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Systemic treatment options for growing teratoma syndrome: A single-center experience with a comprehensive review of the literature


1 Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
2 Department of Medical Oncology, Ankara Dr AY Oncology Training and Research Hospital, Ankara, Turkey
3 Department of Medical Oncology, Elazig City Hospital, Elazig, Turkey

Date of Submission05-Aug-2019
Date of Decision21-Nov-2019
Date of Acceptance19-Dec-2019
Date of Web Publication28-Oct-2020

Correspondence Address:
Yusuf Acikgoz,
Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara 06100
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_568_19

 > Abstract 


Background: Growing teratoma syndrome (GTS) is a very uncommon phenomena. Given its lower prevalence, there is little data about clinichopathological features and management of GTS. Literature about disease mostly composed of case reports. In this study, we aimed to report patients characteristics and treatment modalities in our center within a relatively large cohort.
Patients and Methods: We retrospectively reviewed the clinical records 21 patients who fulfilled criteria of GTS. Survival analysis was performed by using the Kaplan-Meier method with the Long-rank test. p<0.05 was considered statistically significant.
Results: The median age at diagnosis was 25 (range 17-51). A total of 12 patients could have undergone surgery. Of patients who underwent surgery, 5 patients remained fully disease free, and 7 patients had experienced disease recurrences. Nine patients had unresectable disease, and treated with either platin-based chemotherapy or interferone α2b. Of those, 5 patients eventually had undergone autologous stem cell transplantation (ASCT) with surprisingly promising response rates. One patient had complete response and three patients had partial response. One patient died soon after ASCT due to infectious complication.
Conclusion: GTS is an unique entity with regard to its clinicopathological features and available treatment options as we mentioned in the text. Despite various agents reported to have efficacy in case reports, surgery remains as the mainstay of treatment. According to result of our study, ASCT and platin-based chemotherapy regimens may be feasible options for patients with unresectable disease.

Keywords: Chemotherapy, germ cell tumor, growing teratoma syndrome, stem cell transplantation



How to cite this URL:
Acikgoz Y, Bal O, Ergun Y, Oksuzoglu B, Yildiz B, Doğan M. Systemic treatment options for growing teratoma syndrome: A single-center experience with a comprehensive review of the literature. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299460




 > Introduction Top


The growing teratoma syndrome (GTS) is a rare entity which was firstly described by Logothetis et al. in 1982.[1] GTS is defined by the following three criteria: (i) enlargement of metastatic masses during or after chemotherapy given for nonseminomatous germ cell tumors (NSGCTs); (ii) normal level of serum tumor markers; and (iii) histopathologically confirmed mature teratoma in a resected metastatic site in patients with NSGCT.[2] The prevalence of GTS is reported to be approximately 2%–7%.[3],[4] Although GTS is considered as a disease of adolescents and young adults, it was reported during childhood in a case report.[5] GTS is supposed to be refractory to chemotherapy and radiotherapy due to its histopathology involving mature teratomatous elements.[6] Thus, early and complete surgical resection is the best choice of treatment for GTS.[7] Delayed surgery might cause difficulties in resection of tumor or lead to malignant transformation.[8] Due to its rare prevalence, GTS is not a well-known phenomenon in clinical practice. In this study, we aimed to report the clinicopathological features and treatment modalities of GTS patients followed up in our center with a review of the literature.


