Annals of Surgical Oncology 10:131-135 (2003)
© 2003 Society of Surgical Oncology
Non–Germ Cell Malignancy in Residual or Recurrent Mass After Chemotherapy for Nonseminomatous Testicular Germ Cell Tumor
Martijn F. Lutke Holzik, MD,
Harald J. Hoekstra, MD, PhD,
Nanno H. Mulder, MD, PhD,
Albert J. H. Suurmeijer, MD, PhD,
Dirk Th. Sleijfer, MD, PhD and
Jourik A. Gietema, MD, PhD
From the Departments of Surgical Oncology (MFLH, HJH), Medical Oncology (NHM, DTS, JAG), and Pathology (AJHS), University Medical Center Groningen, Groningen, The Netherlands.
Correspondence: Address correspondence and reprint requests to: H. J. Hoekstra, MD, PhD, Department of Surgical Oncology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands; Fax: 31-50-3614873; E-mail: h.j.hoekstra{at}chir.azg.nl
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ABSTRACT
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Background: After chemotherapy for nonseminomatous testicular germ cell tumor (NSTGCT), residual masses or recurrent disease may contain a non–germ cell malignancy (NGCM).
Methods: Over 20 years, 369 patients with disseminated NSTGCT were treated with cisplatin-based polychemotherapy at the University Medical Center Groningen. Residual tumor masses were resected in 244 patients and recurrent tumor masses in 37 patients. Histology was reviewed, focusing on the presence of NGCM.
Results: Nine patients developed an NGCM. Four patients had an NGCM in the resected residual tumor mass after chemotherapy: three patients had a sarcoma, and one patient had both a sarcoma and an adenocarcinoma. Five patients developed a late recurrence with an NGCM after 39, 40, 72, 72, and 84 months. One patient had a primitive neuroectodermal tumor, one had a sarcoma, and three had an adenocarcinoma in the resected recurrent tumor mass. A complete surgical resection was achieved in five (56%) of the nine patients. After a median follow-up of 48 months (range, 3–271 months), five patients had no evidence of disease (56%), three patients were dead of disease (33%), and one patient was alive with disease (11%).
Conclusions: Sarcoma, adenocarcinoma, or both in residual or recurrent tumor masses after combined-modality NSTGCT treatment are rare. Complete surgical resection of the tumor mass is the only curative treatment option.
Key Words: Testicular neoplasm • Nonseminoma • Malignant transformation • Chemotherapy • Surgery • Sarcoma
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INTRODUCTION
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Testicular germ cell tumors are a classic example of a curable malignancy even if dissemination has occurred, with a long-term survival between 50% and 90% related to prognostic factors. Survival has improved substantially, mainly because of the advent of cisplatin-based polychemotherapy in the late 1970s, as well as interdisciplinary treatment.1–4 An important part of standard treatment is resection of residual disease after cisplatin-based polychemotherapy; this occurs in approximately 30% to 55% of patients.5,6 Resected residual retroperitoneal tumor masses (RRRTMs) contain necrotic debris in 45%, mature teratoma in approximately 40%, and residual viable germ cell tumor in 10% of the patients.1,6 The frequency of necrosis, teratoma, and viable residual tumor in resected pulmonary nodules and mediastinal lymph nodes is similar to that in the retroperitoneum.7 Therefore, residual disease at these sites is also resected, if possible. If the completely resected residual disease shows teratoma, necrosis, or fibrosis, the prognosis is good, and no further treatment is necessary. In patients with residual viable germ cell tumor, additional salvage chemotherapy is frequently given. Resection of residual (mature) teratoma is an important part of the (surgical) treatment because (mature) teratoma may grow locally at an unspecified rate and could cause the so-called growing teratoma syndrome. In rare cases, non–germ cell malignancies (NGCMs) are present in the resected residual tumor mass. Sarcomas and adenocarcinomas are examples of these NGCMs. These NGCMs can be present in the resected residual disease after chemotherapy, but they may also be found in resected (late) recurrent disease. The outcome of these NGCMs is not well characterized, nor are the therapeutic options.5,8–13 Therefore, we studied the single-center experience of the University Medical Center Groningen (UMCG) with NGCMs in all consecutive testicular cancer patients treated for disseminated nonseminomatous testicular germ cell tumor (NSTGCT). The literature is reviewed, and recommendations with respect to the treatment and follow-up for these patients are discussed.
