Marie‐Pierre Vullierme

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System : Well-Differentiated Pancreatic Non-Functioning Tumors

Contrast-enhanced computed tomography (CT) of the neck-thorax-abdomen and pelvis, including 3-phase examination of the liver, constitutes the basic imaging for primary neuroendocrine tumor (NET) diagnosis, staging, surveillance, and therapy monitoring. CT characterization of lymph nodes is difficult because of inadequate size criteria (short axis diameter), and bone metastases are often missed. Contrast-enhanced magnetic resonance imaging (MRI) including diffusion-weighted imaging is preferred for the examination of the liver, pancreas, brain and bone. MRI may miss small lung metastases. MRI is less well suited than CT for the examination of extended body areas because of the longer examination procedure. Ultrasonography (US) frequently provides the initial diagnosis of liver metastases and contrast-enhanced US is excellent to characterize liver lesions that remain equivocal on CT/MRI. US is the method of choice to guide the biopsy needle for the histopathological NET diagnosis. US cannot visualize thoracic NET lesions for which CT-guided biopsy therefore is used. Endocopic US is the most sensitive method to diagnose pancreatic NETs, and additionally allows for biopsy. Intraoperative US facilitates lesion detection in the pancreas and liver. Somatostatin receptor imaging should be a part of the tumor staging, preoperative imaging and restaging, for which <sup>68</sup>Ga-DOTA-somatostatin analog PET/CT is recommended, which is vastly superior to somatostatin receptor scintigraphy, and facilitates the diagnosis of most types of NET lesions, for example lymph node metastases, bone metastases, liver metastases, peritoneal lesions, and primary small intestinal NETs. <sup>18</sup>FDG-PET/CT is better suited for G3 and high G2 NETs, which generally have higher glucose metabolism and less somatostatin receptor expression than low-grade NETs, and additionally provides prognostic information.

Compared with the imaging features of typical hepatic hemangiomas, the imaging features of atypical hepatic hemangiomas have not been well studied or well described. Knowledge of the entire spectrum of atypical hepatic hemangiomas is important and can help one avoid most diagnostic errors. A frequent type of atypical hepatic hemangioma is a lesion with an echoic border at ultrasonography. Less frequent types are large, heterogeneous hemangiomas; rapidly filling hemangiomas; calcified hemangiomas; hyalinized hemangiomas; cystic or multilocular hemangiomas; hemangiomas with fluid-fluid levels; and pedunculated hemangiomas. Adjacent abnormalities consist of arterial-portal venous shunt, capsular retraction, and surrounding nodular hyperplasia; hemangiomas can also develop in cases of fatty liver infiltration. Associated lesions include multiple hemangiomas, hemangiomatosis, focal nodular hyperplasia, and angiosarcoma. Types of atypical evolution are hemangiomas enlarging over time and hemangiomas appearing during pregnancy. Complications consist of inflammation, Kasabach-Merritt syndrome, intratumoral hemorrhage, hemoperitoneum, volvulus, and compression of adjacent structures. In some cases, such as large heterogeneous hemangiomas, calcified hemangiomas, pedunculated hemangiomas, or hemangiomas developing in diffuse fatty liver, a specific diagnosis can be established with imaging, especially magnetic resonance imaging. However, in other atypical cases, the diagnosis will remain uncertain at imaging, and these cases will require histopathologic examination.

