Symptom interval and treatment burden for patients with malignant central nervous system germ cell tumours

Abstract

ObjectivePatients with central nervous system germ cell tumours (CNS-GCTs) commonly initially present to primary care or general paediatricians. Prolonged symptom intervals (SI) are frequently seen in CNS-GCTs and have been associated with inferior outcomes in other brain tumours. This study reviewed the clinical presentation of CNS-GCTs and examined the effect of prolonged SI.Design/Setting/Patients/OutcomesInternational multicentre 10-year retrospective study (2002–2011 inclusive), across six international paediatric oncology treatment centres. All newly diagnosed patients with CNS-GCT were included. Main outcome measure was time interval from first symptom to diagnosis.ResultsThe study cohort included 86 (58 males:28 female) patients (59 ‘germinoma’ and 27 ‘non-germinomatous’ GCTs), with tumours being pineal (n=33), suprasellar (n=25), bifocal (pineal+suprasellar; n=24) and ‘other’ site (n=4), of which 16 (19%) were metastatic. Median age at diagnosis was 14 years (0–23 years). The time to diagnosis from first symptom (SI) was 0–69 months (median 3 months, mean 9 months). A prolonged SI (>6 months) was observed in 28/86 patients (33%) and significantly associated with metastatic disease (11/28 (39%) vs 5/58 (9%); p=0.002)) at diagnosis, but not overall survival. With prolonged SI, endocrine symptoms, particularly diabetes insipidus, were more common (21/28 (75%) vs 14/58 (24%) patients; p<0.002), but raised intracranial pressure (RICP) was less frequent (4/28 (14%) vs 43/58 (74%) patients; p<0.001)) at first symptom.ConclusionsOne-third of patients with CNS-GCT have >6 months of symptoms prior to diagnosis. Delayed diagnosis is associated with metastatic disease. Early symptom recognition, particularly related to visual and hormonal disturbances in the absence of RICP, may improve timely diagnosis, reduce metastatic disease frequency and consequently reduce treatment burden and late effects.

Implications of Deferred Diagnosis of Paediatric Intracranial Germ Cell Tumours

“…No correlation between diagnostic delay and metastatic disease were found, differently from previous studies 17,23 . While Phi et al 20 reported a significant association of deferred diagnosis with a poorer outcome in a subset of germinoma cases (n=13) among a cohort of 181 patients with localised IC-GCT, this result was not seen in other single-centre studies 15,17 nor in our multicentre study.…”

“…The median time to diagnosis of IC-GCT in our cohort was 4 months, shorter than the Japanese report 21 . Nevertheless, we have shown that the interval from the first symptom to diagnosis may vary significantly and, in some cases, may extend to nearly 5 years, confirming the wide variation already reported 17,18,23 . DI was often an early clinical manifestation in our cohort (70.6% of subjects who displayed endocrinopathy as first symptom), as described in other studies 18,19,30 .…”

“…Patient-related interval (PI) was defined as the interval between symptom onset and initial referral to a healthcare specialist; healthcare-related interval (HI) was defined as the interval between specialist evaluation and first brain MRI; tumour-related interval (TI) was defined as the interval between first brain MRI and definitive diagnosis of IC-GCT. Time lag to diagnosis from the first symptom longer than 6 months (TDI >6 months) was identified in all patients, to allow direct comparison of our results with previous studies 15,17,21,23 , whereas PI, HI and TI were investigated only when an endocrine disorder was the presenting symptom. Subgroup analyses by age at diagnosis, tumour grade and tumour location were also performed.…”

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

“…Patients presenting endocrinological symptoms had a significant delay in diagnosis [ 39 ]. Approximately one-third of the patients have prolonged symptomatology (>6 months) before the diagnosis, these cases being associated with a higher risk of metastatic disease [ 46 ]. A summary of the clinical presentation is shown in Table 1 .…”

Hypophyseal Dysfunction and Difficulties in Management of Pediatric Intracranial Germ Cell Tumors

“… 1 , 2 Intracranial GCTs are difficult to be differentiated from various neoplastic or inflammatory diseases due to similar clinical, radiological, and even pathological findings. 3 - 5 …”