British Journal of Radiology 74 (2001),1065-1070 © 2001 The British Institute of Radiology
Imaging appearances of metastases from neuroendocrine tumours of the pancreas
M P Debray, MD1,
O Geoffroy, MD1,
J P Laissy, MD, PhD1,
R Lebtahi, MD2,
O Silbermann-Hoffman1,
M C Henry-Feugeas, MD, PhD1,
G Cadiot, MD, PhD4,
M Mignon, MD, PhD, FRCP(London)3 and
E Schouman-Claeys, MD1
Departments of 1Radiology, 2Nuclear Medicine and 3Gastroenterology, Bichat-Claude-Bernard Hospital, 46 rue Henri Huchard, 75877 Paris Cedex 18 and 4Department of Gastroenterology, CHU de Reims, 51092 Reims Cedex, France
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Abstract
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Endocrine tumours of the pancreas (ETPs) are rare neoplasms that are frequently malignant. Despite their usual slow growth, metastases do occur and have a major impact on prognosis. Metastases may be the first manifestation of disease, and recognition of particular radiological features of these hypervascular metastases should suggest their possible neuroendocrine origin. Although somatostatin receptor scintigraphy has changed the imaging strategy for these tumours and has become their principal imaging modality, radiological techniques are still required for precise localization of scintigraphic hot spots and monitoring of response to therapy. This pictorial review shows the typical radiological features of ETP metastases and emphasizes the role of different imaging modalities.
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Classification
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Endocrine tumours of the digestive tract include endocrine tumours of the pancreas (ETPs) and gastrointestinal carcinoids, which share many features. ETPs are classified as functional or non-functional, i.e. with or without a clinical syndrome associated with hormone overproduction. They commonly secrete more than one hormone and functional tumours are named according to the hormone responsible for the clinical syndrome. Insulinomas and gastrinomas are by far the two most common functional tumours, causing, respectively, hypoglycaemic syndrome and Zollinger–Ellison syndrome. Other functional ETPs include vipomas, glucagonomas, somatostatinomas, GRFomas (producing growth hormone releasing factor) and ACTHomas (producing adrenocorticotropic hormone) [1]. It should be emphasized that the widely used term ETP includes tumours occurring outside the pancreas, usually in the duodenopancreatic area.
ETPs can occur as part of multiple endocrine neoplasia type 1 (MEN 1), especially in the case of Zollinger–Ellison syndrome. MEN 1 is characterized by the association, to varying degrees, of primary hyperparathyroidism, duodenopancreatic endocrine tumours, pituitary adenoma, adrenal tumours and neuroendocrine tumours, mainly bronchial and thymic carcinoids. The search for other endocrine tumours is mandatory in any patient with endocrine duodenopancreatic tumour. Familial screening should be considered owing to genetic inheritance of MEN 1 [2]. ETPs occurring in the setting of MEN 1 are often multiple, small and diffusely spread in the duodenopancreatic area.
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Malignancy
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Approximately 90% of non-functional ETPs and 50–60% of gastrinomas are malignant, while 90% of insulinomas are benign. Liver metastases represent the main criterion of malignancy, as primary tumour histology is unreliable for this purpose. Unlike most neoplasms, malignant ETPs may grow slowly and thus survival may be long, despite metastatic disease (Figure 1
). The main metastatic sites are regional lymph nodes, liver and bones, which are involved in 50%, 30% and 7% of gastrinomas, respectively. The lungs, mediastinum, peritoneum and, rarely, the brain and meninges may also be involved. While regional lymph node involvement has no prognostic significance, liver involvement portends shorter survival [3]. Treatment includes cytoreductive surgery, systemic chemotherapy, hepatic arterial embolisation or chemoembolisation, interferon-alpha, somatostatin analogues and liver transplantation. Bone metastases mostly occur in patients with liver metastases, are frequently multiple at the time of detection and indicate a poor prognosis.
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Figure 1. Because they frequently grow slowly, metastases from endocrine tumour of the pancreas (ETP) may attain a large volume without rapidly compromising life expectancy. On this contrast enhanced CT, the entire right lobe of liver and the fourth segment contain confluent metastases from a non-functional ETP. Coeliac lymphadenopathy is present.
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Somatostatin receptor scintigraphy (SRS)
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Owing to its high sensitivity, Octreoscan, using [111In-DTPA-D-Phe1] octreotide, a somatostatin analogue, is becoming an important and often first line imaging tool for the staging of ETPs [4]. Hot spots indicate the presence of high-affinity somatostatin receptors, located on most tumoral endocrine cells [5]. This whole-body imaging technique is particularly suitable for the detection of metastases (Figure 2) and is helpful in predicting the benefit of somatostatin analogue therapy. However, the contribution of this technique varies depending on the presence and density of somatostatin receptors in the tumour as well as the tumour size. Most gastrinomas, but only half of all insulinomas, have somatostatin receptors. The sensitivity of SRS for the detection of gastrinoma metastases is reported to be as high as 90%. Metaiodobenzylguanidine (MIBG) scintigraphy, although contributive for various neuroendocrine tumours, is less sensitive than SRS in diagnosing ETP and is not routinely used.
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Figure 2. Multiple liver metastases of a non-functional endocrine tumour of the pancreas showing (a) moderate to high hyperintensity on T2 weighted MR images, (b) hypointensity on T1 weighted images and (c) enhancement that is either homogeneous or peripheral after iv gadolinium chelate. (d) Octreoscan, which detected not only this diffuse liver involvement but also multiple metastases in the skull, thoracic spine, ribs, pelvis, shoulders and femurs, provides whole-body metastatic screening.
