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\begin{document}

\title{IMPLICATIONS OF DEFERRED DIAGNOSIS OF PAEDIATRIC INTRACRANIAL GERM CELL
TUMOURS}



\author[1]{Cristina Partenope}%
\author[2]{Gabriella Pozzobon}%
\author[2]{Giovanna Weber}%
\author[3]{Fernando Carceller}%
\author[3]{Assunta Albanese}%
\affil[1]{San Raffaele Hospital}%
\affil[2]{IRCCS Ospedale San Raffaele}%
\affil[3]{Royal Marsden Hospital Sutton}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
AIMS This study analysed the clinical features of children with
intracranial germ cell tumours (IC-GCTs) treated at two European
centres. We retrospectively reviewed timelag between symptoms onset,
clinic-radiological findings, diagnosis and outcomes. METHODS Symptoms
at diagnosis were divided into four groups: 1)raised intracranial
pressure (RICP); 2)visual impairment; 3)endocrinopathy; 4)other. Total
diagnostic interval (TDI), defined as the interval between symptom onset
(including retrospective recall of symptoms) and definitive diagnosis of
IC-GCT, was calculated and compared to survival rates. RESULTS Our
cohort included 55 children with a median follow-up of 78.9 months
(0.5-249.9). The majority (63.6\%) had germinomas and 10.9\% were
metastatic at diagnosis. IC-GCTs were suprasellar (41.8\%), pineal
(36.4\%), bifocal (12.7\%) or in atypical sites (9.1\%). The most common
presenting symptoms were related to RICP (43.6\%); however, by the time
of tumour diagnosis, 50.9\% of the patients had developed endocrine
dysfunctions. All pineal GCTs manifested with RICP or visual impairment.
All suprasellar GCTs presented with endocrinopathies. TDI ranged between
0.25-58.5 months (median 4 months). Pineal GCTs had the shortest TDI
(median TDI 1 month versus 24 months in suprasellar GCTs,
p\textless{}0.001). TDI \textgreater{}6 months was observed in 47.3\% of
patients and was significantly associated with endocrine presenting
symptoms. No statistically significant difference was found in
progression-free survival and overall survival between patients with TDI
\textgreater{}6 months and with TDI ?6 months. CONCLUSION Approximately
half of our patients had TDI \textgreater{}6 months, mostly with
endocrine deficiencies as presenting symptoms. TDI \textgreater{}6
months was not associated with increased relapse rate or mortality.%
\end{abstract}%



\sloppy


IMPLICATIONS OF DEFERRED DIAGNOSIS OF PAEDIATRIC INTRACRANIAL GERM CELL
TUMOURS

Cristina Partenope\textsuperscript{1}; Gabriella
Pozzobon\textsuperscript{1}; Giovanna Weber\textsuperscript{1}; Fernando
Carceller\textsuperscript{2}; Assunta Albanese\textsuperscript{3}

\emph{Affiliations}

\textsuperscript{1} Department of Pediatrics, IRCCS San Raffaele
Scientific Institute, Milan, Italy.

\textsuperscript{2} Paediatric and Adolescent Oncology Drug Development
Team, Children and Young People's Unit, Royal Marsden Hospital and
Institute of Cancer Research, Sutton, UK.

\textsuperscript{3} Department of Paediatric Endocrinology, Royal
Marsden NHS Foundation Trust, London, United Kingdom.

\emph{Correspondence}

Cristina Partenope, MD, Department of Pediatrics, IRCCS San Raffaele
Scientific Institute, via Olgettina 60, Milan, Italy

Email:\emph{partenope.cristina@gmail.com}

Word count for:

Abstract: 249 words

Main Text: 3472 words

This paper includes 2 tables and 3 figures.