In contrast to other common types of malignant tumors, the vast majority of gastroenteropancreatic [endocrine pancreatic (EPTs) and carcinoid] neuroendocrine tumors (NETs) are well differentiated and slowly growing with only a minority showing an aggressive behavior. NETs can produce a variety of metabolically active substances (hormones and amines) leading to distinct clinical syndromes (functioning tumors). However, the majority are non-functioning and present either with locally advanced disease giving rise to site-specific symptoms or distant metastases mainly to the liver. Patients with midgut carcinoid tumors and liver metastases may experience symptoms of the carcinoid syndrome (flushing and diarrhoea), and develop carcinoid heart disease. In such patients, mesenteric involvement may lead to ischaemia and/or intestinal obstruction due to a surrounding desmoplastic reaction with kinking of the bowel and vascular encasement. Approximately 30–40% of these patients may require emergency surgery and are diagnosed at a relatively early stage before liver metastases have occurred.These distinct features in tumor growth, secretory capacity and localisation are consequently reflected in the wide variation in clinical presentation of different NETs. Moreover, a number of NETs may be found incidentally when patients undergo surgery for unrelated reasons or may be an unexpected finding in the histopathological specimen as with appendiceal carcinoids. Accordingly, the need for diagnostic procedures and the choice of imaging methods varies considerably depending on the patient’s tumor status at presentation.The various aspects to consider in the choice of imaging methods are related to primary tumor detection, evaluation of its local extent and relation to adjacent anatomical structures, staging of the tumor concerning regional and distant metastases, evaluation of tumor somatostatin receptor density, therapy monitoring and detection of recurrent disease. In this review, the various applications of current radiological modalities are described, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (US), contrast-enhanced US (CEUS), endoscopic US (EUS) and intraoperative US (IOUS). The corresponding applications of nuclear medicine procedures are presented separately.The participants of the consensus meeting considered the use of various radiological methods for the different imaging applications in relation to documented available figures on sensitivity and specificity together with the expertise of the participants; availability of the various modalities was also taken into account. Further aspects considered were patient preparation and information, clinical information communicated to the radiologist for optimisation of the examination procedure and imaging interpretation, imaging protocols, reporting of results and radiation dose administered to the patient. The use of intravenous (i.v.) contrast media (CM) for CT in patients with impaired renal function and in subjects with previous experience of side effects by i.v. CM was also addressed.In general, data from the literature regarding the sensitivity and specificity of the various radiological modalities used for the diagnosis of NETs suffer from the small number of patients included and the absence of a reliable gold standard for verification of the imaging results. Quite frequently, detection rate is reported instead of sensitivity and specificity. Results are sometimes based on a patient-by-patient analysis and in other reports the results are also, or instead, lesion-by-lesion based. The detection rate merely states the proportion of patients with disease that is detected by the imaging method out of all examined subjects. The sensitivity is instead calculated with reference to a gold standard and equals the proportion of patients with the disease detected by the imaging method out of all patients with the disease according to the gold standard [sensitivity = true positive observations/(true positive observations + false negative observations)]. This review includes imaging data on sensitivity and specificity on a patient-by-patient basis. Detection rates are instead based on lesion-by-lesion analyses and report the proportion positive imaging results in patients with biochemically/clinically evident NETs. Also, the studies that were considered used current standards of imaging. Thus, studies in which incremental CT was performed, those without adequate contrast enhancement, and studies that utilised low field strength MRI (<0.5 T) were excluded.The current presentation, on radiological imaging of NETs, was adapted to the layout of the template for the whole consensus document and is divided into paragraphs according to the various radiological imaging techniques.Modern spiral or helical CT, generally multidetector CT (MDCT) scanners are available in most radiology departments and CT has currently replaced several imaging applications for which earlier other imaging modalities were employed, such as plain film radiography and angiography. By utilising several parallel detector rows, in recent generations of CT scanners at least 64 detector rows and with a tube rotation time of 0.3–0.5 s, hundreds or more of 1-mm or sub-millimetre transaxial images are acquired per second and the whole abdomen and thorax may be examined during one breath hold. These thin, detailed images may be reformatted in any chosen anatomical plane, usually in coronal and sagittal views. The images allow reconstruction in three-dimensional (3D) volumes and can be rotated to better appreciate anatomy and pathological findings. Importantly, as opposed to previous