Islet cell tumour

Islet cell tumour, Table 1. Endocrine tumours of the pancreas.

GRF = growth hormone-releasing factor; PP = pancreatic polypeptide, VIP = vasoactive intestinal polypeptide, WDHA = watery diarrhoea, hypokalaemia, and achlorhydria

Reprinted from: R.J. Jensen and J.A. Norton: Endocrine neoplasms of the pancreas, in: T. Yamada: Textbook of Gastroenterology, 2nd ed. J.B. Lippincott company, Philadelphia; p. 2132, by courtesy of Lippincott.

General features

The actual prevailing concept is that all islet cell tumours have a common origin within the neural crest, originate from cells that are part of the diffuse neuroendocrine ce most numerous, constituting 50-70% of pancreatic islet volume. A cells, which secrete glucagon occupy 5-20% of the cell mass. PP cells account for 10 - 35% of islet volume and secrete pancreatic polypeptide. D cells are less abundant, constituting about 5% of islet volume and secrete somatostatin. In addition other cell types are found in small quantities: the G cells which produce gastrin, the D1 cells which produce vasoactive intestinal polypeptide (VIP) and enterochromaffin or EC cells.

Individual islet cell tumours have been named after the hormone produced. These include Insulinoma, Gastrinoma, VIPoma, Glucagonoma, Somatostatinoma, PPoma and GRFoma. However, some tumours may produce several hormones either from the same lesion or from multiple lesions but usually only one of them will cause clinical symptoms. In various series, more than 50% of all pancreatic endocrine tumours contain more than one hormone as demonstrated by immunochemistry.

Endocrine tumours are rare neoplasms. In one series from a large referral centre in Ireland the average incidence of all islet cell tumours was 3.6 neuroendocrine tumours per 1 million inhabitants per year. Insulinoma and gastrinoma are more frequent than glucagonoma and VIPoma, whereas somatostatinoma is very rare. It is difficult to estimate the frequency of PPomas and of nonfunctional (nonsecretory) endocrine tumours.

Whereas insulinomas and gastrinomas are usually small (less than 2 cm in diameter) glucagonomas and the others are larger at the time of diagnosis. Nonfunctioning tumours may be large (over 7 - 10 cm in diameter) at the time of diagnosis. Both secretory and nonsecretory islet cell tumours can become necrotic and assume the appearance of a cyst with a fluid content and a wall of variable thickness. They have been called "cystic" endocrine tumours.

Histologically islet cell tumours are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. Mitotic figures are uncommon. There is no definite correlation between the histological pattern and the type of clinical syndrome the tumour is associated with.

Most of these tumours tend to be slow growing. It is accepted that all endocrine tumours of the pancreas are potentially malignant but the assessment of malignancy is less based on cellular and even local tissular malignancy than on the occurrence of metastasis which may occur only late. The potential for malignancy is different among the various types of tumour.

Islet cell tumours of the pancreas have some clinical features in common. When they are secretory, they become clinically manifest by the specific symptomatology related to the specific hormone(s). When the tumour is nonsecreting, symptoms caused by the space occupying effects of the tumour mass will mostly lead to the diagnosis. The diagnosis of the secretory forms of endocrine pancreatic tumours is based on the specific clinical symptoms and the laboratory demonstration of excessive secretion of specific hormones.

Radiological study is mainly useful for confirming the clinical diagnosis and for localizing the tumour.

Radiological diagnosis and localization

The radiological detection of endocrine tumours of the pancreas poses a difficult challenge to the radiologist because of the small size of most of these tumours and frequently requires the combined use of different imaging modalities. However, important progress in the detection of these tumours by noninvasive means has been achieved by the introduction of spiral CT and fast MRI and with the combined use of ultrasound, CT and MRI a sensitivity of more than 90% can nowadays be achieved. Failure of these radiological imaging methods to demonstrate a focal lesion in the pancreas in a patient with clinical and biochemical suspicion of endocrine tumour may be due to small size of the lesion (smaller than 2–3 mm) or due to diffuse endocrine cellular hyperplasia without tumour.

