Pearls & Oy-sters: Bifocal germinoma of the brain

DISCUSSION

Intracranial germinoma constitutes 50% to 60% of CNS germ cell tumors (CNSGCT), accounting for 0.5% to 2.0% of all primary intracranial tumors.¹ There is considerable variation in the geographic incidence of intracranial GCT; it is 5–8 times more common in Japan and the far east compared to the western countries.² CNSGCT occurs mainly in children and young adults with a peak age at onset between 10 and 18 years. Overall, male patients are affected more than female patients. WHO classifies CNSGCT into pure germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumor.³ CNSGCT arises from the primordial germ cells. These cells appear in the yolk sac wall by the third gestational week and migrate into the genital ridge by the sixth gestational week. If migration of these primordial germ cells is disrupted, some cells may migrate to the ectopic sites (retroperitoneum, mediastinum, or diencephalon) where they can develop into extragonadal GCT.⁴

Germinoma usually occurs along the midline of the body, common locations being the pineal and the suprasellar regions, but can also develop in the basal ganglia region. Tumor cells can seed within the ventricular cavity and the CSF and drop metastases have been described in the spinal cord.⁵ CSF examination and MRI of the spinal cord are needed for appropriate staging of the disease. At the time of diagnosis, 2%–18% of the intracranial germinomas show bifocal distribution with simultaneous pineal and suprasellar manifestations. It remains unclear whether the bifocal tumors result from simultaneous tumor development or represent metastatic disease.⁶

There is a definite relationship between the clinical presentation and tumor location in cases of germinoma. Lesions in the pineal region can obstruct the cerebral aqueduct and cause hydrocephalus with features of raised intracranial pressure (ICP) as the first presenting symptom; they can also present with Parinaud syndrome.⁷ Tumors involving the suprasellar region usually present with hypothalamic–pituitary axis dysfunction such as DI, delayed growth, menstrual irregularities, hypogonadism, or precocious puberty. Patients may also have visual disturbances due to compression of the visual pathways. Interestingly, patients with bifocal germinoma tend to present with symptoms associated with the suprasellar mass initially.⁶ The central endocrinopathy associated with suprasellar GCT is thought to be a consequence of direct pressure by the tumor on the critical hypothalamic areas. These endocrine symptoms tend to occur sooner than a similar sized mass in the pineal region. Additionally, in patients with bifocal disease, the suprasellar mass is frequently the larger of the 2 mass lesions in children.⁶ Thus the diagnosis may be missed if this possibility in not considered as headache and features of raised ICP may be a late manifestation.

The role of protein markers such as β-HCG and AFP that can be measured in the serum or more preferably in the CSF plays an important part in the diagnosis of CNSGCT.³ Yolk sac tumor secretes AFP and choriocarcinoma secretes β-HCG. Embryonal carcinoma usually does not secrete tumor markers but it occurs with other GCT-like yolk sac tumors and is considered as a mixed GCT.⁸ Pure germinomas do not secrete tumor markers. Ancillary tests with typical neuroimaging findings can aid in the diagnosis of CNSGCT without the need for performing brain biopsy.

Intracranial germinoma is considered as a highly curable brain tumor. Radiotherapy is the standard modality of treatment in such patients. With an irradiation dose of 4,000–5,000 cGy, long-term survival is achieved in more than 90% of patients.⁹ Metastatic intracranial germinoma requires simultaneous radiation to the craniospinal axis.⁶ The side effects of CSI, like neurocognitive deficits, pituitary dysfunction, and secondary malignancies, are of real concern, particularly for younger patients. In order to minimize these, combined modality therapy using cisplatin-based chemotherapy regimens with reduced volume and dose irradiation have shown promising results, showing only 9%–14% local failure rate and a salvage rate of over 50%.¹⁰

There were a number of distractors in the clinical history of this case. Headaches with positive visual phenomena could have been interpreted as migraine with aura. However, our patient had several features which were atypical for migraine, such as bilateral location of the headache, persistent daily headache from the onset, and early morning severe headaches associated with vomiting.

The polydipsia and polyuria were thought to be of psychogenic etiology because there were serious psychosocial issues in the family though the urine specific gravity was clearly low. The differential diagnosis of polydipsia and polyuria should exclude diabetes mellitus and salt-losing nephropathy from end-stage renal disease. In absence of those disorders, one should consider primary polydipsia/psychogenic polydipsia, central DI, and nephrogenic DI. The above disorders can be differentiated based on careful history, checking serum sodium and urine osmolality, performing water deprivation test, and noting the response to exogenous antidiuretic hormone (ADH). In central DI, serum sodium is normal to high with low urine osmolality, and the urine does not become concentrated despite excessively concentrated serum after water deprivation. The urine osmolality increases by more than 50% in response to exogenous ADH as noted in our patient. Oligomenorrhea soon after menarche in our patient was considered to be within normal limits. The combination of new onset headache along with the history of DI and oligomenorrhea pointed to the possibility of intracranial tumor in the suprasellar/hypothalamic region. Endocrine abnormalities and visual field defects are common initial features of pediatric sellar/suprasellar masses. These symptoms may antedate headache and should be thoroughly investigated to look for abnormalities of the hypothalamic-pituitary-gonadal axis. Intracranial germinomas are exquisitely radiosensitive and chemosensitive and thus are highly curable. New therapeutic strategies are focusing on dose reduction of therapy (radiation and chemotherapy) while still achieving the same cure rates we currently experience.