Key words multiple endocrine neoplasia type 1 - neuroendocrine tumor - magnetic resonance imaging
- endoscopic ultrasonography
Introduction
Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant neoplastic disorder
caused by germline mutations in the MEN1 gene and characterized by combined occurrence
of tumors of the parathyroid glands, the anterior pituitary and the endocrine pancreas
[1 ]. The MEN1 phenotype is extremely diverse with variable expressivity, considerable
heterogeneity and a wide age range of penetrance of its different components. Although
rare, MEN1-related Pancreatic Neuroendocrine Neoplasms (PanNEN) represent the second
most frequent manifestation of MEN1 after primary hyperparathyroidism with a clinical
penetrance of 50–70% [2 ]
[3 ]. They are characterized by early onset, multifocality and malignant potential with
a propensity for development of locoregional and distant metastases depending on the
size on the neoplasm. Additionally, PanNENs are one of the leading causes of cancer-related
death in MEN1 patients [4 ]. Thus, prompt initial detection and life-long subsequent imaging monitoring of pancreatic
lesions, already from 10 years of age, is crucial in patient management [5 ]
[6 ].
The majority of MEN1- related PanNENs are nonfunctional (NF), clinically silent tumors,
whereas in a subset of MEN-1 patients, they may secrete hormones leading to distinct
clinical syndromes [7 ]. Different imaging modalities are currently available to localize functional PanNENs
(F-PanNENs) prior to treatment (mainly surgical), but still their detection may be
challenging. On the other hand, the surgical management of MEN1-related NF-PanNEN
relies basically on tumor size, as the risk of malignant transformation and metastatic
potential rises in larger tumors [8 ]
[9 ]. However, the cut-off for surgery to minimize the risk of extra-pancreatic extension
is still debatable and currently most of the clinical practice guidelines for surgical
exploration in MEN1 patients with NF-PanNEN recommend a cut-off size of 2 cm [5 ]
[10 ]
[11 ]. MEN1 patients with a NF-PanNEN may undergo imaging of the pancreas every 6 to 12
months to assess the growth rate of the tumor [5 ]
[12 ]. Importantly, as MEN-1 patients are subjected to life-long imaging monitoring, concerns
also arise about the radiation risk in younger patients, regarding the routine use
of Computed Tomography [13 ]
[14 ].
To date, Endoscopic Ultrasonography (EUS) and Magnetic Resonance Imaging (MRI) have
produced complementary results for detecting MEN1-related PanNENs, concerning both
F-PanNEN localization and NF-PanNEN assessment. EUS may be combined with fine needle
aspiration and provide information of the neuroendocrine origin of the tumor and grading.
However, it is an invasive procedure and may be operator dependent [15 ]
[16 ]. Additionally, the accuracy of EUS-guided fine needle aspiration compared to biopsy
specimens is not great for low ki67 values. Nevertheless, it is still unclear which
imaging modality should be routinely implemented at initial assessment and particularly
during MEN1 patient follow-up. The main reasons for this are that the most sensitive
modality for detecting clinically significant changes in NF-PanNEN has not yet been
clearly determined. Moreover, the tumor size cut-off, as well as the least significant
change in tumor diameter, that would lead to surgery are still not fully defined [5 ]
[17 ].
The aim of the present study was to evaluate whether a non-invasive imaging modality,
such as MRI of the pancreas could be implemented in MEN1 patient surveillance, as
compared to EUS. We also aim to compare the concordance of these two modalities at
the size cut-offs of 20 mm, the main indication for surgery, and 10 mm, inconsequential
for the management of NF-PanNEN in MEN1 patients, respectively.
Patients and Methods
Thirty-one consecutive patients with MEN1-related PanNENs, who had been followed up
at the Endocrine Oncology Unit, EKPA-Laiko Hospital, Athens, Greece from January 2005
through August 2018 were included. All patients underwent concurrent evaluation by
EUS and MRI of the pancreas with a less than three months interval at initial assessment
and/or at follow-up. Data were prospectively collected and retrospectively evaluated.
MEN1 patients, who did not have concurrent MRI and EUS imaging were not included in
this study.
Ethical approval
All procedures performed in studies involving human participants were in accordance
with the ethical standards of the institutional and/or national research committee
and with the 1964 Helsinki declaration and its later amendments or comparable ethical
standards. Institutional Review Board approval was obtained. Informed consent was
obtained from all individual participants included in the study.