 > Materials and Methods Top


Study population

We retrospectively reviewed the clinical records of the 315 patients with NSGCT followed-up in our center between January 2004 and February 2018. Of these 315 patients, 21 (6.6%) fulfilled Logothetis' criteria of GTS through serial evaluations during chemotherapy and follow-up. Patients with elevated tumor markers (alpha-fetoprotein [AFP], β-human chorionic gonadotropin [HCG], and lactate dehydrogenase [LDH]) before surgery or pathologically confirmed viable tumor in resected mass were excluded from the analysis. We gathered various data from oncologic follow-up files including age at diagnosis, given treatments, serum tumor marker levels before and after chemotherapy as well as before surgery, metastatic sites, pathology reports, survival status, and stage according to the eighth edition of the American Joint Committee on Cancer manual for testis TNM staging.[9]

Statistical analysis

Statistical analysis was performed by using the Statistical Package for the Social Sciences Version 22.0 for Windows (SPSS Inc., Chicago, IL, USA). We used Kaplan–Meier test for survival, and outcomes were analyzed by the Log-rank test. Overall survival (OS) was calculated from the date of the diagnosis of GTS to date of death from any cause or last known alive. We reported two-sided P values, and P < 0.05 considered as statistically significant.


 > Results Top


A total of 21 patients who fulfilled the GTS criteria were included in this study. The median age of patients was 27 years (range 17–51), and the median follow-up time was 60.9 months (range 8.8–184.7). At the time of diagnosis, 19 (90%) patients had mixed germ-cell tumor (MGCT), while remaining had immature teratoma (n: 1, (5%)) and mature cystic teratoma (n: 1, (5%)). Of these 19 patients with MGCT, all of the patients' primary tumor consisted of teratomatous components as well as 17 patients (81%) had embryonal carcinoma, 11 patients (52.4%) had yolk sac tumor, and 3 patients (14.3%) had choriocarcinoma. All patients had received four cycles of BEP (bleomycin 30 units on days 1, 8, and 15, etoposide 100 mg/m2 on days 1–5, cisplatin 20 mg/m2 on days 1–5) chemotherapy regimen. The most frequent metastatic site was retroperitoneum (n: 14, (66%)) followed by the lung (n: 5, (24%)) and brain (n: 1, (5%)), respectively. In addition, one patient had synchronous retroperitoneal and lung metastasis. While 12 patients (57%) could undergo surgery, 9 patients (43%) could not undergo surgery due to unresectable disease. After a median 60.9 months of follow-up, 16 patients were alive, and 5 patients died in consequences of GTS. Five-year OS was 73.7%, and survival analysis is illustrated in [Figure 1]. The clinicopathological characteristics are summarized in [Table 1].
Figure 1: Kaplan-Meier survival curve for all patients

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Table 1: Patient and tumor characteristics for all patients

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Surgery was performed to 12 patients (57%) because of either increasing size of the known metastatic lesion or recurrent metastatic lesion in the absence of elevated serum tumor markers (AFP, β-HCG, and LDH) elevation. The median time to surgery was 10.1 months (range 4.6–104). The pathology reports of 12 patients who underwent surgery revealed that ten patients had pure mature teratoma, and 2 patients had only necrosis without any viable tumor. None of these patients received postoperative chemotherapy. During follow-up, 5 of the 12 patients who underwent surgery remained disease-free, whereas 7 of them had disease recurrence that needed to be treated with salvage chemotherapy (TIP: paclitaxel 250 mg/m2 on day 1, ifosfamide 1500 mg/m2 on days 2–5, mesna 1500 mg/m2 on days 2–5, and cisplatin 25 mg/m2 on days 2–5). Of patients who received salvage TIP treatment, two patients had a partial response (PR), and two patients had stable disease (SD), whereas three patients had progressive disease. Patients who had progressive disease after TIP were treated with EP (cisplatin 20 mg/m2 on days 1–5, etoposide 100 mg/m2 on days 1–5) chemotherapy. Of those, one patient experienced PR and two patients had SD. At the time of the final analysis, nine patients (75%) were alive, and three patients (25%) died during follow-up. The patients' characteristics are summarized in [Table 2].
Table 2: The baseline features of patients underwent surgery

