Zara Shah  ( Section of Neurosurgery, Department of Surgery, Aga Khan University, Karachi, Pakistan. )
Hafiza Hifza Bashir  ( Liaquat National Hospital and Medical College, Karachi, Pakistan. )
Saqib Kamran Bakhshi  ( Section of Neurosurgery, Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan. )
Muhammad Shahzad Shamim  ( Section of Neurosurgery, Department of Surgery, Aga Khan University Hospital, Karachi. )

Brain metastasis from testicular germ cell tumour (TGCT) is rare and represents only 2% of metastatic brain tumours. Although TGCTs have a good survival rate, the prognosis of brain metastasis is poor. Due to the rarity of the diagnosis, there are limited studies on the topic and a standardized treatment protocol does not exist. Surgical management has long been considered a positive prognostic factor; however, recent studies have investigated the impact of chemotherapy and radiotherapy in these patients. Current literature suggests multiplicity of brain lesions and treatment with chemotherapy or radiotherapy alone can have a poor impact on the prognosis of the disease. However, studies with larger cohorts are required to understand and develop the optimal treatment protocol for patients with brain metastasis from TGCT.

 

DOI: 10.47391/JPMA.23-37

 

Introduction

 

Testicular germ cell tumour (TGCT) is the most common malignancy in males aged between 20 to 40 years and carries a high risk of metastasis.¹ Cerebral metastasis of TGCT is rare and comprises of 2% of metastatic brain tumours.² TGCTs are highly curable, however, metastasis to the brain bears a poor prognosis.³ Although TGCTs are highly sensitive to chemotherapy,  the blood brain barrier (BBB) presents as a therapeutic challenge as most of the standard chemotherapeutic drugs cannot cross it.⁴ Contrary to the high cure and survival rates in patients with TGCT, it is currently difficult to manage patients with cerebral metastases as the optimal treatment is still unknown partly due to the rarity of its presentation.⁵ Although surgical management has long been considered a positive prognostic factor, recent studies have mostly investigated the impact of chemotherapy and radiotherapy in these patients. Figures 1,2 and 3.

 

 

 

 

Review of evidence

 

Due to the rarity of brain metastasis of TGCTs, deciding on the optimal treatment presents as a challenge. We conducted a thorough search on PubMed and Google Scholar for evidence on TGCT metastasizing to the brain. Nonomura et al. retrospectively reviewed 27 cases of TGCT with brain metastasis. Twenty-six of the patients were diagnosed with non-seminomatous GCT, while seminomatous GCT occurred only in one patient. All 27 of the patients received chemotherapy whereas 24 of the 27 also received radiotherapy. Five of the 27 patients were managed with surgical resection with chemotherapy alone or in addition to radiotherapy. The authors reported that the 5- and 10-year disease-specific survival rates for all cases were both 35.9%. Patients who were initially diagnosed with brain metastasis had a better survival than those who developed brain metastasis during the treatment  of TGCT although the difference was not significant. Additionally, survival of patients with a single brain metastasis was significantly better than patients with multiple brain metastases. However, the authors found that on multivariate analysis multiplicity was the only significant prognostic factor for survival from the initial diagnosis and survival from the appearance of brain metastasis. Moreover, the survival benefit of surgical resection for brain metastasis could not be identified in this study. The authors concluded that due to the small cohort, providing definitive treatment guidelines for brain metastases of testicular germ cell tumours is difficult and that further studies based on larger clinical series would be helpful in treating patients with such brain metastasis.⁵

Salvati et al. reported their experience of 15 patients who were diagnosed with cerebral metastasis from testicular non-seminomatous GCTs. The authors classified the patients into two groups; Group A included patients who were diagnosed with brain metastasis at the initial diagnoses (n=7) and Group 2 included patients who had developed brain metastasis during or after chemotherapy (n=8). The mean age of the patients was 33 years. All of the patients had undergone surgery plus whole-brain radiotherapy (WBRT), and chemotherapy based on cisplatin. The mean survival time of the patients was 37.7 months, and 5-year survival rate was 53%. There was statistically significant difference between the two groups in survival times (mean 54 months in A, mean 26 months in B, P<0.05). On univariate analysis, the presence of a trophoblastic component at histopathological analysis of the metastasis negatively influenced survival. However, the authors reported that multiple brain metastasis proved to be a significant prognostic factor at both univariate and multivariate analysis. The authors noted that the relatively positive outcomes in terms of survival could have been influenced by surgical treatment and that surgery had offered better survival results than other types of treatment in this study cohort. The authors, as a result of their findings, have advocated for aggressive treatment with surgery plus adjuvant radiotherapy and chemotherapy for patients with brain metastasis from testicular non-seminomatous GCTs especially in patients with large (diameter >3 cm) metastases.⁶