The diagnosis of MEN1 was confirmed in all patients based on standard international
guidelines, including MEN1 gene mutation detection and/or pathognomonic clinical, biochemical and radiological
signs of MEN1–associated tumors [5 ]. Additionally, all patients had a confirmed radiological diagnosis of PanNEN either
on previous Computed Tomography (CT) scan or the modalities (MRI and EUS) assessed
in this study ([Fig. 1 ]). Patient surveillance included the measurement of conventional imaging with MRI
every 3–9 months according to existing ENETS guidelines [5 ]. However, the interval between assessments was increased if the disease was stable
(especially for the relatively indolent grade 1, subcentimeter lesions). EUS was used
at baseline along with MRI and thereafter upon identification of new pancreatic lesions
on MRI at an annual or biannual basis, mainly for functional lesions, in cases demonstrating
tumor growth at conventional imaging as well as in the preoperative setting. As computed-tomography
is associated with repeated radiation exposure, this modality was not assessed in
patient surveillance in our study [13 ]
[14 ]. Pathology reports were scrutinized for the subset of patients undergoing pancreatic
resective surgery (n=5) after concurrent imaging to assess the validity of these modalities.
All patients had biochemical surveillance using standard immunoassays for MEN1 to
assess the functional status of PanNENs [5 ].
Fig. 1 Multiple small Pancreatic Neuroendocrine Neoplasms in pancreatic head on axial Magnetic
Resonance Imaging and on Endoscopic Ultrasonography.
Fig. 2 STARD Flow chart for Diagnostic Test Accuracy.
Median age at the time of PanNEN evaluation was 44 yrs (range: 16–78). The concurrent
PanNEN evaluation with MRI and EUS was conducted in a preoperative setting in 5 patients,
whereas 3 patients had previously undergone resective pancreatic surgery at the time
of initial evaluation with these modalities. For the five patients who underwent pancreatic
resective surgery after concurrent EUS/MRI evaluation, pathology reports were thoroughly
reviewed. All cases with available histology/cytology [surgical specimens or EUS-guided
fine needle aspirations (FNA)] had well differentiated tumors (18 Grade 1, 8 Grade
2 and 5 tumors of unknown Grade; 24 tumors were NF-PanNENs and seven were F-PanNENs.
Eighteen patients had a confirmed MEN1 gene mutation, 6 patients had negative mutational status, whereas the remaining 7
patients were not genetically tested.
MRI (1,5 T GE Signa Explorer 16 channel) was performed according to an axial T1 with
and without fat saturation and T2-weighted (with optional T2 with fat saturation),
diffusion-weighted imaging (DWI) and axial 3-dimensional volumetric dynamic intravenous
gadolinium-enhanced T1 fat-saturated gradient echo sequence protocol. Dedicated high-spatial
resolution sequences were used with the reconstruction interval being 4 mm. Patients
were fasted for 6 h before the examination. Scans were subsequently scrutinized and
reported by a dedicated not blinded radiologist (DK).
EUS was performed under conscious sedation with a linear ultrasonographic endoscope
(HV Avious Hitachi console with elastography mode for contrast enhanced technique,
compatible to EG3870UTK Pentax Echoendoscope) by the same operator (IK). The scanning
frequency varied between 5–10 MHz. The presence of vascularity was assessed with Doppler.
EUS-guided fine-needle aspiration (FNA) for cytologic confirmation was performed with
a 22 gauge needle (Boston Expect Needle 22 G) on demand by the referring physician
or as needed depending on the morphology of the lesion and the judgement of the EUS
operator. The pancreas was explored trans-gastrically and trans-duodenally with meticulous
peri-pancreatic lymph node exploration/mapping, as well as duodenal exploration in
cases of Zollinger–Ellison syndrome.
Finally, we performed a cost-analysis, assessing the costs of a hypothetical routine
implementation of MRI of the abdomen versus that of EUS in an outpatient basis for
the imaging surveillance of MEN1 patients in health care systems of different countries
(Table 1S . To ensure the quality of data reporting, we followed the STARD statement (Standards
for Reporting of Diagnostic Accuracy Studies) ([Fig. 2 ]) [18 ].
Statistics
Data were described as mean with standard deviation (SD) for parametric data or median
with range for non-parametric data, as appropriate. All statistical analyses (frequencies,
descriptive statistics, Wilcoxon signed rank sum test, McNemar test, and Cohen’s kappa
for paired data) were computed with the SPSS 23.0 software package (IBM SPSS Statistics,
Armonk, NY, USA). Tests were two-sided and p-value<0.05 was considered statistically
significant.
The frequencies and concordance of EUS and MRI for tumor sizes of ≥10 mm and ≥20 mm
PanNEN, respectively were presented; inter-rater reliability and sensitivity/specificity
for MRI compared to EUS for the aforementioned cut-offs were evaluated with Kappa
coefficients. PanNEN minimum sizes, multifocality assessment and number of lesions
detected per patient were computed with Wilcoxon signed sum rank tests, Fisher exact
tests or McNemar test for paired data, as appropriate. Finally, the Bland-Altman plot
was used to compare the two imaging techniques. In this graphical method the differences
between maximal lesion diameter by MRI and EUS were plotted against the EUS measurements,
with the latter being considered the reference or "gold standard" method [19 ]. The limits of agreement were defined as the mean difference±1.96 SD of differences.
