A Case of Multifocal Ectopic Germinoma Manifesting with Medial Longitudinal Fasciculus Syndrome

Intracranial germinoma constitutes approximately 60–70% of all intracranial germ cell tumors and 0.5–2% of primary brain tumors [1]. Intracranial germ cell tumors are most commonly observed in adolescents and young adults, accounting for approximately 3% of all brain tumors in this age group [2]. Among intracranial germinomas, the pineal gland is the primary site in 50–53% of cases, whereas the tumor arises in the neurohypophyseal region in approximately 13–21% of cases [3]. Intracranial germinomas are relatively rare compared to other brain tumors, but they are more frequently reported in East Asian populations, comprising a higher percentage of intracranial germ cell tumors in this ethnic group. The pineal gland and neurohypophyseal region are the primary sites of germinoma occurrence, but occasionally, these tumors arise in ectopic locations within the brain, such as the basal ganglia.

Ectopic germinomas, referring to instances in which these tumors develop in locations other than the standard sites, account for approximately 5–10% of all germinomas [4]. The rarity and potential ectopic occurrence of germinomas emphasize the importance of thorough clinical evaluation and imaging studies for accurate diagnosis and appropriate management.

We report a rare case of multifocal ectopic germinoma with no lesions in the pineal gland, neurohypophysis, or basal ganglia. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000538088).

The patient was a 34-year-old pregnant woman who had diplopia since approximately 14 weeks of gestation, and she visited another hospital at 30 weeks of gestation because of repeated lightheadedness and loss of consciousness starting at approximately 26 weeks of gestation. She was referred to our department because head MRI revealed an intracranial neoplastic lesion. At the time of the visit, left gaze disorder and gait disturbance were observed. Her visual acuity and visual field were normal, but her right eye did not turn inward during left gaze, which was thought to be caused by impairment of the right medial longitudinal fasciculus (MLF syndrome). Head MRI revealed neoplastic lesions in two areas, with one lesion spanning from the septum pellucidum to the right anterior horn and the other spanning from the pons to the dorsal medulla oblongata, as well as cystic changes in some areas and hydrocephalus (Fig. 1). We strongly suspected primary central nervous system lymphoma based on the imaging findings, such as homogeneous tumor contrast on contrast-enhanced T1-weighted images and strong diffusion restriction on diffusion-weighted images. She was transferred to our department after cesarean section at approximately 34 weeks of gestation. The results of blood tests were as follows: sIL-2R, 431.0 U/mL; HCG-β, 0.2 ng/mL; and AFP, 85.1 ng/mL. Although AFP levels were elevated, the data were obtained 8 days after cesarean section, and thus, it was considered a physiological event. We decided to perform a partial tumor resection rather than a biopsy to confirm the pathological diagnosis as well as to improve the hydrocephalus. Using a transcortical approach, the tumor near the right anterior horn and the tumor in the septum pellucidum were partially removed, and the right and left lateral ventricles were connected. In addition, the tumor near the foramen of Monro was also removed to improve hydrocephalus. Postoperatively, the hydrocephalus was resolved and the gait disturbance improved. Pathological analysis revealed dense proliferation of tumor cells with pale to moderately acidic sporocytes, a swollen nucleus with well-defined nucleoli, and a large infiltrate of small lymphocytes in the background. The lesions were immunohistochemically positive for c-kit, D2-40, and SALLA4, and a pathological diagnosis of germinoma was made (Fig. 2). The intraoperative spinal fluid cytology was class V in Papanicolaou classification. Three courses of ifosfamide, carboplatin, and etoposide (chemotherapy) combined with whole-brain irradiation (25.2 Gy in 14 fractions) led to complete elimination of the lesions and improvement of the MLF syndrome 3 weeks after the start of chemotherapy. After 18 months of follow-up, there was no evidence of recurrence. We have compiled a timeline chart of the patient’s progress before and after surgery, which is shown in Figure 3.

The selection of appropriate treatment strategies for brain tumors relies heavily on the preoperative diagnosis. There were two distinct lesions in our case, including one extending from the septum pellucidum to the right frontal horn of the lateral ventricle and another spanning from the dorsal aspect of the midbrain to the medulla. Germ cell tumors (germinomas) typically originate in the pineal and neurohypophyseal regions. Occasional reports mention their occurrence in the basal ganglia, but cases with separate lesions in two different locations, especially without involvement of the pineal and suprasellar regions, are extremely rare. Therefore, germinoma was not considered in the preoperative differential diagnosis.

