Molecular Pathology and Targeted Therapies for Personalized Management of Central Nervous System Germinoma

Abstract

Intracranial germinomas are rare tumours, usually affecting male paediatric patients. They frequently develop in the pineal and suprasellar regions, causing endocrinological disturbances, visual deficits, and increased intracranial pressure. The diagnosis is established on magnetic resonance imaging (MRI), serum and cerebrospinal fluid (CSF) markers, and tumour stereotactic biopsy. Imaging techniques, such as susceptibility-weighted imaging (SWI), T2* (T2-star) gradient echo (GRE) or arterial spin labelling based perfusion-weighted MRI (ASL-PWI) facilitate the diagnosis. Germinomas are highly radiosensitive tumours, with survival rates >90% in the context of chemoradiotherapy. However, patients with resistant disease have limited therapeutic options and poor survival. The aim of this review is to highlight the genetic, epigenetic, and immunologic features, which could provide the basis for targeted therapy. Intracranial germinomas present genetic and epigenetic alterations (chromosomal aberrations, KIT, MAPK and PI3K pathways mutations, DNA hypomethylation, miRNA dysregulation) that may represent targets for therapy. Tyrosine kinase and mTOR inhibitors warrant further investigation in these cases. Immune markers, PD-1 (programmed cell death protein 1) and PD-L1 (programmed death-ligand 1), are expressed in germinomas, representing potential targets for immune checkpoint inhibitors. Resistant cases should benefit from a personalized management: genetic and immunological testing and enrolment in trials evaluating targeted therapies in intracranial germinomas.

Radiographic Findings of an Intracranial Germinoma in a 42-Year-Old Male

“…Recurrence, however, is not uncommon, and protracted follow-up is advised [9]. In these instances, because the individual was already subjected to radiation, a combination of chemotherapy and radiation is strongly advised, as opposed to radiation therapy alone [10,11]. Furthermore, it has been suggested that even at its initial presentation, radiation should be limited to "reduced-volume-radiotherapy plus boost" instead of craniosacral radiotherapy [12].…”

Diagnosis and Management of Pineal Germinoma: From Eye to Brain

“…The most common type of metastasis associated with germinomas are spinal “drop” metastasis. 27 Occurrence of these drop metastases synchronously with pineal germinoma is unusual, 50 although Lo et al find an incidence of synchronous presentation in 11% of pineal germinoma. 51 When these spinal metastases occur, symptoms may consist of low back pain, 52 monoparesis, 53 paraparesis, or quadriparesis or tetraparesis, 54 paresthesia, 55 numbness with a sensory level, spasticity, 54 and urinary retention.…”

“…Symptoms which suggest hydrocephalus include headaches, nausea, projectile vomiting, and lethargy. 27 But because patients with papilledema can be asymptomatic, a fundoscopic exam is essential, regardless of symptoms.…”

“… 32 Compared to other pineal tumors, up-gaze paresis is more common in germinoma because the pattern by which germinoma grows near the midbrain compresses or infiltrates the vertical gaze centers near the superior colliculus, including the interstitial nucleus of Cajal and the rostral interstitial nucleus of the medial longitudinal fasciculus (riMFL). 27 The superior rectus and inferior oblique muscles are responsible for upward elevation of the eyes. The riMFL sends information directly to the superior rectus and inferior oblique muscles.…”

Neoplasms and tumor-like lesions of the sellar region: imaging findings with correlation to pathology and 2021 WHO classification

“…Mature teratomas are usually treated with surgery, while the other NGGCTs are usually managed with a combination of surgery, chemotherapy, and radiotherapy depending on the tumor type. Molecular targeted therapy with inhibitors of KIT/RAS activation and the AKT1/mTOR pathway potentially represent promising therapeutic strategies [ 62 ]. Prognosis is usually good for germinomas and mature teratomas, while choriocarcinomas and embryonal carcinomas are often associated with a poorer outcome.…”