Keywords: intracranial germ cell tumour; children; deferred diagnosis;
delay; central nervous system; diabetes insipidus; diagnostic interval

Abbreviations table\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
AFP & alpha-fetoprotein\tabularnewline
\midrule
\endhead
Beta-HCG & beta-human chorionic gonadotropin\tabularnewline
CI & confidence interval\tabularnewline
CSF & cerebral spinal fluid\tabularnewline
HI & healthcare-related interval\tabularnewline
IC-GCTs & intracranial germ cell tumours\tabularnewline
IQR & interquartile ranges\tabularnewline
MRI & magnetic resonance image\tabularnewline
NGGCTs & non-germinomatous germ cell tumours\tabularnewline
OR & odds ratio\tabularnewline
OS & overall survival\tabularnewline
PFS & progression-free survival\tabularnewline
PI & patient-related interval\tabularnewline
PLAP & placental alkaline phosphatase\tabularnewline
RICP & raised intracranial pressure\tabularnewline
TDI & total diagnostic interval\tabularnewline
TI & tumour-related interval\tabularnewline
TYA & teenage and young adult\tabularnewline
WVI & whole ventricular field irradiation\tabularnewline
\bottomrule
\end{longtable}

Data included in this paper have been partially previously published as
meeting abstract titled ``Delayed diagnosis of paediatric intracranial
germ cell tumours (IC-GCTs)'' for the ESPE (European Society for
Paediatric Endocrinology) 59th annual meeting online on 22nd-26th
September 2021, available at
https://abstracts.eurospe.org/hrp/0094/eposters/.

ABSTRACT

AIMS

This study analysed the clinical features of children with intracranial
germ cell tumours (IC-GCTs) treated at two European centres. We
retrospectively reviewed timelag between symptoms onset,
clinic-radiological findings, diagnosis and outcomes.

METHODS

Symptoms at diagnosis were divided into four groups: 1)raised
intracranial pressure (RICP); 2)visual impairment; 3)endocrinopathy;
4)other. Total diagnostic interval (TDI), defined as the interval
between symptom onset (including retrospective recall of symptoms) and
definitive diagnosis of IC-GCT, was calculated and compared to survival
rates.

RESULTS

Our cohort included 55 children with a median follow-up of 78.9 months
(0.5-249.9). The majority (63.6\%) had germinomas and 10.9\% were
metastatic at diagnosis. IC-GCTs were suprasellar (41.8\%), pineal
(36.4\%), bifocal (12.7\%) or in atypical sites (9.1\%). The most common
presenting symptoms were related to RICP (43.6\%); however, by the time
of tumour diagnosis, 50.9\% of the patients had developed endocrine
dysfunctions. All pineal GCTs manifested with RICP or visual impairment.
All suprasellar GCTs presented with endocrinopathies. TDI ranged between
0.25-58.5 months (median 4 months). Pineal GCTs had the shortest TDI
(median TDI 1 month versus 24 months in suprasellar GCTs,
p\textless{}0.001). TDI \textgreater{}6 months was observed in 47.3\% of
patients and was significantly associated with endocrine presenting
symptoms. No statistically significant difference was found in
progression-free survival and overall survival between patients with TDI
\textgreater{}6 months and with TDI [?]6 months.

CONCLUSION

Approximately half of our patients had TDI \textgreater{}6 months,
mostly with endocrine deficiencies as presenting symptoms. TDI
\textgreater{}6 months was not associated with increased relapse rate or
mortality.

INTRODUCTION

\textbf{Background}

Diagnosis of intracranial germ cell tumours (IC-GCTs) occurs
predominantly in children with peak incidence during the second decade
of life \textsuperscript{1-3}.

The two most frequent brain locations are the pineal gland and the
suprasellar region or both sites simultaneously (``bifocal disease'').
IC-GCTs can also arise in the basal ganglia, thalamus, cerebral
hemisphere, and cerebellum \textsuperscript{4,5}.

According to the WHO classification system, IC-GCTs are divided into
germinomas (GTs) and non-germinomatous (NGGCTs) \textsuperscript{6}.
Germinomas comprise 60-65\% of all paediatric IC-GCTs. IC-GCTs can also
be divided into ''secreting'' and ''non-secreting'' tumours based on the
presence of tumour markers measured in the cerebral spinal fluid (CSF)
and/or serum: alpha-fetoprotein (AFP) and beta-human chorionic
gonadotropin (beta-HCG) \textsuperscript{7}.