One of the theories regarding the origin of germinomas is the traditional “germ cell theory,” which indicates that gonadal germ cell tumors arise from primordial germ cells through transformation. The development of extragonadal tumors is explained by the presence of ectopic germ cells that deviate from fetal primordial germ cell migration [5]. This theory aligns with the findings in our case, in which two lesions were located near the midline, supporting the idea of ectopic germ cell development during migration.

There are six reported cases of germ cell tumors in the septum pellucidum, three of which were germinomas [1, 6‒10]. Common imaging features in all six cases included high-signal areas on T2-weighted images, which are indicative of cysts. The tumor parenchyma had well-defined borders with moderate-to-strong contrast enhancement, and diffusion-weighted imaging revealed diffusion restriction in three cases, in line with our findings. The pathological characteristics of germinoma include large tumor cells with distinct nucleoli and the infiltration of small lymphocytes, termed the “two-cell pattern.” Diffusion restriction on diffusion-weighted images might reflect increased cell density attributable to lymphocyte infiltration; however, because primary malignant lymphoma of the nervous system also exhibits similar diffusion restriction, the two types of lesions must be carefully distinguished.

For brainstem lesions, 22 cases of medullary germinomas have been reported [11]. These cases, predominantly observed in East Asia, are often present as cystic lesions with heterogeneous components on imaging. The findings of our case, despite the patient’s older age and female sex, align with the imaging characteristics described in the literature.

The symptoms of tumors in the pineal gland region can include hydrocephalus symptoms caused by obstruction of the cerebral aqueduct and tectal plate syndrome resulting from compression or infiltration of the tectal plate by the tumor. Tectal plate syndrome can lead to upward gaze palsy (Argyll-Robertson pupils), and central hearing loss is occasionally observed. The symptoms of tumors originating in the neurohypophyseal region include diabetes insipidus, visual field impairment, and anterior pituitary insufficiency, with diabetes insipidus being a prevalent initial symptom in almost all cases. If the tumor arises in the basal ganglia, pyramidal tract signs, which typically manifest as contralateral hemiparesis, are common. Various other symptoms, including abnormal behavior and psychiatric manifestations, can also occur. In this case, the patient presented with atypical symptoms of germinoma, such as diplopia, due to right MLF disturbance caused by the tumor located on the right side of the dorsal pons.

The definition of metastatic disease varies in clinical trials, creating challenges in treatment decision-making. In ongoing clinical trials, such as ACNS1123 and SIOP GCT II, metastatic disease is defined as the presence of two or more intracranial lesions, excluding spinal and bifocal lesions, together with cerebrospinal fluid cytology positivity. However, in JCNS GCT SG, only spinal lesions are considered metastatic, highlighting the lack of consensus concerning the definition. Cases deemed metastatic by any of these definitions are typically treated with brain and spinal cord irradiation. The discrepancy in the definition of metastatic disease poses a challenge in the interpretation of clinical trial data. In our case, there were two intracranial lesions and the cerebrospinal fluid cytology was positive, but no spinal lesions were observed, so we considered the lesions not to be metastasis. The treatment involved whole-brain irradiation because of the involvement of multiple sites including right frontal lobe. The differing definitions of metastatic disease in ongoing clinical trials illustrate the need for a standardized approach. With an observation period of 18 months and no signs of recurrence, we remain vigilant concerning the potential appearance of spinal lesions outside the irradiation field.

The findings of this case indicate that even in patients with multiple lesions not involving the pineal gland or neurohypophysis, germinoma should be considered in the preoperative differential diagnosis if there are lesions in midline structures such as the septum pellucidum or dorsal brainstem, especially when accompanied by cystic components. This recognition is crucial for guiding subsequent appropriate treatment.

The study was approved by the review board of Kyoto Prefectural University Graduate School of Medicine (Kyoto, Japan) under ERB-C-2048. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

The authors have no conflict of interest to declare.

The authors have no funding sources to declare.

T.D. and Y.T. wrote the article. M.S. collected the imaging data and clinical data. N.H. supervised the conduct of this study. All authors approved the final version of the manuscript for publication.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.