INTRODUCTION

Germ cell tumor (GCT) is a rare tumor, accounting for 3% of childhood cancers.1 Extracranial germ cell tumor (EGCT) is more common than intracranial germ cell tumor (IGCT), and more than half of EGCT was extragonadal in origin1. EGCT can be classified based on histological features into 2 categories: teratoma and malignant GCT. The clinical manifestations are varied,

depending on the location of the tumor. EGCT is found to be associated with several genetic syndromes causing gonadal dysgenesis such as Klinefelter syndrome, Turner syndrome, and Swyer syndrome.2-4 Those with EGCT appear to respond well to the treatment and can attain long term remission. The mainstay of treatment of EGCT is surgery, although chemotherapy may be beneficial in some cases which harbor a malignant component. The

outcome of EGCT in developed countries was relatively favorable.5 Previous study in Thailand demonstrated the 5-year overall survival (OS) rate of pediatric germ cell tumor (GCT) of 70.6%; however, this study included both IGCT and EGCT.6 The clinical information regarding Thai patients with EGCT has been scarce. Our study aimed to determine the clinical features and outcomes of pediatric EGCT in one of the tertiary centers in Thailand.

MATERIALS AND METHODS

This retrospective study was conducted in patients diagnosed with EGCT at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, from January 2004 to December 2013. All patients with newly diagnosed EGCT during the study period were recruited; those who refuse the treatment were further excluded. The diagnosis of EGCT was established based on clinical features, tumor markers, and radiographic findings. Patients who had normal serum tumor markers must have a histopathology result to confirm a diagnosis of EGCT. The clinical staging of testicular, ovarian, and extragonadal GCT was determined by the Children’s Oncology Group staging system.7,8 Surgery was a primary treatment for resectable tumors. Those who had an unresectable tumor received neoadjuvant chemotherapy consisting of cisplatin, etoposide, and bleomycin (PEB) before surgery.9 Patients with teratoma were treated with surgery solely. However, those children with immature teratoma (IT) either greater than stage II or grade III tumor may have received PEB upon physician discretions. Among patients with nonteratomatous EGCT, those with stage I testicular GCT did not receive adjuvant chemotherapy after surgery, while other patients were subsequently treated with adjuvant PEB. The responses to the treatment were classified using RECIST guidelines.10 This retrospective study was approved by the Siriraj Institutional Review Board (SIRB), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (Si 380/2020).

Statistical analysis

The collected data were analyzed using SPSS Statistic version 22.0 for Windows (SPSS Inc., Chicago, IL). Demographic data were described using mean, medians, and percentage. The Kaplan-Meier survival curve was used to demonstrate the OS and event- free survival (EFS) rate of EGCT patients; event was defined as tumor relapse or death. The patients’ age at diagnosis, stage, histopathology subtype, site of tumor, and adequacy of surgery were analyzed using the Cox regression analysis to determine the predictors

Original Article SMJ

of survival. The adjusted hazard ratio (HR) and 95% confidence intervals (CIs) were calculated. A p-value of <0.05 was regarded as being statistically significant.

RESULTS

Forty-seven patients were diagnosed with EGCT; 3 patients were excluded due to treatment refusal. There were 44 patients included in this study, with the median age at diagnosis of 1.74 years (range 1 day-14.7 year). Twenty-eight patients (64%) had extragonadal tumor; sacrococcygeal area was the most common primary tumor location. Majority of the patients (61%) had malignant EGCT. Yolk sac tumor (YST) was the most common histopathological diagnosis, followed by mature teratoma (MT) and mixed GCT. Of all 10 patients with mixed GCT, MT with a component of YST was the most common diagnosis. The demographic data, clinical features, histopathology and staging of EGCT are presented in Table 1. Three patients had underlying genetic diseases, including 1 Down syndrome (DS) with stage I retroperitoneal IT grade II, 1 DS with stage I ovarian dysgerminoma, and 1 Cornelia de Lange syndrome (CdLS) with stage III sacrococygeal mixed GCT comprising of MT and YST.