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Of nine patients with unresectable disease, four patients had the clinical benefit (SD) with interferon α2b, and the remaining five patients were treated with salvage chemotherapy (TIP) followed by autologous stem cell transplantation (ASCT). Of the patients who underwent ASCT, one patient had a complete response, and three patients had SD; however, one patient died 1 month after ASCT due to infection. All patients who had a response with ASCT were still alive at the time of the final analysis. Among patients who did not undergo surgery, seven patients (77.5%) were alive, and two patients (22.5%) were dead at the final analysis. The patients' baseline features are shown in [Table 3].
Table 3: The baseline features of patients who had not surgery

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 > Discussion Top


This study represents a novel approach to patients with GTS. All patients in our study had undergone surgery and received adjuvant BEP at the time of the first diagnosis. Most of the primary tumor pathologies were MGCT (n: 19, (90%)). In the literature, the most common site of metastasis reported being retroperitoneum with a ratio of 67%–85%.[8] In accordance with the literature, the most common site of metastasis was the retroperitoneum (n: 14, (66%)) in our study. Pulmonary metastasis is very rare and reported to be up to 10%, according to the study conducted by Lee et al.[8] The second-most common metastasis site was the lung (n: 5, (24%)) in our study with a slightly higher frequency. Moreover, there was one patient with brain metastasis (n: 1, (5%)) which has never been reported in previous studies to the best of our knowledge. Brain metastasis was confirmed by the surgery, which was performed with curative intent. This patient experienced an early recurrence after surgery and more chemoresistant disease compared with other patients. The progress of this patient showed similarity regarding disease course to other tumors in the metastatic stage. A total of 12 patients could undergo surgery, and the remaining patients could not undergo surgery owing to unresectable disease. The median duration of time to surgery was 10.1 months (range 4.6–104) in our study, whereas it was reported to be as early as 2 months in previous studies.[10] Due to the fact that none of the patients who underwent surgery received postoperative chemotherapy, we could not make an interpretation on the role of postoperative chemotherapy in GTS management. Of patients who underwent surgery, seven patients had experienced relapse and treated with TIP chemotherapy for the recurrence. We consider that a higher recurrence rate probably related to delayed surgery. Of patients who had relapsed after surgery, two patients had PR, and two patients had SD with TIP treatment. Furthermore, we observed clinical benefit (PRand SD) with EP treatment after progression on TIP chemotherapy. On the other side, among patients who could not undergo surgery, four patients experienced modest benefit with the treatment of interferon α2b, while four patients had impressive benefits with ASCT. Of patients treated with ASCT, four patients were still alive, and only one patient died due to ASCT-related complications. The benefit of chemotherapy which we observed both in patients who relapsed after surgery and in patients without surgery support role of chemotherapy in GTS. These findings suggest that ASCT, interferon α2b, and platinum-based chemotherapy may be feasible treatment options for patients with refractory or unresectable GTS.

The GTS is a rare disease with a prevalence of 2%–7%.[3],[4] Due to its low prevalence, there is little data in the literature which mostly composed of case series.[10] Although GTS was described over 30 years ago by Logothetis in 1982, the pathogenesis of disease has not been fully elucidated. Two possible mechanisms have been proposed for the explanation of the development of the disease. First, a possible mechanism is that chemotherapy can induce the elimination of malignant cells after which only mature cells remain within the tumor.[11] The second postulated mechanism is that chemotherapy can lead to the transformation of malignant cells of immature teratoma into benign mature teratoma.[12] The latter phenomena are called chemotherapeutic retroconversion, which was first described in three patients with immature teratoma of the ovary by DiSaia et al. in 1977.[13] Amsalem et al. claimed that GTS and chemotherapeutic retroconversion are the same phenomena, and also that possible mechanism underlying the GTS is the elimination of malignant cells by chemotherapy.[14] Despite these hypotheses, the exact underlying mechanism of GTS still has not been clearly defined. The major concern about GTS is compression of adjacent organs, including mesenteric vasculature, renal artery vein, and intestines through massive tumor growth which makes complete surgical removal difficult.[3],[4],[15] The local mass effect, higher growth rate, and rarely occurring malignant transformation of GTS impose early surgical intervention as the critical point of treatment.