Results
In 31 patients, 129 pancreatic lesions were detected in total. MRI detected 73 lesions
in 31 patients, whereas EUS detected 110 lesions in 30 patients (p=0.006). Applying
a 20 mm and 10 mm cut-off of maximal lesion diameter, MRI exhibited a concordance
of 97% and 87% with EUS, respectively. Inter-rater reliability of MRI compared to
EUS was deemed excellent for lesion diameter >20 mm and good for lesions >10 mm (Cohen’s
kappa=0.912 and 0.718, respectively). MRI sensitivity and specificity compared to
EUS in this patient cohort for these cut-off values were 96 and 88% (20 mm cut-off)
and 90 and 82% (10 mm cut-off), respectively. Lesions < 10 mm were detected more often
with EUS than MRI (p=0.025).
Twenty-seven patients exhibited multifocal lesions on either modality. Multifocality
assessment did not differ significantly on MRI compared to EUS (p=0.092), even if
more lesions were detected with the latter. In the subset of F-PanNEN (n=7) in these
series, the tumor size was >10 mm in four cases (EUS localized all four, whereas MRI
three F-PanNEN), whereas functional lesions <10 mm were evident in three cases (EUS
identified two lesions, whereas MRI all three). The pathology report review for patients
undergoing pancreatic resective surgery (n=7) showed that both modalities were in
100% concordance with the pathology findings at the aforementioned cut-offs. Both
modalities identified the sequential growth of NF-PanNETs during a minimum two year
period in patients subjected to sequential concurrent imaging. Concurrent imaging
was applied to assess tumors exhibiting substantial growth rates and also to acquire
new fine needle aspirates as necessary for tumor grading [n=7 (mean±SD: 2 mm/year±3.4 mm
vs. 1.9 mm/year±3.6 mm)]. Both MRI and EUS did not demonstrate any significant differences
in maximal lesion diameter measurements in patients with available pathology report
(p=0.236 for MRI and p=0.176 for EUS), all of whom had maximal lesion size >10 mm.
Although the number of patients undergoing surgery was indeed small in order to obtain
meaningful data, the mean differences between the pathology report and either EUS
or MRI, regarding maximal lesion diameter, did not differ significantly (p=0.933),
that is, neither MRI nor EUS seemed to over- or underestimate the tumor size of PanNENs
in the few cases with available pathology report.
In Bland–Altman analysis for maximal lesion diameter measurements with the two imaging
modalities used (mean of differences±SD=0.38±9.56, p=0.827), the limits of agreement
did not exceed differences within the mean±1.96 SD in the majority of the patients
(two outliers), thus the two methods were considered to be in agreement and may be
used interchangeably (Supplemetary Fig. 1S ).
One patient manifested acute pancreatitis requiring hospitalization secondary to EUS
guided FNA. No other procedure-related complications were reported in this series.
Finally, the routine implementation of MRI instead of EUS in MEN1-related PanNEN surveillance
would result in variable cost-reduction ranging from 0–67%, as depicted by the cost
of these modalities in the outpatient setting for MEN1 surveillance across different
countries (Supplemetary Table 1S ).
Discussion
In our study, in a single-centre cross-sectional setting we demonstrate that the concordance
of MRI compared to EUS in MEN-related PanNENs with tumor size >10 mm is as high as
87%. These findings suggest that routine MRI implementation in pancreatic imaging
surveillance of MEN1 patients with NF-PanNEN is highly efficient, as smaller NF lesions
are considered to be inconsequential for patient management. Additionally, such an
implementation in MEN1 patient surveillance would also minimize the risk of potential
complications from an invasive procedure as EUS. A subset of patients with NF-PanNEN
was subjected to sequential concurrent imaging with EUS and MRI in order to assess
tumoral growth rate and potentially acquire new fine needle aspirates, as clinically
indicated. This analysis, as well as the assessment of available pathology reports
in connection to MRI and EUS maximal lesion measurements, revealed comparable figures,
confirming the applicability of MRI in MEN1-related PanNEN surveillance. Finally,
cost-analysis of the modalities investigated here, in an outpatient setting and across
different countries exhibited a variable cost-reduction ranging from 0–67% by routinely
implementing MRI instead of EUS in the annual imaging surveillance of these patients.
Generally, MRI has the advantage of not using ionizing radiation, being therefore
the imaging modality of choice in screening and long-term follow-up of patients, such
as these with MEN1. Additionally, it has become more widely available in many countries
compared to EUS, and it is a non-invasive procedure with considerable progress in
imaging resolution in recent years. On the other hand, EUS still plays a crucial role
in the assessment of NENs in the duodeno-pancreatic region and has been the reference
examination for accurate preoperative PanNEN assessment with an increase in PanNEN
detection after other modalities are attempted [20 ]. This is particularly relevant for small functional tumors, which can be challenging
to localize [20 ]. It is also utilized to assess critical surgical details such as the proximity of
the main pancreatic duct and vascular structures in this region. Additionally, the
use of EUS-guided fine needle aspiration and biopsy of PanNEN and locoregional lymph
nodes is indeed of paramount importance in obtaining a cyto/histological confirmation
of NEN diagnosis, when necessary. However, a possible disadvantage of EUS, is that
it may overestimate the size of MEN1-related PanNENs, especially those with a tumor
size<20 mm [21 ]. This was not evident in our series in the subset of patients undergoing surgery
after concurrent imaging; however, the number of patients who underwent surgery was
relatively small to make a strong argument. Nevertheless, the overestimation in size
reported by Polenta et al. should probably be taken into consideration for tumors
15–20 mm that approach the currently accepted cut-off of 20 mm necessitating surgical
exploration [21 ].
EUS and MRI have produced complementary results for detecting MEN1-related PanNEN
at initial evaluation, according to the largest study to date by the French Endocrine
tumor Study Group [15 ]. Interestingly in this study, EUS missed more PanNEN>20 mm than MRI [15 ], whereas in other studies, both EUS and MRI performed well in detecting large size
lesions [22 ]
[23 ]
[24 ]. In our study, EUS missed one case only of an 11 mm lesion that was detected by
MRI instead; however this single patient had previously undergone a gastric procedure.
Previous studies have shown that MRI exhibits high diagnostic performances in PanNEN
with reported sensitivities of 74–94% and specificities of 78–100% [25 ]. However, a recent meta-analysis comparing EUS and MRI in MEN1 patients in terms
of their sensitivities to localize small F-PanNEN (insulinomas) preoperatively reported
a sensitivity of 80% for EUS and 66% for MRI, respectively [26 ]. Hence, EUS seems to be more sensitive than MRI in localizing small F-PanNENs preoperatively
and this is also in accordance with the findings of our study, where EUS detected
lesions <10 mm more often than MRI.
The overall reported risk of complications from EUS and EUS-FNA is relatively low
and the safety of these procedures appears to be acceptable [27 ]. However, MEN1 patients are subjected to repeated life-long surveillance and there
was one patient in this series manifesting a severe complication (pancreatitis) requiring
hospitalization secondary to EUS-FNA.
68 Gallium-PET-CT is a further sensitive imaging modality for PanNEN localization as
it has a spatial resolution of 0.5–1 cm [28 ]. There is general consensus that it may be performed in any surgical candidate with
PanNEN, as well as patients with advanced and/or disseminated disease to provide a
comprehensive staging of the disease extent; however, to date 68 Gallium-PET-CT is not used as a surveillance tool in asymptomatic MEN1 patients with
or without an established diagnosis of PaNEN [29 ]. Importantly, regarding functional imaging, the subset of patients with MEN-1 related
insulinomas may be in need of special localization with novel modalities, such as
68 Gallium DOTA-Exendin PET/CT [30 ].
Control randomized studies on diagnostic test accuracy are of course the design of
choice to determine the benefits of a surveillance protocol to be implemented or compare
alternative surveillance strategies. However, the scarcity of MEN1 disease makes such
a trial difficult to be conducted. Additionally, the small sample size of our study
and the inclusion of MEN1-related PanNEN at different time points in the disease course,
when concurrent imaging was available and differences in prior surgical management
in a subset of this cohort may all have confounded the results. Another limitation
is that final histopathology for tumor size validation in the majority of the patients
in this series was not available and therefore EUS was used as the reference modality.
Additionally, the raters of MRI as well as the EUS operator were not blinded to patient
MEN1 diagnosis and previous panNEN imaging if available; hence, the present study
might be limited by recall bias. Nevertheless, observational research on diagnostic
test accuracy in MEN1 patients subjected to life-long surveillance, such as the present
study is required, to determine which imaging surveillance strategies are most effective
for implementation into practice in the field of MEN1.
In conclusion, MRI is a non-invasive modality, which performs equally well as EUS
for lesion detection larger than 10 mm and subsequent surveillance of MEN1-related
PanNENs, as smaller non-functional lesions are generally considered inconsequential
in patient clinical management. Both modalities could be used at initial assessment
of MEN1-related PanNENs, as EUS identifies more, smaller than 1 cm neoplasms and therefore
has a complementary role. Thereafter, a more conservative and cost-effective surveillance
approach with MRI alone may be utilized in MEN1 patient follow-up.
Author Contribution Statement
Author Contribution Statement
Drs. Daskalakis and Tsoli contributed equally to this study; had full access to all
the data in the study, and take responsibility for the integrity of the data and the
accuracy of the data analysis. Dr. Kaltsas was the study supervisor.
