Outcomes
With median follow-up time from diagnosis of 78.9 months (range 0.5 to
249.9), 14 patients (25.4%) experienced relapses (5-year PFS 78.2%,
95%CI 0.67-0.91) (Fig. 3A ). Eleven patients (20%) died of
disease within 20.6 months (range 0.7–75.5) from diagnosis, resulting
in 5-year OS of 80.2% (95%CI 0.70-0.92) in the whole cohort
(Fig. 3B ). GCTs in deceased subjects had various histology
(germinoma n=2, NGGCTs n=7, undetermined n=2) and tumour location
(suprasellar n=1, pineal n=5, bifocal n=2, other n=3).
OS and PFS were not statistical different between patients with TDI
>6 months and with TDI ≤6 months (HR 0.39; 95% CI
0.10-1.48; p=0.168 and HR 0.39; 95% CI 0.14-1.05; p=0.05, respectively)(Fig. 3C and 3D) .
DISCUSSION
In this observational, retrospective cohort study we reviewed the
different clinical presentations of patients diagnosed with IC-GCT and
analysed the impact of several factors on diagnostic delay.
The prevalent histology was germinoma, whilst infants and young children
<5 years old were affected exclusively by NGGCTs, congruently
with previous reports 2,26. This finding suggests that
IC-GCTs in this age group may belong to a biologically different subset
as proposed by others 27. Elevated tumour markers were
suggestive of NGGCT, although normal levels did not exclude the
diagnosis of IC-GCT (teratoma or germinoma in our cohort)28.
The clinical presentation depends on the size and position of the
tumour. Our study confirmed that endocrine deficiencies manifested in
sellar/suprasellar IC-GCTs, whereas pineal GCTs presented with symptoms
of hydrocephalus. Moreover, a progression of symptoms was identified
from the first initial presentation and most patients developed symptoms
of RICP, which led to eventual diagnosis. In suprasellar tumours,
hydrocephalus is usually a late and more insidious event but can be
life-threatening and may contribute to visual and neurocognitive
sequelae 29.
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 reported17,18,23. 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. In a
subset of patients with nondiagnostic first MRI, infundibular thickening
was present with DI. The ideal management of these patients is unclear.
Maghnie et al 31 reviewed the outcomes of 29 children
with central DI and infundibular thickening on the first MRI. In these
children, the eventual diagnosis was idiopathic DI in 18 cases,
Langerhans cell histiocytosis in 5, GCT in 5, and autoimmune
polyendocrinopathy in 1. Because GCTs were rarer than idiopathic DI, the
authors recommended pursuing the diagnosis of GCT only in those patients
with progressive infundibular enlargement.
A limitation of our study is that the estimated duration of symptoms is
subject to recall bias. We acknowledge that the first symptom was
derived from referral information and clinical notes and, consequently,
the symptoms that patient/family described may not necessarily have been
reported to healthcare professionals at the time. Only two patients were
able to recognize in retrospect and define the onset of unnoticed
endocrine manifestations several months prior to referral for headache
or visual impairment.
In our study, nearly half of patients (47.3%) had TDI >6
months. Jennings et al.26 in a meta-analysis of 215
patients, found that 35% of the patients were symptomatic for
>6 months before being diagnosed with GCT. In 2007,
Crawford et al. 15 analysed time from symptom onset to
diagnosis in 30 patients with IC-GCTs: a small proportion of patients
(9/30) had a time to diagnosis >6 months. Like our
findings, however, the authors identified endocrinopathies as the major
feature in deferred diagnosis. In our analysis, deferred diagnosis was
also associated with tumour location. Pineal site of disease, which
usually presents acutely with RICP, was less frequently associated with
TDI >6 months. Conversely, patients with TDI
>6 months were shorter, suggesting that endocrinopathies
including poor growth, presented before the diagnosis of GCT and maybe
neglected by both families and clinicians. Our results therefore
highlight the difficulties faced in diagnosing this rare tumour.
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. In our cohort, OS and PFS was similar in
patients with and without deferred diagnosis.