Different CT and RT treatment regimens have been developed in Western
Countries \textsuperscript{8-11} and in
Japan\textsuperscript{12}according to histology and prognosis.
Intracranial germinomas have an excellent overall survival (OS)
\textgreater{}90\%, whereas the prognosis for patients with recurrent
IC-NGGCTs is poor\textsuperscript{13,14}.

\textbf{Clinical presentation and deferred diagnosis}

Initial symptoms depend upon location and size of the tumour. Pineal
tumours typically cause obstructive hydrocephalus with headache,
vomiting, papilledema, and lethargy. Pineal tumours may also present
with `Parinaud's syndrome', caused by tectal plate compression. Patients
with IC-GCTs may show behavioural changes, poor school performance and
altered neurology, especially in tumours arising within the basal
ganglia. Suprasellar GCTs most commonly cause hypothalamic/pituitary
dysfunctions and may compress the optic chiasm causing visual field
defects \textsuperscript{15, 16}.

A prolonged symptom interval (i.e. the time from symptom onset to
diagnosis) has been reported in several paediatric brain
tumours\textsuperscript{17--19}. Reports from two institutional series
have identified a wide variation in symptom interval, with diagnosis
occurring up to 3 years from symptom onset \textsuperscript{17,18}. In
recent single-centre studies, 54\% \textsuperscript{17} and
30\%\textsuperscript{15} of patients with IC-GCT had a symptom interval
\textgreater{}6 months. In another study 17/181 patients with IC-GCT
(9\%) had a deferred diagnosis of \textgreater{}3 months and survival in
a small subset of germinoma patients (13/119 cases; 11\%) was negatively
affected \textsuperscript{20}. Other previous studies have identified
that children with shorter symptom intervals have more aggressive
tumours, suggesting a relationship between diagnostic delay and
survival\textsuperscript{21,22}.

Our study evaluates retrospectively the clinical features and outcomes
of paediatric patients with IC-GCTs treated at two centres over 25
years. We reviewed the timing interval between symptoms onset,
radiological manifestations, and definitive diagnosis of IC-GCT.

METHODS

\textbf{Study design and population}

We retrospectively analysed data of patients (\textless{}18 years old)
who were diagnosed with IC-GCT between January 1996 and December 2019 at
the Royal Marsden Hospital, Sutton, UK and at San Raffaele Hospital,
Milan, Italy. Only patients affected by primary IC-GCT with available
complete information were included.

Data collection included patient demographics, height and weight
measurements, timing, and features of symptoms at diagnosis, laboratory
data (tumour markers, hormonal levels), tumour location, histology and
staging. Since laboratory tests were performed in different
institutions, we stratified tumour markers into 4 categories: normal,
mild, moderate, and severe elevation. We chose 5 IU/L and 10 ng/mL as
cut-off values for normal HCG and AFP levels, respectively; 50 IU/L and
25 ng/mL as cut-off levels distinguishing mild and moderate HCG and AFP
levels; \textgreater{}500 IU/L and \textgreater{} 1000 ng/mL for severe
HCG and AFP levels. Placental alkaline phosphatase (PLAP) staining on
pathologic specimens was reported when available. Brain and spine MRI
were mandatory for diagnosis and staging. Metastatic IC-GCT was defined
as the presence of \textgreater{}1 intracranial focus (except for
bifocal disease), spinal metastases, metastases outside the CNS, or the
presence of tumour cells in CSF cytology. Definition of bifocal disease
required radiological synchronous detection of tumour in both the pineal
gland and the suprasellar region. The diagnosis of IC-GCT was
histologically confirmed in 52/55 cases (94.5\%). For two pathological
undetermined specimens clinic-radiologic suspicion of IC-GCT was
confirmed by raised CSF tumour markers; one patient did not undergo any
biopsy as presumptive diagnosis of IC-GCT was based on tumour
localization (bifocal disease with leptomeningeal dissemination).