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PATIENTS AND METHODS
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The medical records of all 369 consecutive patients with disseminated NSTGCT treated from 1979 to 1999 with cisplatin-based polychemotherapy at the UMCG, The Netherlands, were reviewed with respect to the occurrence of an NGCM. After completion of chemotherapy, all patients were restaged with computed tomographic (CT) scans of the chest and the abdomen and by monitoring serum tumor markers. If serum tumor markers were increased or failed to decrease according to their serum half-life, supplementary salvage chemotherapy was administered. Patients who had normal tumor marker levels after completion of chemotherapy but who showed radiological residual disease underwent resection of the RRRTM. Patients with normal tumor markers and a normal CT scan after chemotherapy, but who had a teratoma component in the primary tumor, underwent an exploratory laparotomy and eventual resection of the RRRTM. Patients who had no evidence of disease after restaging with CT scan and who had no mature teratoma in the primary tumor entered a standard regular follow-up scheme that included physical examination, determination of tumor markers, and chest x-ray. If a recurrence occurred in these patients (clinical or radiological diagnosis with or without increased serum tumor makers), patients were treated with radical surgical resection of the recurrent tumor mass, if possible, and with additional chemotherapy in the case of viable testicular cancer. An NGCM was defined as the histologically proven presence of malignant non–germ cell elements within the resected residual or recurrent residual tumor.
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RESULTS
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During 1977 to 1999, 369 patients received chemotherapy for an NSTGCT. Adjuvant surgery as part of the initial treatment was performed in 244 patients. Four (1.6%) had an NGCM in the resected residual tumor mass. Surgery for recurrent disease was performed in 37 patients, and in 5 (14%) of them, an NGCM was documented. The median age of the nine patients was 29 years (range, 21–58 years) at diagnosis of the NSTGCT. Patient characteristics are listed in Table 1. Two of these nine patients (patients 5 and 8) have been previously described.14,15 Eight of the nine patients had mature teratoma components in their primary testicular tumor. One patient had only teratoma components in the recurrent tumor. Of the four patients who had an NGCM in their resected residual tumor mass after chemotherapy, a sarcoma element was diagnosed in three patients and one patient had sarcoma and adenocarcinoma elements. In three of these four patients, radical surgical resection was obtained, and no recurrence developed during follow-up periods of 20, 152, and 271 months. In one patient palliative surgery was performed; the patient died as a result of disease 33 months after surgery.
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TABLE 1. Clinical and pathologic details of patients with a non–germ cell malignancy after treatment for disseminated NSTGCT
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Of the five other patients who subsequently relapsed with an NGCM after 39, 40, 72, 72, and 84 months, three developed an NGCM after primary completing of chemotherapy and resection of retroperitoneal residual disease containing mature teratoma or necrosis/fibrosis. Two patients had a previous complete biochemical and radiological remission after chemotherapy and were therefore observed clinically according to the UMCG protocol. All five patients underwent an exploratory laparotomy for the relapse. One patient had a primitive neuroectodermal tumor, one had a sarcoma, and three had adenocarcinoma elements in their relapsed tumor mass. Complete surgical resection of the tumor was achieved in two patients, and these remained free of disease during follow-up (48 and 210 months). In the three remaining patients, radical surgical resection was not possible. Two of these patients died as a result of disease, and one patient is alive with disease. In the patients in whom complete surgical resection was not obtained, further palliative treatment was applied. At the time of this survey, with a median follow-up of 48 months (range, 3–271 months), five patients (56%) had no evidence of disease, three patients (33%) had died of disease, and one patient (11%) was still alive with disease.
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DISCUSSION
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The finding of an NGCM in metastases resected after chemotherapy for disseminated NSTGCT is rare. Malignant transformation of teratomatous residual masses occurs in 3% to 6% of patients with metastatic germ cell tumors treated with cisplatin-based polychemotherapy.8 In the UMCG series, the frequency of an NGCM was 2.4% (9 of 369 patients) of all patients with disseminated NSTGCT, 1.6% (4 of 244 patients) of all patients treated with adjuvant surgery as part of the initial treatment, and 14% (5 of 37 patients) of all recurrences. No clinical characteristics were specific for malignant transformation. Suspicion can be raised when a patient is responding well to chemotherapy and serum tumor markers decline, but the radiological tumor mass is growing.