Although the underlying mechanism of GTS is still not clearly identified, various predictive factors, including pathology of primary tumor, growth rate of metastatic masses, and radiological changes of masses in computed tomography (CT) have been argued in some studies.[8],[10],[14] However, the low number of patients and wide variability of data from these studies do not allow to identify those factors as a definitive predictor except for the radiological features of metastatic masses. The changes in CT images of metastasis were first described from the study including seven patients by Moskovic et al. Those changes were called as “radiologic maturation” (retroconversion) by the authors, and were defined as increased density of mass lesions, whose margins became better circumscribed in relation to adjacent tissues, and the internal calcification with fatty areas and cystic change through serial CT evaluations performed after the first surgery and during chemotherapy until second surgery.[16] Based on the available data, it can be claimed that radiologic changes might be a predictive factor. Due to insufficient data about radiological features of lesions during follow-up, we cannot claim that the radiological changes might be a definitive predictor based on our study.

Currently, surgical management is the main treatment of GTS, which should be performed earlier with the complete removal of metastatic masses.[17] Delayed surgery may lead to increased risk of surgical complications owing to mechanical compression of tumor to vital organs and vessels.[17] The incomplete resection may lead to an increased risk of recurrence with a frequency of approximately 72%–83%, whereas it is only 0%–4% in patients with complete resection.[18] Moreover, malignant transformation has been also observed in up to 3% of reported cases.[19] Taken together, early and complete surgical intervention should be performed in all patients with GTS. Although little research has been conducted to evaluate the effectiveness of systemic chemotherapy, some agents, including interferon, bevacizumab, and CDK 4/6 inhibitors, only had a modest benefit in the treatment of GTS.[20],[21],[22] Of those agents, only CDK 4/6 inhibitors could achieve PR in one patient, and the remaining two patients had SD for 22 months.[22]


 > Conclusion Top


GTS is an uncommon entity. Clinicians should be aware of the diagnosis of GTS in the case of patients with NSGCT with an increased number or size of lesions in the absence of serum tumor marker elevation. Histologically confirmed benign mature teratoma is indispensable for the diagnosis of GTS. Early and optimal surgery is mandatory to reduce the risk of recurrence and malignant transformation in the management of the disease. Among the chemotherapeutics, CDK 4/6 existed as an encouraging treatment option. Moreover, ASCT, interferon α2b, and platinum-based chemotherapy seem to be promising options and based on our observations, and we believe that these treatment modalities might be a reasonable option for patients with refractory or unresectable GTS. Regular follow-up must be performed. The major limitation of our study is its retrospective nature with relatively smaller sample size. Finally, multicentric prospective clinical trials with a larger number of patients are needed to define better medical management of GTS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Logothetis CJ, Samuels ML, Trindade A, Johnson DE. The growing teratoma syndrome. Cancer 1982;50:1629-35.  Back to cited text no. 1
    
2.
Bentivegna E, Azaïs H, Uzan C, Leary A, Pautier P, Gonthier C, et al. Surgical outcomes after debulking surgery for intraabdominal ovarian growing teratoma syndrome: Analysis of 38 cases. Ann Surg Oncol 2015;22 Suppl 3:S964-70.  Back to cited text no. 2
    
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André F, Fizazi K, Culine S, Droz J, Taupin P, Lhommé C, et al. The growing teratoma syndrome: Results of therapy and long-term follow-up of 33 patients. Eur J Cancer 2000;36:1389-94.  Back to cited text no. 3
    
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Jeffery GM, Theaker JM, Lee AH, Blaquiere RM, Smart CJ, Mead GM. The growing teratoma syndrome. Br J Urol 1991;67:195-202.  Back to cited text no. 4
    