incremental CT scanning, the development of the fast MDCT technique allows considerably better use of i.v. CM and CT imaging can now be performed in several contrast-enhancement phases, i.e. early arterial (or CT angiography), the late arterial (or portal-venous inflow) and the venous contrast-enhancement phase. MDCT has therefore developed as one of the basic techniques for imaging including specificity and detection rate and based on the number of patients and for various NETs is presented in studies on patients, CT a sensitivity and specificity for an The detection rate for of a studies including patients was on these studies that included patients the sensitivity and detection rate for an was with a considerably wide variation a generally specificity studies reporting on the detection of liver metastases in patients the sensitivity was the specificity was In a including patients, the detection rate was studies the of metastases in patients a sensitivity and specificity on patients reported detection rate reports on imaging of various metastases in the abdomen and thorax included patients and a sensitivity of and specificity of The detection rate in a including patients was a sensitivity and specificity in patients with NETs to the corresponding figures were and In patients with small bowel tumors, CT a sensitivity and specificity of and and of these tumors were CT of the thorax and the CT allow spiral by and be to at a and The of the is for examination of the liver and is also in to during contrast for CT and the various contrast-enhancement for examination of the liver and for reconstruction and for images and are generally with the CT with technique and may need better patient and examination the patient be well and Patients information the examination generally CT, patients need to at the in for of the bowel by to of patients are on the examination and into a i.e. the CT patients may and be with CM is an i.v. this may lead to a of The of a previous of renal and i.v. this was or be In the of previous effects the contrast be side effects with are with and are during before the In patients with impaired renal function is of to the patient that or to be before the examination in to the of renal on the radiation dose is generally for the patient. be documented on the imaging according to local have a reaction by and CM are with and according to local before the contrast-enhanced CT for procedures the i.v. is the of CM for a previous or current reaction this information is be documented in the radiological Further use of this CM may be the side is related to the CM and to in patients with the the or at the the as the CM and have before is be with in the and in such can be used instead patients at for renal in such with at least of before and CM is is CT examination is generally performed without i.v. contrast an various is available to an of the by the patient’s and as according to the = in in is a which is for and for on the of i.v. as a CM in patients with renal is of the patients generally of during before the CT examination of the of CM may be to the However, for CT examination of the or when disease is the to be with without of This is when the patient the of a before CT is usually to of the bowel an before CT of the abdomen and the may be to of an to bowel is CT of the small CT the of the bowel a of The patient can the during before the examination or can be administered a By a of the whole small bowel may be during CT can also be performed during i.v. contrast of the i.v. contrast and is performed the bowel and or as for CT examination for to a CT examination and to is that the adequate This includes the current previous and information regarding the of renal and previous The results of previous imaging are imaging used for CT of the including the liver and thorax and according to the local experience and that the are taken into and that technique is various examination usually in this consensus document is on basic examination instead of detailed protocols, and imaging aspects are MDCT of the thorax and is performed to 64 in and MDCT of is The is the per tube rotation divided by the of the number of the The to transaxial images be reformatted in to the coronal and the sagittal a to to and presentation at clinical CM is administered that the patient’s renal function is i.v. contrast of the or contrast be used at a The use of a is by which a of can be administered the CM This that the whole CM is utilised for contrast-enhancement and the CM in the and the and examination of the liver and is performed this is the examination for CT is s, portal-venous the late arterial and venous or portal-venous CM CT may be in the usually the examination in the portal-venous is to the anatomy of the and relation to the Also, the portal-venous is in most for and examination in the pancreatic CM which is for CT of pancreatic is generally as for examination of the a of be in to adequate of the liver in the venous contrast-enhancement to of the CM at least results in of the and the for CT angiography. i.v. CM is for of liver metastases in the portal-venous and to adequate of the and renal Also, a CM rate allows a better time the various contrast-enhancement CT a tube is to the and of are administered by a at or is and CT is performed during i.v. contrast of at small are reconstruction of thin, are and and is the thorax and/or the is examined together with the the of CM and the rates are to is to a CT of the the thorax and/or the by are examined the of CM and the rate can be MDCT of the also a CM of CM is to be at and a CT examination of the CM and a rate can be Approximately of CM is administered at