One patient presented with hemophagocytic lymphohistiocytosis (HLH) and subsequently diagnosed with mediastinal germinoma. He ultimately died of infectious complication before receiving treatment for EGCT. Thirty patients (68%) were treated with upfront surgery while 13 patients (29%) received chemotherapy as an initial treatment. Of all 30 patients undergoing upfront surgery, 16 patients did not receive adjuvant chemotherapy since their tumors were completely resected and contained no malignant component. Twenty-four patients (55%) received combination treatment of surgery and chemotherapy, while 16 patients (36%) were solely treated with surgery and 3 patients (7%) received chemotherapy without surgical treatment (Fig 1). Chemotherapy (PEB) was prescribed for 27 patients, including 26 patients with malignant EGCT and 1 patient who had sacrococcygeal IT grade III with lymph node metastasis.

Three patients with a pathological diagnosis of sacrococcygeal IT grade II (1 patient) and III (2 patients) had elevated serum tumor markers, but did not receive chemotherapy. All of them were alive and free of disease at the end of the study.

One patient died before the treatment of EGCT was initiated. Thirty-eight patients (86%) had a complete response; 5 patients who were unresponsive to treatment subsequently died of disease. Relapse occurred in 3

patients, with a median time to relapse of 1 year (range

3.3months-1.1 years). Of all 3 patients with relapse, 2 patients (1 patient with YST at vaginal wall and the other with IT at mandible) achieved remission after a combination of surgery and chemotherapy, and 1 patient died of disease progression. The mortality of EGCT in this study is detailed in Table 2. Among 27 patients who received chemotherapy, 19 patients (70%) experienced treatment-related toxicity. The most common adverse reaction from chemotherapy were infection (55%) and hematotoxicity (55%), followed by renal toxicity (37%). Two patients with mediastinal mixed GCT had concomitant hematologic malignancies. One of them developed prolonged cytopenias during treatment; his bone marrow aspiration result was compatible with acute megakaryoblastic leukemia. The other patient had tumor progression and subsequently died of disease; the autopsy result revealed a component of myeloid sarcoma within the remaining mediastinal mass with the presence of isochromosome 12p abnormality.

The 5-year EFS and OS were 78.3% (95%CI 10.3-

13.9) and 81.1% (95%CI 10.8-14.2), respectively (Fig 2). The median follow-up time was 6.9 years (range 14 days-

15.2years). The comparison of EFS and OS according to clinical factors is demonstrated in Table 3. Cox regression analysis was performed to determine the predictors of mortality; the only factor associated with survival was

Original Article SMJ

the adequacy of surgery (HR 8.69, 95% CI 1.44-52.26, p-value 0.018).

DISCUSSION

In our study, EGCT was common among patients under 2 years of age, with a female preponderance; this was concordant with other studies.1,11 Sacrococcygeal area appeared to be the most common primary site, which corresponds with a previous study.11

Klinefelter syndrome, Turner syndrome, and Swyer syndrome were found to be associated with EGCT2-4 but none of the patients in our study harbor those conditions. However, 3 of our patients had underlying genetic diseases including DS and CdLS. Individuals with DS have been reported to have EGCT, but the incidence of EGCT in DS was relatively low compared to that of hematologic malignancies.12 CdLS is a rare syndrome resulting from mutation in cohesin protein13, and typically affected craniofacial, gastrointestinal and central nervous systems. Although mutation of cohesin might be associated with the development of cancer, there was no clear evidence that CdLS increased the risk of cancer. Few case reports of CdLS with Wilms tumor and liver hemangioendothelioma have been documented14, but there was still no report of EGCT in CdLS. Hence, we believe that the finding of EGCT in CdLS in our study might be an incidental finding.

Several type of hematologic malignancies, especially acute megakaryoblastic leumemia, were reported in patients with mediastinal GCT.9,15 Isochromosome 12p might be responsible for the concomitant hematologic malignancies in these patients.16 Although only one of our patients harbor this abnormal chromosome, we believed that the hematologic malignancies in both of them were related to the mediastinal GCT rather than a secondary malignancy related to cancer treatment since theirs myeloid neoplasms developed very early after the initiation of chemotherapy.