Because of their rare occurrence, little is known about the natural history, treatment, prognosis, or follow-up of NGCMs after combined-modality treatment for NSTGCT. Only a few studies describe these NGCMs and the various treatments and outcomes (Table 2). Sarcoma and adenocarcinoma are the most common NGCM elements. In the largest series, reported by Little et al.,5 different types of sarcoma were found in 23 patients and adenocarcinoma was found in 18 of 45 patients. There are several reasons to hypothesize a relation between mature teratoma and the development of NGCM. The NGCM is, in most cases (in this series, eight out of nine), accompanied by mature teratoma, while other nonseminomatous elements are lacking. This phenomenon was also found by others.5,8,12 Oosterhuis et al.16 concluded that mature teratoma is found significantly more often in metastases derived from primary tumors containing mature teratoma areas; apparently chemotherapy causes selective destruction of components other than mature teratoma. Although mature teratoma is histologically benign, aneuploidy is frequently found.5 Moreover, Castedo et al.,17 using cytogenetic analysis of mature residual teratomas, found an abnormal chromosomal constitution with an under- and overrepresentation of several chromosomes, suggesting a chromosomal imbalance and, therefore, a malignant constitution. Thereby, Motzer et al.10 were able to identify in NGCMs isochromosome 12p, reflecting germ cell tumor clonity. Therefore, it seems that a mature teratoma can develop into a malignant transformation with a variety of histologies and aggressive growth.
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TABLE 2. Non–germ cell malignancies after nonseminomatous testicular germ cell tumor treatment: overview of the literature
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In this series, nine patients developed an NGCM. The patients can be divided into two groups: one in which the NGCM was found in the resected residual tumor mass as part of the initial treatment of disseminated NSTGCT. Because in most cases the malignant transformation is present in foci adjacent to mature teratoma areas, this phenomenon is a plea for complete surgical resection of any residual tumor mass. The other group developed a secondary or late recurrence containing an NGCM. In case of a nonradical resection of RRRTM or after a complete response after cisplatin-based polychemotherapy, microscopic residual teratoma may remain dormant for prolonged periods before it grows and additional malignant transformation occurs. The treatment of choice for any residual or recurrent mass, whether it contains NGCM or not, is complete surgical resection. Several authors previously reported that a complete resection of NGCM had a favorable affect on survival.5,10,12 The results of this study support these data in the literature and point to the important role of radical surgery in the treatment of patients with an NGCM. In five of nine patients, a complete surgical resection was achieved (patients 2, 3, 4, 7, and 8; Table 1), and these patients are alive with no evidence of disease; however, for patients in whom a complete resection was not possible, disease progression was encountered. The possibility of performing a complete surgical resection is mainly based on the tumor size and the localization of the NGCM.
In contrast to germ cell tumors, NGCMs do not respond to cisplatin-based chemotherapy. The results of several cytostatic agents have been disappointing, even when chemotherapy has been adapted to histology.11,18 Also, intraoperative radiotherapy has been unsuccessful.14
Table 2 summarizes the literature with respect to the NGCM publications. It seems that patients with NGCM in their resected tumor mass after combined-modality treatment for NSTGCT do worse than patients without NGCM elements. Recently we reported that 82% of patients who had mature teratoma only in their resected RRRTM after chemotherapy for NSTGCT were alive with no evidence of disease after a median follow-up of 7 years (range, .5–16 years).6 This is in contrast to this series of NGCMs, in which only 56% of the patients are alive with no evidence of disease after a median follow-up of 48 months (range, 3–271 months). This difference in prognosis is also found in other studies8 and seems to be related to patients in whom complete surgical resection is not possible. In this series, no recurrences were observed after radical surgical resection of tumor containing NGCM. Only an aggressive surgical approach may influence the outcome of patients with NGCM and prolong overall and disease-free survival, because no adjunctive therapies are effective.
The main question is still how to proceed in patients with disseminated testicular cancer after chemotherapy: how much is too much, and how much is enough? The protocol used at the UMCG has advantages and disadvantages. By performing only a so-called resection of RRRTM, patients will have less treatment-related morbidity in comparison with the classic retroperitoneal lymph node dissection, unilateral retroperitoneal lymph node dissection, or nerve-preserving retroperitoneal lymph node dissection; however, there is a theoretical chance of an increased risk of relapse. The group of patients with normal tumor markers and CT scans, in whom no further surgery was performed, also have the theoretical risk of developing a relapse, but not the treatment-related morbidity of retroperitoneal surgery. For the follow-up of these patients, we recommend a standard regular follow-up scheme with physical examination and monitoring of serum tumor markers.19
In conclusion, NGCM after combined-modality treatment for disseminated NSTGCT is rare. Several arguments point to malignant transformation of mature teratoma cells in the metastatic or recurrent tumor. Radical surgical resection is the only curative treatment. Chemotherapy and/or radiation treatment are ineffective and can be used only with palliative intent.
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Footnotes
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Non–germ cell malignancy in residual or recurrent tumor after treatment for disseminated nonseminomatous testicular germ cell tumor is a rare event, and complete surgical resection of these lesions is the only curative treatment option.
Received for publication May 21, 2002.
Accepted for publication October 8, 2002.
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ABSTRACT
INTRODUCTION
