Neuroendocrine tumors (NETs) are often well differentiated and show indolent tumor growth. Since NETs express up to 95% somatostatin receptors (SSTRs), the introduction of SSTR PET/CT represented an important improvement in the diagnosis of NETs (1). Imaging with ⁶⁸Ga-DOTA somatostatin analogs is the current recommended modality for staging and re-staging of well-differentiated NET patients and shows in particular high detection rates for lymph node and bone metastases, as well as peritoneal lesions and unknown primary tumors (1, 2). Magnetic resonance imaging on the other hand is the modality of choice for assessing the presence of liver metastases due to better soft-tissue contrast (3). The detection and characterization of liver lesions can be further increased by using liver-specific contrast agents. Thus, MRI is integrated as a complement to PET/CT in the (re)-staging of patients with NET in clinical routine.

Following the ENETS guidelines and the AWMF S2k guideline postoperative follow-up for NET patients is recommended for at least 15 years, which includes MRI liver/abdomen and SSTR-based PET/CT alternating at certain time intervals (1). So, follow-up imaging of NET patients is much more intensive compared with other tumor entities such as pancreatic or colorectal carcinoma, and the patient collective includes many relatively young patients. Against this background, the cumulative radiation exposure should be kept as low as possible to avoid increased secondary malignancies due to intensive follow-up with PET/CT scans.

Especially in low-risk patients, it would be interesting to implement whole-body MRI as an alternative or in addition to PET/CT to rule out metastases in the long-term risk-adapted tumor follow-up. Whole-body MRI is increasingly evaluated for staging various tumor entities (e.g., breast carcinoma or melanoma), with promising results considering the diagnostic accuracy (4, 5). Due to the technical development of MRI in recent years, the image quality has improved, while acquisition times were reduced, which allows the integration of whole-body MRI protocols into clinical routine.

The examination area of liver MRI includes the base of the lungs and the entire upper abdomen (liver, spleen, and pancreas) up to the kidneys. Diffusion-weighted sequences (DWI) are routinely included in the upper abdomen MRI protocol, since it can improve the detection and characterization of liver lesions but seems to be also helpful in detecting other hematogenous or lymphogenous metastases (6–8).

The evaluation of liver MRI includes not only the assessment of hepatic metastases but also evaluation regarding the presence of extrahepatic metastases.

Therefore, it is of great interest to assess the diagnostic accuracy of different sequences integrated in the routine liver MRI protocol in patients with NET compared with the gold standard PET/CT to improve clinical routine by a better understanding of extrahepatic findings in liver MRI and to prepare the groundwork for the development of an MRI whole-body protocol for patients with NET.

This study is a retrospective cohort analysis. Patients with neuroendocrine tumors who were examined between 2010 and 2021 with liver MRI with liver-specific contrast agent and ⁶⁸Ga -DOTATATE (-TOC) or ¹⁸F-SIFA-TATE PET/CT with a maximum interval of 3 months between the two imaging modalities were included. Exclusion criteria were severe imaging artifacts and a missing acquisition of DWI. Approval by the local research ethics committee was obtained, and need for written informed patient consent was waived.

In the present study, lesion- and patient-based diagnostic performance of different MRI sequence combinations of routine liver- for the detection of extrahepatic disease of patients with NET was evaluated.

In total, the highest lesion-based detection rates were found by combining NC+DWI or NC+DWI+CE with 71% each. Concordantly, highest overall sensitivities for the presence of extrahepatic metastases in the patient-based analysis were reached by the combination of NC+DWI (85%) and NC+DWI+CE (78%), with higher specificity when combining all available sequences (100%). Regarding the extrahepatic disease pattern, we found especially good results for the detection of bone and lymphatic metastasis with the addition of DWI only (81 and 77%, respectively) as well as for pancreatic tumor manifestations (87%) when adding both DWI and CE.

Schraml et al. reported higher sensitivities (98%) for overall patient-based assessment of metastatic status comparing the diagnostic performance for ⁶⁸Ga-DOTATOC PET/CT and whole-body MRI (wbMRI). However, the authors also assessed the presence of liver metastases, which constituted a high proportion of all analyzed lesions (12). Since MRI represents the best modality for hepatic metastases, due to higher soft tissue-contrast and the availability of liver-specific contrast agents, higher overall performance in their study was not surprising. By contrast, the focus of our work was a better characterization of the potential of MRI for extrahepatic disease. Schraml et al. reported significantly higher sensitivities of PET/CT for metastasis of lymph nodes (100 vs. 73%) and lungs (100 vs. 87%), while wb MRI showed higher detection rates for bone metastases (96 vs. 82%) (12). By comparison, we reached a slightly higher sensitivity (77%) for the detection of lymph node metastases using only DWI in addition to the non-contrast enhanced sequences, which was significantly higher than sensitivities in the other readings. Subsite analysis revealed that the integration of DWI to the reading led to high detection rates for retroperitoneal and mesenterial lymph node metastases, while for the assessment of cardiophrenic lymph nodes contrast enhanced (NC+DWI+CE and NC+CE) sequence combinations showed improved detection and error rates. However, one must be aware that both normal lymph nodes and metastatic lymph nodes may have a high-signal intensity on DWI (13). In addition, DWI is prone to artifacts due to respiratory and heart movement, so that these results may not be reproducible in the thoracic region. This is underlined by rather low detection rates and high error rates for NC+DWI in the evaluation of cardiophrenic lymphatic metastasis, while the addition of contrast-enhanced sequences led to good detection rates for this region (up to 78%).

Lesion-based detection rates for bone metastases were highest in NC+DWI and NC+DWI+CE (75 and 74%, respectively). In the patient-based assessment of bone metastases, the addition of DWI significantly increased sensitivity compared with non-enhanced imaging and NC+CE. This is in accordance with previous published studies that have shown that MRI including DWI represents an excellent diagnostic method for detection of bone metastases (13–15). Multiple studies suggested that wb MRI with DWI (often without CE) showed similar or even better detection rates than CT or PET/CT for bone metastases of renal cell carcinoma (8), breast cancer (4), and prostate cancer (16, 17). However, it should be noted that bone metastases differ in their appearance, for example sclerotic skeletal metastases show low-signal intensities on MRI while visual contrast is better with PET/CT in these metastases (18–20). Baur et al. showed that sclerotic bone metastases treated with chemotherapy had a hypointense appearance on DWI due to low water content (21). Notably error rates for bone metastasis were not improved by contrast-enhanced sequences in our study.

Overall detection rates of peritoneal metastases turned out to be only mediocre; however, addition of DWI could significantly improve the sensitivity compared with NC+CE. Cianci et al. also showed also that the sensitivity for the detection of peritoneal metastases by combined interpretation of conventional MRI with DWI was significantly higher compared with conventional contrast-enhanced sequences alone (22). In our analysis, peritoneal manifestations were best detected when located subphrenic or at the gerota fascia while detection rates were lowest for lesions located at the gastric serosa or paracolic, which might be explained by respiratory motion artifacts or difficulties in differentiation from colonic diverticula, respectively. When developing a whole-body MRI protocol, sopolamine would probably be useful as a drug to reduce bowel motility. Furthermore, the sensitivity could improve if readers had access to previous PET/CT scans as it would be the setting in clinical routine.

Lesion- and patient-based detection rates for lung metastases were low for all four readings, however these results were expected since MRI is not the modality of choice for assessing lung metastases and a low-dose CT should therefore be considered as a screening supplement to a possible wb MRI.

Evaluation of tumor manifestations in other abdominal organs was limited by small total numbers of lesions apart from pancreatic tumors (n = 23) (see Table 2 ). Detection rates for pancreatic NET manifestations were notably improved by the addition of DWI (18 of 23 lesions) compared with NC or NC+CE (11 of 23 or 13 of 23, respectively) and were highest for NC+DWI+CE (20/23). Schmid-Tannwald et al. also reported that the detection of pancreatic NET was significantly increased by DWI as adjunct to T2w imaging and performance was comparable with CE T1w imaging (23).

At first glance, it seems surprising that detection rates with the combination of non-contrast NC+DWI+CE are sometimes lower than those of non-contrast NC+DWI. This might be explained by the fact that when assessing a diffusion-restricted and therefore suspicious lesion, a lack of or only low contrast enhancement leads to this lesion being falsely assessed as benign. This may especially play a role in NET tumor manifestations, since this tumor entity is primarily arterially hypervascular and the arterial phase is particularly susceptible to artifacts, especially with Eovist/Primovist if the injection is too rapid causing transient severe respiratory motion (24). On the other hand, if the lesion is diffusion-restricted and shows the typical contrast uptake, this leads to higher specificity with the combination of non-contrast, contrast-enhanced sequences and DWI compared with the combination of non-contrast-enhanced sequences alone and DWI, as we also found in our study.

Limitation of this study was its retrospective character with some of the patients already undergoing therapy at the time of the analysis, so that possible therapy effects might have influenced our evaluation. Another limitation represents the lack of pathological confirmation as gold standard; however, SSTR-PET/CT is currently the most accurate imaging modality for NET and follow-up imaging was available in case of doubtful findings. However, it is known that NET metastases can lose their SSTR expression during dedifferentiation and were not being taken into account. As the study focused on clinically available liver/upper-abdomen MRIs the range of included field of view varied intra-individually from patient to patient and other field of interests such as neck and thorax were not evaluated in this study. Whole-body MRI might be an interesting alternative for future studies; however, we also wanted to emphasize experience relevant to everyday clinical practiceOne major limitation which warrants mention is that MRI may be detecting disease that PET did not, particularly in lesions that are too small to detect on PET or which were PET-negative lesions. Therefore some of the false positives may in fact be true disease. However, in the event that lesions found on MRI were not positive on PET/CT, follow-up imaging and other imaging techniques were used to form a consensus.

The combination of NC+DWI showed better overall detection of extrahepatic NET than the combination of NC+CE. The combination of NC+DWI showed similar, sometimes even better sensitivities than NC+DWI+CE, ​​but with slightly lower specificity. Upper-abdomen MRI showed especially good detection rates for bone metastases, lymphatic metastasis, and pancreatic tumors, while the detection of peritoneal metastases was only good for lesions located subphrenic and at the gerota fascia. The addition of intravenous contrast especially improved detection rates for cardiophrenic lymph nodes and pancreatic NET.

These results should be considered in the daily routine when examining liver MRI with regard to extrahepatic metastases and should be taken into account for the development of a wb MRI protocol, since selection of a combination of sequences with the best diagnostic performance are key questions for the implementation of wb MRI into clinical routine (25, 26). However, further research is needed to improve relatively low detection rates in some categories compared with PET/CT despite usually more sequences of contrast enhancement in liver MRI compared with a wb MRI protocol.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethikkommission bei der LMU München (local ethics committee). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

All authors contributed to the study conception and design. Material preparation and data collection were performed by MI, FV, HK, MW, and CS-T. Formal analysis was performed by RS and MI. The first draft of the manuscript was written by MI and CS-T and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.