Symptoms at diagnosis were classified into four groups: 1)raised
intracranial pressure, RICP (headache, vomiting); 2)visual impairment;
3)endocrinopathy (polyuria/polydipsia, poor growth); 4)other
(neurological signs, ataxia, fatigue, behavioural changes, worsen school
performance).

\textbf{Outcome measures and definitions}

The key outcome measures regarding diagnostic intervals were calculated
for each patient \textbf{(Fig. 1)} . Total diagnostic interval (TDI) was
defined as the interval between date of the first reported symptom onset
(including retrospective recall of symptoms) and diagnosis.
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 \textgreater{}6 months) was identified in all
patients, to allow direct comparison of our results with previous
studies\textsuperscript{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.

We recorded oncologic treatments (chemotherapy, surgery, radiotherapy),
tumour recurrence and death.

\textbf{Statistical analysis}

Continuous variables are presented as medians and interquartile ranges
(IQR) and were compared with the Mann-Whitney U test and Kruskal-Wallis
H test (independent groups) or Wilcoxon signed rank test (paired
groups). Categorical variables are presented as numbers/percentages and
were compared with the \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test or Fisher's exact test.
Results of logistic regression are reported as odds ratio (OR) and 95\%
confidence interval (CI). The survival rate was estimated using the
Kaplan--Meier method. Five-year progression-free survival (PFS) and OS
were calculated from diagnosis to the date of last follow-up,
progression, or death. P-values \textless{}0.05 were considered
statistically significant. Statistical analyses were performed using
SPSS Statistics (v.24; IBM Corp.-USA) and RStudio (v.1.3.1093; RStudio,
PBC).

RESULTS

\textbf{Baseline characteristics/demographics}

Fifty-five children (52 from Royal Marsden Hospital and 3 from San
Raffaele Hospital) were included. The characteristics of the study
population are detailed in \textbf{Table 1} . The median age at tumour
diagnosis was 12 (IQR 9--16) years, with a peak age between 9 and 10
years. Adolescents aged \textgreater{}11years accounted for 60\% of
cases. Most patients were boys (67.3\%) and prepubertal at the time of
diagnosis (54.5\%).

Germinomas comprised most diagnoses (63.6\% of the cohort). Children
\textless{}5 years old (n=2) were diagnosed with teratoma, whilst
germinoma occurred more frequently in older patients (p=0.052),
especially in the 11-18 age group (n=24, 75\%). Seven biopsies reported
mixed GCT, all with a germinoma component.

Regarding the distribution of histology according to tumour locations,
germinomas were significantly dominant in the suprasellar region
(82.5\%, p=0.047); together, NGGCTs accounted for 57.9\% of the pineal
tumours. Teratomas were also found in suprasellar region (n=3) and in
atypical sites (n=2, right cerebro-pontine angle and thalamus). Seven
cases occurred bifocally (7/55, 12.7\%); among them, five were
germinomas and two did not receive a histopathological diagnosis.

Six tumours were metastatic at diagnosis (10.9\%), of which 4/6 were
germinomas.

Serum AFP and beta-HCG were available for 53/55 (96.4\%) and 52/55
(94.5\%) subjects, respectively \textbf{(Table 1)} . For cytological
detection of microdissemination, sampling of CSF was obtained; however,
data on CSF tumour markers were missing for 6/55 subjects. Of the 4
tumours with severely elevated serum HCG, one case was teratoma and the
remaining 3 cases had a mixed histology. Similarly, serum AFP was
severely raised only in NGGCTs (2 yolk sac tumour, 1 teratoma and 1
mixed histology). On the contrary, normal levels of serum AFP and HCG
were reported in 41 cases and 39 cases, respectively; they were all
germinomas, aside from one teratoma that showed normal serum HCG levels
and moderate elevation of both CSF HCG and AFP. PLAP results on biopsy
samples prior to treatments were available in 30/55 cases (54.4\%) and
all of those that showed a positive PLAP staining were then diagnosed
with germinoma, except for one (mixed histology with a predominant yolk
sac component).