Analysis of diagnostic sub-intervals in patients with endocrinopathies
as presenting symptoms showed a lengthy TI in those subjects presented
with DI and thicken pituitary stalk on MRI: the “occult” sellar
tumours were only recognized on biopsy with a latency of up to 58.5
months. In a recent retrospective study of 55 cases from a large
pituitary centre in China, average duration of MRI follow-up was
21.5±21.2 months in this subset of patients 32. While
TI depends sometimes on unchangeable and unpredictable factors (e.g.
size and location of tumour for biopsy), time from onset of symptoms
until first MRI, i.e. PI+HI, is clinically more relevant, because it
gathers the importance of patient/family awareness (PI) with the
clinical suspicion of the clinician to make an early diagnosis (HI). HI
in our cohort was modest and did not appear to contribute considerably
to TDI. A prolonged HI could also be due to lack of resources within the
healthcare system. For example, waiting times for tertiary care clinics
or for an MRI under general anaesthetic can cause substantial delays of
weeks or months. The National Institute for Health and Care Excellence
guideline suggests that paediatric patients with a suspected brain
tumour should wait no longer than 4 weeks for an MRI33. While it is difficult (and less relevant as we
demonstrated) to make changes to national healthcare service resources,
education to improve awareness among healthcare professionals to aid
early diagnosis is imperative. In 2011 the HeadSmart campaign was
launched in the United Kingdom to enhance knowledge of brain tumour
symptomatology and led to a reduction of the interval to diagnosis from
a median of 14 weeks in 2006 to just 6.7 weeks in 201334.
As in other published studies 35,36, we found that TDI
also increased with age, with the PI contributing the most towards TDI
in the 12–18 age group. Since this deferred presentation trend has been
noted across all specialties, there has been an increasing focus on
teenage and young adult (TYA) groups in healthcare over the last
decade37. The reasons for delays in the TYA group are
multifactorial; adolescence is a period of unique psychological and
physical change. It is well known that young people have difficulties
forming therapeutic relationships with healthcare professionals and
accessing health services38. Identifying ways to
engage young people and empowering them with knowledge and resources
(i.e. school visits, social media, celebrity ambassadors), may create an
opportunity for earlier diagnosis.
CONCLUSION
Patients with IC-GCT are often evaluated by a broad spectrum of
paediatric providers. Lack of specific clinical symptoms and an interval
between initial symptoms and radiological detection contribute to the
diagnostic difficulties. If an endocrine abnormality appears clinically
or from laboratory results, especially together with the presence of
neurological symptoms, an IC-GCT should be considered, and a brain MRI
should be performed. Early diagnosis is important to minimise late
effects from tumour growth and treatment, although we demonstrated no
significant difference in PFS and OS in patients with and without
deferred diagnosis. Therefore, in most cases the cerebral alterations
could be monitored until a formal diagnosis is reached.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest. FC is partly
funded by the Giant Pledge via the Royal Marsden Cancer Charity. The
Paediatric Neuro-Oncology and Drug Development Units receive charitable
funding from the Hall-Hunter Foundation via the Royal Marsden Cancer
Charity.
ACKNOWLEDGMENTS
The authors thank Dr Kavitha Srivatsa, Specialty Doctor, Paediatric
Oncology, The Royal Marsden NHS Foundation Trust, London, UK, for her
kind help in data acquisition.
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FIGURE LEGEND
Figure 1 – Diagnostic intervals between symptom onset and definitive
diagnosis of Intracranial Germ Cell Tumour (IC-GCT). Patient-related
Interval, Healthcare-related Interval, and Tumour-related Interval only
apply to tumours presenting with endocrine symptoms.
Figure 2 – Total diagnostic interval by tumour location.
Figure 3 – Kaplan-Meier curve of 5-year progression-free survival
(panel A) and overall survival (panel B) at last follow-up in the entire
cohort. Five-year progression-free survival (panel C) and overall
survival (panel D) for all patients with TDI >6 months
(orange dashed curve) and TDI ≤6 months (blue solid curve) diagnosis.