Bokemeyer et al. reported a study on 44 patients diagnosed with brain metastasis from TGCT. The median age of the patients was 27 years and the median time from the initial diagnosis of TGCT to the occurrence of brain metastasis was 16 months. Forty-two patients had non-seminomatous GCT and only two patients had seminomatous GCT. The authors classified the patients into three groups based on the occurrence or detection of the cerebral metastasis. Group 1 included patients who presented with brain metastasis at primary diagnosis (n=18), Group 2 included patients who developed brain metastasis at relapse after a previous favourable response to combination chemotherapy (n=4,) and Group 3 included patients who developed brain metastasis during or directly after treatment with cisplatin-based chemotherapy (n=22). The median overall survival time was 6 months. Patients in Group 1 and Group 2 had a significantly better prognosis (p value <.01). Additionally, patients who were treated with either chemotherapy or radiotherapy alone did not achieve long term survival. The authors reported that on univariate analysis, patients who had developed only one brain lesion (p<.02), patients who were diagnosed with brain metastasis at initial diagnosis of TGCT (p<.01) and patients who received combined chemotherapy and radiotherapy had a significantly better prognosis (p<.03).⁷

Syu et al. reported a single case of TGCT with metastasis to the brain. A 19-year-old male presented with a single episode of a seizure. Subsequent computed tomography (CT) showed three brain lesions with the largest measuring at 2.3 cm. Further investigation led to the diagnosis of testicular mixed germ cell tumour with multi-organ metastasis including metastasis to the lymph nodes, lungs, liver and brain. After the initial chemotherapy and radiotherapy was administered for the brain tumour and the whole brain, CT imaging of the brain showed increase in brain tumour size and compression of the brain stem. A craniectomy was performed after which chemotherapy and radiation was administered. The residual tumour was resected  and one month after brain tumour resection, only scant degenerated tumour cells in the residual brain tumour area were noted. The authors concluded that although their treatment protocol for the brain tumours demonstrated  a good response, longer follow up is required to assess its impact.

 

Conclusion

 

Brain metastasis from TGCT is rare and results in poor outcomes. Surgical resection has long been considered a positive prognostic factor; however, recent studies additionally advocate for chemotherapy along with radiotherapy as part of the treatment protocol. However, more studies are the key to develop the optimal treatment protocol for patients with brain metastasis from TGCT.

 

References

 

1.      Badia RR, Wong D, Ghandour R, Chertack N, Meng X, Hutchinson R, et al. Validation of testicular germ cell tumor staging in nationwide cancer registries. Urol Oncol. 2021;39:838 e1- e6.

2.      Klos KJ, O'Neill BP. Brain metastases. Neurologist. 2004;10:31-46.

3.      International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol. 1997;15:594-603.

4.      Voutsadakis IA. The chemosensitivity of testicular germ cell tumors. Cell Oncol (Dordr). 2014;37:79-94.

5.      Nonomura N, Nagahara A, Oka D, Mukai M, Nakai Y, Nakayama M, et al. Brain metastases from testicular germ cell tumors: a retrospective analysis. Int J Urol. 2009;16:887-93.

6.      Salvati M, Piccirilli M, Raco A, Santoro A, Frati R, Lenzi J, et al. Brain metastasis from non-seminomatous germ cell tumors of the testis: indications for aggressive treatment. Neurosurg Rev. 2006;29:130-7.

7.      Bokemeyer C, Nowak P, Haupt A, Metzner B, Kohne H, Hartmann JT, et al. Treatment of brain metastases in patients with testicular cancer. J Clin Oncol. 1997;15:1449-54.