and a of is CT of the a examination is This examination before and during i.v. contrast in the portal-venous and in the venous phase. of liver metastases, CT examination to the venous contrast-enhancement and only when the imaging has better of the liver metastases in the examination and/or in the portal-venous one or of these are This is a that metastases may Also, of the which may be by can the imaging metastases diagnosed during the venous may be at in the examination and/or the portal-venous contrast-enhancement phase. The of of in a liver as metastases is also by CT Moreover, of an may be performed when a examination is also of CT in relation to the CM is by the for which is together with the CT This allows monitoring of the during contrast in to the time for the examination also in the use of the CT and examination in the portal-venous contrast-enhancement a in the may be used to the an a may be used to the examination to be by a In CT of the abdomen and including CT of the the that of these is performed on the technique is of the liver is generally the liver is examined in the portal-venous and the thorax and abdomen in the venous phase. an examination of the thorax early CM is and that the of the liver is performed in the portal-venous and the whole abdomen is examined in the venous radiation dose administered to the patient varies with the examination and the of CT tube and tube a tube rotation time and a low the In to a in patients, the tube current is This may be in This results in a radiation dose to to a MDCT with the relatively of to be rotated more in to the patient in an MDCT with and a detector tube the of radiation at the and of the detector to the radiation consequently in a dose to the patient in the examination in a MDCT of a patient of results in an radiation dose of for the whole abdomen and for the abdomen from the to the MDCT examination of the abdomen CT of the liver and examination of the in this patient results in a radiation figures for MDCT of the thorax is and of the By the radiation dose is when a MDCT and NETs are diagnosed by The of CT in these is to regional and distant metastases for staging of the disease. and CT is for and tumors detected by tumors are in the and of the and are in with and are usually and the which is to are with a more and more that may These tumors can also into the surrounding the NETs are usually small tumors and in the of may be CT diagnosis of the primary tumor is to the with and to the examination during i.v. contrast this detection of the usually tumor which is the low in the bowel are and can be in patients with the These tumors to be as tumors in the portal-venous in the pancreatic contrast-enhancement CM In the venous contrast-enhancement usually the surrounding are usually and may have that are in the are usually as well and may of contrast is as and usually an CT also the of the tumor in relation to the pancreatic and common vascular and the disease with to regional involvement and of distant metastases, mainly to the liver. can be with pancreatic However, with a usually slowly growing the pancreatic this is to the and the surrounding pancreatic is and a surrounding the small bowel are found in the in the and are usually small and these small tumors are to as at CT the use of a positive CM the usually carcinoid is more to detection when the is by a low CM such as to was regarding diagnosis of midgut present as mesenteric These can an desmoplastic reaction and of the adjacent bowel in or intestinal of the mesenteric and may bowel CT, this is reflected as an with one or several of by in the mesenteric in a The mesenteric and/or or of these may be by the NETs of the and the the of CT is to the primary tumor or to appreciate its of the the surrounding and adjacent which instead is most better performed by MRI or NETs are generally diagnosed by and and CT is therefore utilised to stage and NETs by regional and distant liver metastases due to NETs from any other malignant liver metastases are well and during i.v. contrast in the portal-venous as in the liver liver metastases also These are in the venous contrast-enhancement as low to the contrast-enhanced liver metastases are in the images in which of are contrast and in liver metastases are of the CT examination be performed for of and liver and is to the and the and to the in the contrast-enhanced images to CT of metastases is to those from other malignant tumors, a contrast is However, anatomical be in during in the and in the metastases from midgut can be found in the thorax adjacent to the and to the heart Also, metastases are as well as and metastases from midgut carcinoids. the CT examination for metastases, in anatomical these may be by is to the by the to Also, the use of images is for of small is most in the of the abdomen metastases from NETs, to those from other malignant tumors, as usually and generally metastases are can be and sometimes a the in are used as the reference standard by which tumor to is reported and these are therefore when the results of different However, in the clinical the are usually or be metastases, and disease are for the of the and the of or according to the and also a of the tumors regarding be The contrast-enhancement in which the are be In to the diagnostic information, and is number of studies on MRI in patients is to The specificity and detection rate and based on the number of patients and for NETs at various anatomical is presented in studies on MRI for detection of 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are is usually time to the most technique and the examination to be performed with and without contrast-enhancement