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Standard radiography, ultrasound, CT and MRI
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These radiological techniques provide essential anatomical information for localizing hot spots found on SRS. They indicate the number and size of lesions and can guide biopsies. Although most studies have considered them less sensitive than SRS for detecting metastases, they may demonstrate metastases not found on SRS. MRI is considered the most sensitive of these radiological techniques for liver and bone metastases, and appears to be the best imaging method for monitoring response to treatment.
Liver involvement
Hepatic metastases are most frequently hypointense or isointense compared with normal liver on T1 weighted MR images and hyperintense on T2 weighted images (Figure 2
). They rarely show hyperintensity on T1 weighted sequences or hypointensity on T2 weighted sequences. Some hypervascular metastases can display sufficient T2 hyperintensity to mimic haemangioma. Dynamic gadolinium chelate enhanced sequences help to differentiate these lesions, with enhancement of ETP metastases being typically early, transient and not showing peripheral nodularity (Figure 3) [6]. The same enhancement pattern is observed on CT. Arterial phase enhanced images should be combined with the usual unenhanced and portal phase images, as liver-to-lesion contrast is usually higher during the arterial phase (Figure 4). Calcifications are attributed to spontaneous calcification of the tumour or to prior embolisation. Cystic transformation or even intralesion gas, indicative of necrosis, can also be seen after embolisation.
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Figure 3. MRI showing pseudoangiomatous liver metastasis from a non-functional endocrine tumour of the pancreas. T2 weighted spin echo image shows a homogeneous, hyperintense, sharply limited nodule in the posterior sector of the liver, mimicking haemangioma (left). Gradient recalled echo image obtained 40 s after injection of gadolinium chelate shows peripheral non-globular enhancement of the lesion (right), which was no longer visible on delayed images (not shown).
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Figure 4. (a) Gastrinoma liver metastases on CT following iv iodinated contrast medium are markedly enhanced during the arterial phase. (b) Some of the metastases are difficult to detect during the portal venous phase. Low attenuation and calcified lesions are the result of prior chemoembolisation.
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Because liver ultrasound can demonstrate the disease, showing hyperechoic hepatic lesions mimicking haemangiomas, ETP metastases should be included in the differential diagnosis of pseudoangiomatous liver nodules (Figure 5). Hypoechoic or isoechoic metastases with a hypoechoic halo are also seen.
Bone involvement
Bone metastases frequently have an osteosclerotic or mixed osteolytic and osteosclerotic pattern on standard radiography (Figure 6); 10% are purely osteolytic [7]. Healing of metastases on treatment can lead to the formation of further sclerosis, which can be misdiagnosed as disease progression. MRI is considered to be highly sensitive but, compared with SRS, is hampered by the usually relatively limited area studied. Lesions are hypointense on T1 weighted images and enhance after iv gadolinium. Although frequently osteoblastic, they commonly generate a heterogeneous signal or hyperintensity on T2 weighted images (Figure 7). Bone metastases are located in the axial skeleton. Epidural involvement is not uncommon.
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Figure 6. Lateral radiograph of the lumbar spine shows heterogeneous sclerosis of the body and anterior part of the pedicles of the second lumbar vertebra, indicative of mixed osteolytic and osteosclerotic spinal metastases of a non-functional endocrine tumour of the pancreas.
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Figure 7. Numerous gastrinoma metastases in L1–L4 vertebrae are (a) hypointense on T1 weighted MR images and (b) hyperintense on T2 weighted MR images. (c) They are partly enhanced after iv gadolinium chelate.
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Other metastatic sites
Thoracic metastases present as lung nodules and mediastinal lymph adenopathy, and are best visualized by CT (Figures 8 and 9). An isolated metastatic lung nodule may be indistinguishable from a primary bronchial carcinoid associated with the pancreatic tumour in the setting of MEN 1.
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Figure 9. (a) Lung nodule on CT. Although Octreoscan was more sensitive, detecting a hot spot before the nodule became visible on CT, thoracic CT performed several months later precisely located the nodule in the right superior lobe close to the ventral bronchus (arrow). (b) In another patient with insulinoma and gastrinoma related to multiple endocrine neoplasia type-1 (MEN 1), an enhanced mass in the anterior mediastinum on CT proved, after histological examination of the resected tumour, to be a thymic carcinoid. In both cases, neither radiological imaging nor somatostatin receptor scintigraphy was able to distinguish a solitary lung or mediastinal node metastasis from a primary bronchial or thymic carcinoid related to MEN 1.
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Peritoneal carcinomatosis has been described in association with non-gastrinoma ETP [8]. As for other primary tumours that spread to the peritoneum, CT can detect peritoneal nodules, ascites or the presence of soft tissue masses in the greater omentum (Figure 10).
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Figure 10. Peritoneal carcinomatosis in a patient with a non-functional endocrine tumour of the pancreas. CT shows multiple enhanced nodules (arrows) involving the peritoneum adjacent to the rectum, associated with ascites (arrowheads).
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Conclusion
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Detection of ETP metastases has important prognostic and therapeutic consequences. SRS is highly sensitive and is emerging as the first line screening method. Owing to their good spatial resolution, radiological techniques provide essential anatomical information. MRI is considered the most sensitive for liver and bone metastases, and is recommended for precise monitoring of response to therapy. MRI helps to recognize misleading hyperechoic pseudoangiomatous liver metastases. CT is suitable for detecting thoracic involvement.
Received for publication June 1, 1999.
Revision received November 28, 2000.
Accepted for publication January 24, 2001.
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References
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Abstract
Classification