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Daher P, Riachy E, Khoury A, Raffoul L, Ghorra C, Rehayem C. Growing teratoma syndrome:First case report in a 4-year-old girl. J Pediatr Adolesc Gynecol 2015;28:e5-7.  Back to cited text no. 5
    
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Spiess PE, Kassouf W, Brown GA, Kamat AM, Liu P, Gomez JA, et al. Surgical management of growing teratoma syndrome: The M. D. Anderson cancer center experience. J Urol 2007;177:1330-4.  Back to cited text no. 6
    
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Tanaka K, Toyokawa G, Tagawa T, Ijichi K, Haratake N, Hirai F, et al. Successful treatment of growing teratoma syndrome of the lung by surgical resection: A case report and literature review. Anticancer Res 2018;38:3115-8.  Back to cited text no. 7
    
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Lee DJ, Djaladat H, Tadros NN, Movassaghi M, Tejura T, Duddalwar V, et al. Growing teratoma syndrome: Clinical and radiographic characteristics. Int J Urol 2014;21:905-8.  Back to cited text no. 8
    
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Priod F, Lorge F, Di Gregorio M, Dupont MV, Nollevaux MC, Faugeras L, et al. Recurrent masses after testicular cancer: Growing teratoma syndrome. A case report and review of the literature. Case Rep Oncol 2017;10:910-5.  Back to cited text no. 11
    
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Shibata K, Kajiyama H, Kikkawa F. Growing teratoma syndrome of the ovary showing three patterns of metastasis: A case report. Case Rep Oncol 2013;6:544-9.  Back to cited text no. 12
    
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DiSaia PJ, Saltz A, Kagan AR, Morrow CP. Chemotherapeutic retroconversion of immature teratoma of the ovary. Obstet Gynecol 1977;49:346-50.  Back to cited text no. 13
    
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Amsalem H, Nadjari M, Prus D, Hiller N, Benshushan A. Growing teratoma syndrome vs. chemotherapeutic retroconversion: Case report and review of the literature. Gynecol Oncol 2004;92:357-60.  Back to cited text no. 14
    
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Tongaonkar HB, Deshmane VH, Dalal AV, Kulkarni JN, Kamat MR. Growing teratoma syndrome. J Surg Oncol 1994;55:56-60.  Back to cited text no. 15
    
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Moskovic E, Jobling T, Fisher C, Wiltshaw E, Parsons C. Retroconversion of immature teratoma of the ovary: CT appearances. Clin Radiol 1991;43:402-8.  Back to cited text no. 16
    
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Kataria SP, Varshney AN, Nagar M, Mandal AK, Jha V. Growing teratoma syndrome. Indian J Surg Oncol 2017;8:46-50.  Back to cited text no. 17
    
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Panda A, Kandasamy D, Sh C, Jana M. Growing teratoma syndrome of ovary: Avoiding a misdiagnosis of tumour recurrence. J Clin Diagn Res 2014;8:197-8.  Back to cited text no. 18
    
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Kampan N, Irianta T, Djuana A, Pei Shan L, Hashim Omar M, Hatta Mohd Dali AZ. Growing teratoma syndrome: A rare case report and review of the literature. Case Rep Obstet Gynecol 2012;2012:134032.  Back to cited text no. 19
    
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Inoue M, Hisasue S, Nagae M, China T, Saito K, Isotani S, et al. Interferon-α treatment for growing teratoma syndrome of the testis. Case Rep Nephrol Urol 2013;3:40-5.  Back to cited text no. 20
    
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Mego M, Recková M, Sycova-Mila Z, Obertova J, Brozmanova K, Salek T, et al. Bevacizumab in a growing teratoma syndrome. Case report. Ann Oncol 2007;18:962-3.  Back to cited text no. 21
    
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Vaughn DJ, Flaherty K, Lal P, Gallagher M, O'Dwyer P, Wilner K, et al. Treatment of growing teratoma syndrome. N Engl J Med 2009;360:423-4.  Back to cited text no. 22
    


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