Chemotherapy treatment in IT is controversial, especially in ovarian IT.17 However, several reports have revealed that chemotherapy might not benefit for other IT patients, even if they have malignant foci or elevated tumor markers.18,19 In accordance with the aforementioned studies, all 3 IT patients with elevated serum tumor markers in our study survived after having a solely surgical intervention.

Previous reports revealed that teratoma usually had a better outcome than malignant EGCT.20 In contrast, patients with teratomatous EGCT in our study had an inferior survival rate compared to malignant EGCT, but without statistical significance. However, other factors, such as treatment abandonment or a patient’s preexisting conditions, might have affected the treatment outcome. Among the 3 teratomatous EGCT patients who died in this study, only 1 patient died of a refractory disease, while another patient died of disease progression due to treatment refusal and the other patient with DS died of infection not related to cancer treatment several months after completing therapy.

The 5-year OS rate of 81.1% in this cohort was comparatively favorable to 70.6% of the previous Thai study.6 However, the aforementioned study included both IGCT and EGCT; the interpretation should be cautious. Improvements in supportive care may account for the better outcome in our study, given the fact that the chemotherapy protocol has not drastically changed. The outcome of present study was inferior to that of developed countries5; this may be due to the higher proportion of teratomatous EGCT in that study compared to our study, 78.7% versus 38.6%.

The survival rate of advanced-stage disease was still inferior to early-stage disease5, including the results of our study. Although several treatment approaches, such as an intensive dose of PEB21 and high dose chemotherapy with autologous stem cell rescue22 were initiated in patients with advanced disease, they failed to demonstrate any survival benefit. In addition, disease progression was the major cause of death in our study

Original Article SMJ

especially in patients with advanced stage. More effective treatment approaches may be required for such patients. Younger age at diagnosis i.e. less than 11 years old and gonadal tumor in origin were also reported to be a good predictor for survival.23 Both groups also provided the better survival in our study but without statistical significance, a larger sample size might be needed to better determine the prognostic factors.

A few patients with relapse can be salvaged by surgery. The Cox regression analysis in our study also demonstrated that surgery significantly improved the survival rate. Therefore, for patients whose tumor cannot be completely removed, repeated surgery may be warranted.

There were limitations in this study that need to be mentioned. First, as is common with retrospective studies, some data might be missing or incomplete. Secondly, the sample size in this cohort appears to be small; some significant prognostic factors might be not salient. Thirdly, our center often receives complicated cases, possibly limiting the generalizability of our data and findings.

CONCLUSION

The outcome of EGCT in this study seemed to be favorable but still inferior to that of developed countries, possibly due to the higher proportion of nonteratomatous EGCT in our study. The adequacy of surgery appeared to be factor-associated with better clinical outcomes, whereas novel therapy may be warranted for those patients who are unresponsive to the current treatment.

Conflict of interest:The authors have no conflicts of interest to declare.

REFERENCES

1.Kaatsch P, Hafner C, Calaminus G, Blettner M, Tulla M. Pediatric germ cell tumors from 1987 to 2011: Incidence rates, time trends, and survival. Pediatrics 2015;135:e136-43.

2.Matsumoto F, Shimada K, Ida S. Tumors of bilateral streak gonads in patients with disorders of sex development containing y chromosome material. Clin Pediatr Endocrinol 2014;23:93-7.

3.Piazza MJ, Urbanetz AA. Germ cell tumors in dysgenetic gonads. Clinics (Sao Paulo) 2019;74:e408.

4.Williams LA, Pankratz N, Lane J, Krailo M, Roesler M, Richardson M, et al. Klinefelter syndrome in males with germ cell tumors: A report from the children’s oncology group. Cancer 2018;124:3900-8.

5.De Backer A, Madern GC, Pieters R, Haentjens P, Hakvoort- Cammel FG, Oosterhuis JW, et al. Influence of tumor site and histology on long-term survival in 193 children with extra- cranial germ cell tumors. Eur J Pediatr Surg 2008;18:1-6.