\textbf{Treatment}

Biopsy was performed in 46 patients and gross tumour resection in 8.
Forty-two children received chemotherapy, which differed across time and
centres, according to the International CNS Germ Cell Tumour Study Group
and the Children's Oncology Group guidelines \textsuperscript{8,24,25}.
For 7 relapsed GCTs rescue treatment consisted in an aggressive approach
of myeloablative high-dose chemotherapy (Etoposide/Thiotepa) followed by
autologous stem cell transplant.

Radiation therapy was delivered to 50/55 patients (90\%), with a median
age of 11.6 years (range 5.4-18.3) at first radiation treatment. Among
them, 13/50 patients (26\%) received craniospinal irradiation (CSI) of
24-30.6 Gy (with boosted metastasis irradiation of 16 Gy in 8 cases),
9/50 patients (18\%) whole brain irradiation of 54 Gy, 2/50 patients
(4\%) whole ventricular field irradiation (WVI) of 24 Gy without primary
site simultaneous integrated boost, 21/50 patients (42\%) WVI of 24 Gy
with boost (16 Gy) and 5/50 patients (10\%) received focal irradiation
only (40-54 Gy).

\textbf{Clinical presentation}

The presenting symptoms included those attributable to RICP (24/55;
43.6\%), endocrine disturbances (17/55; 30.9\%), visual impairment
(5/55; 9.1\%) and other symptoms such as neurological signs, behavioural
changes, and fatigue (9/55; 16.4\%). Retrospectively, two patients
exhibiting headache and visual disturbance reported previous history of
uninvestigated endocrine manifestations (precocious puberty and
polyuria/polydipsia). Among those patients who displayed endocrinopathy
as first symptom, the majority (12/17; 70.6\%) had diabetes insipidus, 4
patients (23.5\%) with poor growth, and 1 boy (5.9\%) with precocious
puberty. By the time of tumour diagnosis, however, over half of the
patients had developed hydrocephalus (29/55; 52.7\%) or endocrine
dysfunctions (28/55; 50.9\%).

The symptom profile differed by tumour location: pineal GCTs manifested
with symptoms of hydrocephalus (19/20) or visual defects (1/20), whereas
all suprasellar GCTs initially caused symptoms related to
endocrinopathies. Among the 7 bifocal tumours, 3 patients presented with
RICP symptoms, 2 with an endocrinopathy (polyuria/polydipsia in both
cases), 1 with diplopia and 1 with fatigue for 3 months.

\textbf{Diagnostic intervals analysis}

Overall, the TDI ranged from 0.25 to 58.5 months (median 4 months, mean
12 months); most patients were diagnosed within 10 months after the
onset of symptoms. A statistically significant difference was found in
subgroup analysis of TDI by tumour location and histology
(p\textless{}0.001 and p=0.006, respectively). Pineal GCTs had the
shortest interval compared with other locations, with a median TDI of 1
month (range 0-17) versus a median TDI of 24 months (range 0.25-58.5) in
suprasellar GCTs (\textbf{Fig. 2} ). Ranking of tumour histology
identified germinoma as the one with the longest interval, but also with
the most skewed distribution, with a median TDI of 7 months (range
0.25--58.5) and a mean TDI of 16.5 months. Patients aged \textless{}5
years and aged 5--11 years had similar TDI (median 6.3 months and 7.4
months, respectively), whilst older patients displayed a shorter TDI but
with a wider range (median 3 months, 1--19), although without
statistical significance (p=0.88).