MRI that are generally for the detection of NETs are transaxial available and available and transaxial in and out of MRI of the also be performed by coronal with including the and the pancreatic to better the regional anatomy and the relation of the to the pancreatic and the with is also are when such as and bowel are contrast-enhanced MRI be This at and and at are for which can be in various anatomical and only to produce transaxial MRI with a to that of CM used for CT, the standard for i.v. contrast-enhanced i.v. CM for of liver are as contrast are with in the during a relatively of time depending on the and tumor is a contrast that a to an in the liver may also be used for MRI of the are of with or and are taken by the are in tumor The effects in the liver which tumors to the liver a as a low in and a in The MRI of NETs are to those of CT concerning tumor contrast-enhancement and various is with MRI CT, the better contrast of MRI the detection of small of small is with MRI with and is with pancreatic and and this is by the at of small liver metastases is also by MRI these and that are or at CT and may better be by the various MRI and also examination with i.v. liver metastases on from arterial imaging Thus, liver metastases a during the arterial contrast-enhancement In the the contrast the and during the late contrast-enhancement a of the is The to the liver the of the CM from a liver the relatively imaging on in patients with NETs, reported that was in of patients during the arterial phase. low were in the late and in the portal-venous was found in of of MRI for staging of NETs is earlier in the CT of this of distant metastases in and is by and reporting of results of MRI is to that of The report used for according to the consensus be is to be an leading to wide variation regarding sensitivity and specificity of the reported The and specificity and detection rate and based on the number of patients and for NETs at various anatomical is presented in a detection rate was found in studies including patients is the most method for and a detection rate was in studies patients In a on patients the sensitivity was and the specificity is also a method for with a detection rate reported in studies that included patients are considered the detection rate of was in studies including patients and that of in studies on patients tumors and metastases, the detection rate of US was in a on patients and that of in studies patients reporting on US for the detection of liver metastases from NETs are However, in one including patients with various NETs, US an sensitivity and in a of patients with carcinoid tumors the corresponding figures were and has to be more for the diagnosis and of liver In patients with NETs and of liver metastases, the sensitivity of was The diagnostic of in patients was to by to US were to by by US of different with is The of the abdomen require better of a more a is the recent development of US the in one may be according to the different during the By imaging technique the sensitivity of US can be The use of i.v. 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CM for US in these patients is are by such and recent is a due to the of also in the corresponding regarding CT and opposed to CT, which allows detailed examination of the whole abdomen and of at the US is better for examination of of the for the and the US is an an examination technique is by different is better allow for The and of the and low be considered during the examination and used for examination of and of the are generally to during a breath and is to the patient in different on the examination and US the patient is or during a the This can be for the examination of the when bowel in the techniques are in to the tumor and are in vascular from the and of tumor and and of the CM may be may therefore be considered for localisation of and liver By liver metastases in the to may be detected and tumor at or CT, may be is when of liver metastases is of the is that the whole liver may be by US during all of contrast of negative US in patients with the US is by which the and pancreatic can be and CT are radiological methods used to liver metastases, and mesenteric metastases and these are an for the to a tumor specimen By the the pancreatic and may be for and tumor and in the abdomen and may be tumors are detected are as a low or which is well locally advanced intestinal the surrounding is more The of US to an of the from a is is a low and with CT and the local extent of the tumor be The relation of the to the pancreatic and the common be as well as any or of the and the mesenteric and metastases from a midgut carcinoid and mesenteric and metastases are as low The desmoplastic which by CT and MRI is a of a mesenteric from a midgut be detected by liver metastases be differentiated from any other of liver metastases generally as low metastases usually are with a low and may have low These by techniques and In patients with of the in a the metastases may instead low and reporting of results by US is to that of CT and However, for therapy the reported by US are generally to with those by CT and This is the of the according to the and are in the transaxial CT and MRI images by US these tumors are in anatomical imaging the US is performed in the in which the by US Also, an of the tumor is generally to by US in patients with disease. the of the tumor by US in a patient in the liver is replaced by metastases is generally US is for diagnosis or therapy monitoring in clinical to tumor as an to the by However, in the clinical US is an method for diagnosis and of NETs. 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