6.Wiangnon S, Veerakul G, Nuchprayoon I, Seksarn P, Hongeng S, Krutvecho T, et al. Childhood cancer incidence and

Laohverapanich et al.

survival 2003-2005, thailand: Study from the thai pediatric oncology group. Asian Pac J Cancer Prev 2011;12:2215-20.

7.Olson TA, Murray MJ, Rodriguez-Galindo C, Nicholson JC, Billmire DF, Krailo MD, et al. Pediatric and adolescent extracranial germ cell tumors: The road to collaboration. J Clin Oncol 2015;33:3018-28.

8.Rogers PC, Olson TA, Cullen JW, Billmire DF, Marina N, Rescorla F, et al. Treatment of children and adolescents with stage ii testicular and stages i and ii ovarian malignant germ cell tumors: A pediatric intergroup study--pediatric oncology group 9048 and children’s cancer group 8891. J Clin Oncol 2004;22:3563-9.

9.Sowithayasakul P, Sinlapamongkolkul P, Treetipsatit J, Vathana N, Narkbunnam N, Sanpakit K, et al. Hematologic malignancies associated with mediastinal germ cell tumors: 10 years’ experience at thailand’s national pediatric tertiary referral center. J Pediatr Hematol Oncol 2018;40:450-5.

10.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer 2009;45:228-47.

11.Schneider DT, Calaminus G, Koch S, Teske C, Schmidt P, Haas RJ, et al. Epidemiologic analysis of 1,442 children and adolescents registered in the german germ cell tumor protocols. Pediatr Blood Cancer 2004;42:169-75.

12.Hasle H. Pattern of malignant disorders in individuals with down’s syndrome. Lancet Oncol 2001;2:429-36.

13.Liu J, Krantz ID. Cornelia de lange syndrome, cohesin, and beyond. Clin Genet 2009;76:303-14.

14.Maruiwa M, Nakamura Y, Motomura K, Murakami T, Kojiro M, Kato M, et al. Cornelia de lange syndrome associated with wilms’ tumour and infantile haemangioendothelioma of the liver: Report of two autopsy cases. Virchows Arch A Pathol Anat Histopathol 1988;413:463-8.

15.Nichols CR, Roth BJ, Heerema N, Griep J, Tricot G. Hema- tologic neoplasia associated with primary mediastinal germ- cell tumors. N Engl J Med 1990;322:1425-9.

16.Bosl GJ, Ilson DH, Rodriguez E, Motzer RJ, Reuter VE, Chaganti RS. Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst 1994;86:349-55.

17.Faure-Conter C, Pashankar F. Immature ovarian teratoma: When to give adjuvant therapy? J Pediatr Hematol Oncol 2017;39:487-9.

18.Mann JR, Gray ES, Thornton C, Raafat F, Robinson K, Collins GS, et al. Mature and immature extracranial teratomas in children: The uk children’s cancer study group experience. J Clin Oncol 2008;26:3590-7.

19.Marina NM, Cushing B, Giller R, Cohen L, Lauer SJ, Ablin A, et al. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A pediatric oncology group/children’s cancer group intergroup study. J Clin Oncol 1999;17:2137-43.

20.Rescorla FJ, Sawin RS, Coran AG, Dillon PW, Azizkhan RG. Long-term outcome for infants and children with sacrococ- cygeal teratoma: A report from the childrens cancer group. J Pediatr Surg 1998;33:171-6.

21.Cushing B, Giller R, Cullen JW, Marina NM, Lauer SJ, Olson TA, et al. Randomized comparison of combination chemo- therapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: A pediatric intergroup study--pediatric oncology group 9049 and children’s cancer group 8882. J Clin Oncol 2004;22:2691-700.

22.Necchi A, Mariani L, Di Nicola M, Lo Vullo S, Nicolai N, Giannatempo P, et al. High-dose sequential chemotherapy (hds) versus peb chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: Mature results of an italian randomized phase ii study. Ann Oncol 2015; 26:167-72.

23.Frazier AL, Hale JP, Rodriguez-Galindo C, Dang H, Olson T, Murray MJ, et al. Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol 2015;33:195-201.