TDI \textgreater{}6 months was observed in 26/55 patients (47.3\%),
whose demographic and clinical characteristics are summarized
in\textbf{Table 2.} There was no significant correlation for TDI
\textgreater{}6 months with age, histology, and metastatic disease at
diagnosis, but we found a negative correlation with height at diagnosis
(p=0.043). Regarding location of disease, pineal site was observed less
frequently in those with TDI \textgreater{}6 months (3/26 patients;
11.5\%) than in those with a TDI [?]6 months (17/29 patients; 58.6\%)
(p\textless{}0.001), whereas suprasellar tumours were predominant in the
TDI \textgreater{}6 months group (17/26; 65.4\%) (p=0.002). TDI
\textgreater{}6 months was less associated with boys (86.2\% vs 46\%;
p=0.003), although the role of sex was confounded by the 100\% male
predominance among pineal GCTs and the 67.3\% among the whole cohort.
The pattern of presenting symptoms differed significantly in those with
TDI \textgreater{}6 months. Endocrine symptoms were more frequent
(n=17/26; 65.4\%) in those with TDI \textgreater{}6 months compared with
those who were diagnosed in less than 6 months (n=0)
(p\textless{}0.001). In contrast, RICP was an infrequent initial symptom
(n=4/26; 15.4\%) in those with TDI \textgreater{}6 months but was
typically observed in those with TDI [?]6 months (n=20/29; 69\%)
(p\textless{}0.001).

Eight patients (14.5\%) were followed with serial MRI for a median of 27
months (range 0.25--58.5) before the eventual diagnosis of IC-GCT.
Nearly all (7/8; 87.5\%) presented with central DI; the remaining
patient exhibited poor growth. In the first MRI study, all cases
demonstrated pituitary stalk thickening. Serum and CSF markers were
initially mildly raised only in one patient. Progressive changes in the
size of the infundibulum and/or development of new symptoms (especially
hydrocephalus) led to biopsy, that was diagnostic for germinoma in all
patients but one who did not undergo biopsy for the neuroradiological
evidence of bifocal tumour.

In a subgroup of patients with endocrinopathies as presenting symptoms
(17/55; 30.9\%), we performed subgroup analysis of different lag
intervals, referred as PI, HI and TI, stratified by age groups. PI and
HI account for 78\% of the TDI, collectively. PI did not differ
significantly among the three age groups (p=0.83), although the
\textgreater{}11 age group had the longest PI with a range from 8 to
26.5 months (median 18 months), compared with \textless{}5 age group
(median 12) and the 5-11 age group (median 7.5). SI was also similar
across age groups (median 1.0 vs 1.0 vs 1.8 months, p=0.19). Finally,
the longest TI was found in subjects aged \textgreater{}11 years
(p=0.14).

\textbf{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) (\textbf{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
(\textbf{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
\textgreater{}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)\textbf{(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
\textless{}5 years old were affected exclusively by NGGCTs, congruently
with previous reports \textsuperscript{2,26}. This finding suggests that
IC-GCTs in this age group may belong to a biologically different subset
as proposed by others \textsuperscript{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)\textsuperscript{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 \textsuperscript{29}.

The median time to diagnosis of IC-GCT in our cohort was 4 months,
shorter than the Japanese report \textsuperscript{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\textsuperscript{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
\textsuperscript{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
\textsuperscript{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 \textgreater{}6
months. Jennings et al.\textsuperscript{26} in a meta-analysis of 215
patients, found that 35\% of the patients were symptomatic for
\textgreater{}6 months before being diagnosed with GCT. In 2007,
Crawford et al. \textsuperscript{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 \textgreater{}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 \textgreater{}6 months. Conversely, patients with TDI
\textgreater{}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 \textsuperscript{17,23}. While
Phi et al.\textsuperscript{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 \textsuperscript{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\selectlanguage{ngerman}±21.2 months in this subset of patients \textsuperscript{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
MRI\textsuperscript{33}. 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
2013\textsuperscript{34}.

As in other published studies \textsuperscript{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
decade\textsuperscript{37}. 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 services\textsuperscript{38}. 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 \textgreater{}6 months
(orange dashed curve) and TDI [?]6 months (blue solid curve) diagnosis.

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