarcomas or melanoma, primitive neuroectodermal tumour, and ovarian glioblastoma [12]. Because the incidence of teratoma in GCT was markedly high in their series, some authors suggested that a pre-existent teratoma had undergone malignant transformation when TMT was diagnosed [3,5,8]. In our series, 8 of 14 primary tumours contained teratoma. The potential growth of teratoma is described as the growing teratoma syndrome, defined as an increase in tumour size during or after chemotherapy for GCT exclusively due to teratoma, without any other GCT component [13]. Evidence has shown that mature teratoma cells can dedifferentiate in vitro into malignant tissues [14], and this phenomenon may occur after specific chromosomal changes in TMT. The discovery of an isochromosome 12p (i(12p)), a specific marker of GCTs, among non-gct components of TMT, in addition to other chromosomal abnormalities is strong support for this hypothesis [7]. Indeed, in the series from the Memorial Sloan Kettering Cancer Center (MSKCC), chromosome 12 abnormalities were identified in 11 of 12 TMT cases, 10 of which were an i(12p) [7,9]. TMT was incidentally discovered at surgery or in patients with GCT refractory to cisplatin-based chemotherapy, although it was not identified in the primary tumour. Sarcoma was the most frequent histological type in our series (10 patients), with rhabdomyosarcoma ranking first among the subtypes (4 patients). The predominance of sarcomatous elements in TMT is widely recognised [3 5,7,8]. For example, in the MSKCC series, the incidence of sarcoma among TMT patients was 63% [7 9]. Whether the prognosis of TMT containing sarcoma is worse compared with other TMT is open to debate. Recent data seem to indicate that the prognosis of TMT may be more related to disease extension and the operability of such lesions, rather than the histologic subtype [7]. In our series, 3 patients had sarcoma among the 4 who were still alive at the last follow-up visit. We found that adenocarcinoma tended to occur after a long interval between the diagnosis of GCT and the occurrence of a TMT, whereas TMT containing other components occurred within a shorter interval, a finding that was also reported by Donadio et al. [9]. The role of chemotherapy in TMT has not been adequately assessed. TMT is considered far less responsive to cisplatin than is GCT [7]. The first report of chemotherapy in TMT was in 2 patients with TMT containing sarcomas who were treated with a doxorubicin-based regimen. One patient failed to respond, and the second died shortly after the institution of chemotherapy [5]. A patient with rhabdomyosarcoma was also successfully treated by surgery followed by chemotherapy associating cyclophosphamide, dactinomycin, and vincristine, combined with cisplatin and etoposide [5]. In our series, 9 patients were given regimens in line with that used for the standard treatment of the transformed histology (Table 3). Eight patients with disseminated TMT containing sarcoma received an anthracycline combined with ifosfamide and/or cisplatin, and 6 of them achieved a partial response. Another patient with TMT containing adenocarcinoma was given a combination of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan; this patient also achieved a response that lasted 6 mo. Using drugs with a spectrum that include the non-gct component(s) indeed seems logical, although the small number of patients in our study and in previous series precludes definitive conclusions. Prophylactic complete resection of residual masses after chemotherapy for GCT could prevent the malignant transformation of residual teratoma and thus the occurrence of TMT [13,14]. The role of this modality has also been established for postchemotherapy viable NSGCT [15]. Moreover, complete resection of TMT has been reported to impact

6 european urology 51 (2007) favourably on survival [7]. Surgery should therefore be considered the modality of choice for both the prevention and treatment of TMT. Donadio et al. [9] recommend that surgical resection should always be considered the primary modality of treatment in cases with a single tumour site. Surgery is also the recommended treatment for late relapses of GCT. Gene expression profiles of these early/late relapses of GCT correlated with the histological types, and some of these discriminating genes may give potential insights into new drug targets [16]. In summary, the best treatment of TMT currently available seems to be complete resection combined with histologically adapted chemotherapy. Complete resection of postchemotherapy residual masses of disseminated GCT is also recommended as prophylaxis against TMT, especially when the primary tumour comprises teratoma. References [1] Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med 1997;337: [2] Culine S, Kramar A, Biron P, Droz JP. Chemotherapy in adult germ cell tumors. Clin Rev Oncol Hematol 1996;22: [3] Little JSJ, Foster RS, Ulbright TM, Donohues JP. Unusual neoplasms detected in testicular cancer patients undergoing post-chemotherapy retroperitoneal lymphadenectomy. J Urol 1994;152: [4] Ahmed T, Bosl GJ, Hadju SI. Teratoma with malignant transformation in germ-cell tumors in men. Cancer 1985;56: [5] Ulbright TM, Loehrer PJ, Roth LM, Einhorn LH, Williams SD, Clark SA. The development of non-germ cell malignancies within germ cell tumors: a clinicopathologic study of 11 cases. Cancer 1984;54: [6] Loehrer Sr PJ, Hui S, Clark S, et al. Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: a clinicopathological correlation. J Urol 1986;135: [7] Motzer RJ, Amsterdam A, Prieto V, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol 1998;159: [8] Comiter CV, Kibel AS, Richie JP, Nucci MR, Renshaw AA. Prognosis features of teratomas with malignant transformation: a clinicopathological study of 21 cases. J Urol 1998;159: [9] Donadio AC, Motzer RJ, Bajorin DF, et al. Chemotherapy for teratoma with malignant transformation. J Clin Oncol 2003;21: [10] Fizazi K, Culine S, Droz JP, et al. Primary mediastinal nonseminomatous germ cell tumors: results of modern therapy including cisplatin-based chemotherapy. J Clin Oncol 1998;16: [11] International Germ Cell Consensus Collaborative Group. International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997;15: [12] Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol 2005;18:S [13] Andre F, Fizazi K, Culine S, et al. The growing teratoma syndrome: results of therapy and long-term follow-up of 33 patients. Eur J Cancer 2000;36: [14] Sonneveld DJ, Sleijfer DT, Koops HS, Keemers-Gels ME, Molenaar WM, Hoekstra HJ. Mature teratoma identified after postchemotherapy surgery in patients with disseminated nonseminomatous testicular germ cell tumors. Cancer 1998;82: [15] Fizazi K, Tjulandin S, Salvioni R, et al. Viable malignant cells after primary chemotherapy for disseminated nonseminomatous germ cell tumors: prognostic factors and role of postsurgery chemotherapy results from an international study group. J Clin Oncol 2001;19: [16] Sugimura J, Foster RS, Cummings OW, et al. Gene expression profiling of early- and late-relapse nonseminomatous germ cell tumor and primitive neuroectodermal tumor of the testis. Clin Cancer Res 2004;10: Editorial Comment Richard Foster rsfoster@iupui.edu This paper illustrates some important issues regarding the malignant transformation of teratoma. First, though patients may respond to chemotherapy directed at the histology of the transformed teratoma, the likelihood of cure with chemotherapy treatment alone is remote, at best. Complete surgical removal is the only chance for long-term cure, and surgeons undertaking such a procedure should be prepared to do whatever is necessary to ensure complete removal of cancer, including the resection of adjacent organs or resection or replacement (or both) of the great vessels. Chemotherapy can be used in the adjuvant setting after resection of transformed teratoma if particularly high-volume cancer was present at the time of resection. In our experience this has been used mainly for embryonal rhabdomyosarcoma arising in teratoma. Another potential benefit is in the situation in which the histology of the transformed teratoma is known, but the tumor is felt to be unresectable because of position or size. The administration of preoperative chemotherapy in this setting may make the subsequent resection easier and may lower perioperative morbidity.

7 1312 european urology 51 (2007) Fortunately, transformed teratoma is relatively uncommon. However, it is truly remarkable that some of these patients can be cured after having been, in many cases, heavily pretreated with both germ cell cancer-directed therapy, and subsequently, chemotherapy directed at the specific type of histologic cancer present in the transformed teratoma. Editorial Comment Jean-Pierre Droz, Department of Medical Oncology, Lyon-RTH Laennec School of Medicine, Centre Leon Berard, 28 rue Laennec, 69008, Lyon, France Germ cell tumours are fascinating cancers. The first reason for this fascination is that they are curable; they are responsive to chemotherapy but also to surgery, the indication of which has been exactly defined. The second reason lies with the tumour biology. Cancer cells are derived from primordial germ cells. Carcinogenesis occurs very early in embryonal development. Moreover, some external events (possibly environmental factors) may also play a role in malignant transformation. These tumours have a specific cytogenetic signature, the presence of an isochromosome 12p, that helps in understanding their biologic evolution [1]. Specific events are related to their particular biologic behaviour: malignant transformation of teratoma [2], late relapse [3], and secondary hematologic malignancies in patients with mediastinal tumours [4]. El Mesbahi et al. report, in this paper, on the malignant transformation of teratomas. It must be kept in mind that this transformation can be diagnosed both at surgical excision of residual disease after chemotherapy and in cases of late relapse. This form of cancer is rare, but there is no means to identify it before surgery. This is one of many arguments advocating surgery in patients with residual tumours or late recurrences. This is the take home message of the study by El Mesbahi. However, their group did not investigate the biologic characterisation of these tumours. Investigators at the Memorial Sloan-Kettering Cancer Center have shown that the presence of i(12p) is regularly associated with malignant transformation of teratoma. They have studied i(12p) by cytogenetic or fluorescence in situ hybridization (FISH) techniques in 12 of 46 teratomas with malignant transformation. Most tumours harbored the i(12p) marker, and four of these displayed a specific cytogenetic trait of the transformed secondary tumor: rearrangements of either 2q in two rhabdomyosarcomas, 11q24 in a neuroectodermic transformation, or 5q in a hematologic malignancy. Interestingly, in this last case [4], the filiation between the primary mediastinal yolk-sac tumour, the postchemotherapy teratoma, and the eventual occurrence of acute leukemia has been demonstrated by the constant presence of i(12p), with successive additions of cytogenetic abnormalities. This may favour the hypothesis of the presence of primordial germ cells within more differentiated germ cell tumours [5]. Finally, late recurrences also display i(12p). Generally, the number of copies is high, possibly correlated with chemorefractoriness in these tumours [3]. Moreover, molecular characterisation studies have emphasised the importance of the overexpression of a transcription factor, FoxD3, which is a repressor of differentiation [3]. In the study by George et al., the expression of apurinic/apyrimidinic endonuclease (Ape1), a regulator of transcription factors via redox pathways, which may have been implicated in chemoresistance, was not modified. These studies open an interesting avenue for translational research in germ cell tumours, i.e., the clinical and biologic characteristics of very infrequent clinical situations that might be used as biologic models for the study of tumour development and behaviour. References [1] Oosterhuis JW, Looijenga LH. Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer 2005;5: [2] Motzer RJ, Amsterdam A, Prieto V, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol 1998;159: [3] George DW, Foster RS, Hromas RA, Einhorn LH. Update on late relapse of germ cell tumor: a clinical and molecular analysis. J Clin Oncol 2003;21: [4] 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 1990;82: [5] Honecker F, Stoop H, Mayer F, et al. Germ cell lineage differentiation in non-seminomatous germ cell tumours. J Pathol 2006;203: