Imaging surveillance in multiple endocrine neoplasia type 1: Ten years of experience with somatostatin receptor positron emission tomography

Guidelines for multiple endocrine neoplasia type 1 (MEN1) recommend intensive imaging surveillance without specifying a superior regimen, including the role of somatostatin receptor imaging (SRI) with positron emission tomography (PET). The primary outcomes were to: (1) Assess change in treatment of duodenal-pancreatic neuroendocrine neoplasms (DP-NENs), bronchopulmonary NENs, and thymic tumors attributed to use of SRI PET/computed tomography (CT) and (2) estimate radiation from imaging and risk of cancer death attributed to imaging radiation. This was a retrospective single center study, including all MEN1 patients, who had had at least one SRI PET/CT. A total of 60 patients, median age 42 (range 21 – 54) years, median follow-up 6 (range 1 – 10) years were included. Of 470 cross sectional scans (MRI, CT, SRI PET/CT), 209 were SRI PET/CT. The additional information from SRI PET had implications in 1/14 surgical interventions and 2/12 medical interventions. The estimated median radiation dose per patient was 104 (range 51 – 468) mSv of which PET contributed with 13 (range 5 – 55) mSv and CT with 91 mSv (range 46 – 413 mSv), corresponding to an estimated increased median risk of cancer death of 0.5% during 6 years follow-up. SRI PET had a significant impact on 3/26 decisions to intervene in 60 MEN1 patients followed for a median of 6 years with SRI PET/CT as the most frequently used modality. The surveillance program showed a high radiation dose. Multi-modality imaging strategies designed to minimize radiation exposure should be considered. Based on our findings, SRI-PET combined with CT cannot be recommended for routine surveillance in MEN1 patients.


| INTRODUCTION
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by neuroendocrine hyperplasia of the parathyroid glands, neuroendocrine neoplasms (NENs) of the pituitary gland and duodenum/pancreas, and less commonly associated with NENs of the bronchi and thymus and adrenal cortex adenomas. 1,2 Gastroenteropancreatic NENs are divided into well-differentiated neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine carcinomas (NECs). Most duodenal-pancreatic NENs (DP-NENs) in MEN1, are G1 (low-grade, Ki-67 <3%) or G2 (medium-grade, Ki-67 3%-20%) tumors. 3 DP-NENs are very common in MEN1 with an estimated prevalence of 90% at the age of 70 years. 4 Increased mortality has been reported in patients with MEN1 with a reduction in life expectancy of around 10 years. 5,6 Metastatic DP-NENs and thymic tumors, represent the leading causes of premature death in these patients. 7 In contrast to DP-NENs, thymic tumors are rare with a prevalence of 3%-10%, but they are often highly aggressive. 8 Bronchopulmonary NETs in MEN1 usually have an indolent growth pattern, 9 and pituitary tumors are almost always benign. 10 The vast majority of DP-NENs are multifocal, non-functioning and remain small and localized. Therefore, watchful waiting with imaging instead of surgery is recommended in patients having tumors smaller than 20 mm. 4 However, the optimal imaging surveillance program in MEN1 is debated. 11,12 The most recent clinical practice guidelines, published in 2012, recommend annual imaging of the pancreas with computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS), thoracic imaging with CT or MRI every 1-2 years and imaging of adrenals with CT or MRI every 3 years. 1 On the one hand, metastatic disease or rapid growth tumors should not be missed. On the other hand, lifelong imaging implies a risk of secondary malignancies induced by ionizing radiation. 13 Of particular concern, MEN1 patients harboring mutations in the menin tumor suppressor gene might have reduced DNA repair capacity which could further increase their risk of developing cancer. [14][15][16] The balance between benefits and harms of extensive imaging in MEN1 is a matter of debate. 12 The overexpression of somatostatin receptors on NENs is used for both diagnosis and targeted treatment. Somatostatin receptor imaging (SRI) using positron emission tomography (PET) and radiotracers as 68 Ga-DOTATOC or 64 Cu-DOTATATE is the most sensitive imaging modality when it comes to detection of well differentiated NENs including DP-NENs. 11,17 The 2012 clinical practice guidelines for patients with MEN1 was published before the era of SRI PET. Subsequently, nine studies investigating the use of SRI PET/CT in MEN1 patients, have been published with conflicting results. [18][19][20][21][22][23][24][25][26] The aim of this retrospective study was to investigate the impact of SRI PET in a cohort of MEN1 patients. Primary outcomes were: (1) Change in treatment of DP-NENs, bronchopulmonary NENs and thymic tumors attributed to the use of SRI PET during a 10-year period (2012-2021). (2) Total exposure and estimated increased risk of cancer death attributed to imaging radiation. Secondary outcomes were: (1) Non-treatment related changes in management attributed to the use of SRI PET and (2)  College of Medical Genetics. 27 Genetic screening for MEN1 variants was initially performed based on Sanger sequencing in combination with multiplex ligation-dependent probe amplification (MLPA). The sequencing platform from 2014 and forward was carried out using next-generation gene panel sequencing (Illumina) and copy number variation detection as previously described. 28 Furthermore, included patients had to have undergone at least one SRI PET/CT scan in the period 2012-2021.

| Image acquisition
Since the introduction of SRI-PET in 2010 all our adult patients were offered a baseline SRI-PET unless, for example, high age or concomitant severe illness provided a contraindication for intervention. In younger patients not undergoing intervention the subsequent preferred imaging was abdominal MRI every 1-2 years and low-dose CT every 3-4 years.
In older patients, MRI was often replaced by CT of thorax and abdomen every 1-2 years or SRI-PET/CT. The decision to continue with SRI-PET/CT as surveillance was often based on results of previous SRI-PET.
In other cases, we used SRI-PET to confirm or disprove that a lesion detected by other modalities was a NEN. After surgical or medical intervention imaging strategy was based on an individual approach. We used both 68 Ga-DOTATOC and 64 Cu-DOTATATE as PET radiotracers, after 2017 primarily 64 Cu-DOTATE. In direct comparison between the two modalities in NET patients 64 Cu-DOTATATE PET detect more tumors than 68 Ga-DOTATOC. 11 Whether it has any clinical impact is still uncertain. Furthermore, the shelf life of more than 24 h and the scanning window of at least 3 h make 64 Cu-DOTATATE favorable and easy to use in the clinical setting. PET was analyzed along with CT in accordance with ENETS guidelines. 29 For the 64 Cu-DOTATATE PET/CT 200 MBq of 64 Cu-DOTATATE was administered intravenously, and PET/CT was performed after 60 min.
For the 68 Ga-DOTATOC scan, 100-150 MBq was administered intravenously, and PET/CT was performed after 45 min. PET positive lesions were defined as lesions with higher uptake than the liver (Krenning score  or CT/MR (PO) images, respectively. If a lesion was detected by SRI PET and not by CT or MRI and led to intervention, then SRI PET was considered as the cause of the intervention.

| Radiation exposure and risk of secondary malignancy
The actual individual radiation burden for a given CT procedure depends on factors such as, size of the patients, amount of adipose tissue and number of phases. In the present study we have used the following assumptions: Whole body SRI PET/CT 25 millisieverts (mSv) (including 4-6 mSv from the 64 Cu-DOTATATE or 68 Ga-DOTATOC).
CT of the abdomen and thorax 15 mSv, CT of the abdomen 10 mSv, [30][31][32] low dose CT of the thorax 1.4 mSv. 33 When calculating potential increased risks of cancer, we have used the linear nothreshold theory. This method is widely used and uses the assumption of a 5% excess risk of death from cancer for each 1 Sv

| Ethics
The study was approved by the local data protection agency at Rigshospitalet (2007-58-0015) and by the Danish Patient Safety Authority (31-1521-453). Due to the retrospective design informed consent was not required.

| Baseline characteristics
Sixty (39 female) of 89 patients followed-up at our department fulfilled the inclusion criteria with at least one SRI-PET/CT performed during the study period. The median age at inclusion was 42 (range 21-54) years, and patients were followed-up for a median of 6 (range 1-10) years.

| Imaging characteristics
The imaging characteristics are shown in Table 1 Table 1.

| Surgical intervention
During the study period 14 operations were performed in 11 patients The main indication for surgery was tumor growth (for details see Table 2).
In one case SRI PET (patient no 8, Table 2, woman, age 51 years) had a major impact on the decision to perform total pancreatectomy due to a suspicion of a local lymph node metastasis not visible on CT together with pancreatic tumors which had not increased in size. This information was obtained both from the original imaging description and from the re-evaluation. The subsequent histopathological examination could not identify any lymph node metastases. In the remaining 13 surgical interventions, SRI PET did not lead to surgery, since the tumors were either visualized by MRI or CT (for details see Table 2).

| Medical intervention
During the study period 12 new medical treatments were initiated in nine patients (for details see Table 3).
Initiation of medical treatments with SSA were attributed SRI PET in two patients. One patient (patient no. 9, Table 3) had a PET positive lesion in the pelvic bones most likely representing a bone metastasis (bone lesion visualized on Figure 1). This metastasis was discovered 18 months after resection of a 1.7 cm pancreatic NET with a Ki-67 index of 2%. In the other patient a lesion detected by PET was most likely a lymph node metastasis (patient no. 4, Table 3). In both cases the original description of imaging and the re-reading revealed similar results.

| Radiation exposure
The cumulative estimated median radiation for all scans was 104 (range, 51-468) mSv per person of which 13 (range 5-55) mSv was from PET and 91 mSv (range 46-413 mSv) from CT corresponding to a calculated median increase in cancer death risk of 0.5 (range 0.2%-2.3%). The cumulative estimated radian exposure from SRI PET/CT was 63 (range 25-275) mSv. It is recommended that imaging surveillance already starts in adolescents. Thus, a patient diagnosed in childhood (e.g., due to family history) has an expected follow-up of at least 50 years. If such a patient was followed with the same imaging regimen as during the study period it would lead to an estimated increase in cancer death risk of 4.3 (range, 2.1%-19.5%).  Table 4).    In recent years the strategy of using frequent cross-sectional imaging has been questioned due to lack of evidence and the potential harm of radiation exposure, psychological stress related to imaging and economic burdens. 12 In our study, the calculated increased risk of cancer death attributed ionizing radiation from CT was 0.5% during a period of only 6 years which is in agreement with a previous study from 2017. 13 Setting up a standard imaging program for MEN1 is a complex task. MRI has the advantage of not involving exposure to ionizing radiation, and in a consensus statement from 2021 abdominal MRI is recommended as the first choice. 4 However, there are concerns over repeated exposure to gadolinium-based contrast agents and MRI is inferior to CT in terms of detecting thoracic tumors. 12,35,36 Another concern by exclusive use of MRI is the potential risk of missing some pancreatic tumors of relevant size. 37  physician had access to previous imaging of all modalities, implying that the evaluation of CT versus PET versus MRI and evaluation of non-treatment changes in management were not independent. In the analysis of the impact of SRI-PET on intervention we tried to compensate for the non-blinded design by introducing re-reading of the imaging. It was somewhat reassuring that the information gained by the original description and the re-reading were similar. We decided only to re-read imaging leading to intervention since the decision to intervene is always based on a MDT decision taking into account many clinical relevant aspects and not only imaging. The majority of scans prior to intervention were SRI PET/CT implying that the information gained by PET was compared to the CT result, and not MRI which is the choice if radiation burden should be reduced. We used an estimated average radiation dose per scan, but this dose may not apply to all patients since the radiation dose depends on size of the patient, number of phases, etc. Moreover, the 5% excess risk of death from cancer for each Sv dose is based on low evidence. Compared to previous studies our cohort is larger and have a longer follow-up, however the cohort size is still relatively small.

| Change in management
In conclusion, three of 26 interventions were attributed SRI PET in a large cohort of MEN1 patients followed for a median of 6 years with frequent use of SRI PET/CT. We calculated a high cumulative radiation dose significantly increasing risk of estimated cancer death.
Based on our results we will not recommend the use of SRI-PET for routine surveillance combined with CT which was driving the major part of the radiation burden. SRI PET/MR might in the future be an attempting modality, since it is non-invasive, convenient to the patients, has a low radiation burden and has the advantage of combining two modalities thereby reducing the risk of missing significant tumors.