Arteriographic features

Arteriography performed for detection of islet cell tumour of the pancreas requires meticulous technique and should ideally include examination of the coeliac artery and the superior mesenteric artery followed by selective or superselective injections of the hepatic artery, the splenic artery, the gastroduodenal artery, the dorsal pancreatic artery and the pancreaticoduodenal arteries in order to provide a maximal diagnostic yield. A very important refinement of the technique is the distension of the stomach and the duodenum with gas in order to provide a clear "window" through which the pancreas can be better visualized free of superimposed confusing mucosal folds.
The arteriographic findings in islet cell tumours (Fig. 1) are hypervascular well-demarcated masses, generally small, fed by slightly dilated and enlarged arteries. The lesions usually show a discrete parenchymatous blush which persists during the venous phase. A prominent draining vein can sometimes be observed. Some islet cell tumours especially gastrinomas are hypovascular and will not display the above mentioned typical features but only minimal and discrete displacement of smaller intraparenchymal vessels by the space-occupying lesion.

The published rates for successful localization of islet cell tumours with arteriography vary from 63 - 90% for insulinomas and from 15-88% for gastrinomas. For the group of other islet cell tumours that are usually larger in size an arteriographic sensitivity over 95% has been reported.

Until the advent of the newer cross-sectional modalities (ultrasound, CT, MRI) arteriography was, although invasive, considered to be one of the most sensitive methods to localize pancreatic islet cell tumours. The importance of its role in this respect has now decreased considerably in view of the excellent diagnostic yield of the new noninvasive cross-sectional methods. Arteriography may occasionally still be used to clarify equivocal findings provided by other modalities and it may successfully localize tumours that were not otherwise demonstrated. It has also been used to demonstrate liver metastases particularly in combination with intraarterial chemotherapy (Fig.2).

Transabdominal ultrasound

On transabdominal ultrasonography endocrine pancreatic tumours usually are hypoechoic as compared to the adjacent pancretic parenchyma (Fig.3). Sometimes a thin hyperechoic capsule may be detected. The lesions are mostly rounded or oval and have a sharp interface with the surrounding parenchyma. With the exception of the larger, mostly nonsecretory tumours, the lesion will present a fairly homogeneous echo pattern. Focal areas of liquefaction due to necrosis may be seen as anechoic cystic areas in the case of large nonsecretory lesions or PPomas. "Cystic" endocrine tumours have the nonspecific ultrasound appearance of an anechoic fluid filled mass with thick walls and posterior acoustic enhancement. The success rate of ultrasonography for the detection of insulinoma varies between 25 and 65% probably depending on the expertise of the investigator. It is lower for gastrinoma.

Endoscopic ultrasound

Endoluminal ultrasound (EUS) has proved to be superior to transabdominal ultrasonography in the detection of endocrine pancreatic tumours and is rated with a sensitivity of 82% and a specificity of 95%. The accuracy of EUS should be similar in all regions of the pancreas but detection is more difficult if the tumour is 1 cm or less in size, pedunculated, or isoechoic with the pancreatic parenchyma.

Because EUS depicts very well the different layers of the bowel extrapancreatic gastrinomas, most often found in the duodenal wall, are well visualized by this method. On the other hand EUS imaging is limited to a distance of about 68 cm from the transducer and larger endocrine tumours of the pancreas are less well depicted by this method.

Intraoperative ultrasound

The appearance of most islet cell tumours on intraoperative ultrasonography (IOUS) is similar to that described in transabdominal US. These lesions are typically hypoechoic well demarcated tumours. The sensitivity of IOUS is high and the detection of tumours as small as 3 mm have been reported. Studies including gastrinomas have yielded less good results, mainly because of the relatively low detection rate of extrapancreatic tumours by IOUS. IOUS may localize lesions that were not detected by any imaging technique preoperatively and demonstrate other tumours in addition to the tumour(s) diagnosed preoperatively. By depicting the precise relationship of the islet cell tumour to the pancreatic and the common bile ducts, IOUS will help to determin CT (Fig.5). Problems with dynamic scanning in selecting the optimal scan level during the maximal enhancement of the arterial phase are thus eliminated. A small minority of secretory islet cell tumours are hypovascular and are not readily detected even on spiral CT because they will not enhance.

In "cystic" endocrine tumours, contrast enhancement will be observed only in the nonnecrotic portions or in the walls of the lesion (Fig.6). Because of their larger size, the nonsecretory tumours will cause deformity of the normal pancreatic shape and may be suspected on the precontrast scan. They present as a soft tissue density mass with inhomogeneous attenuation due to the presence of necrosis. These tumours are commonly very vascular and enhance strongly after contrast injection (Fig.7).

Magnetic Resonance Imaging

Most islet cell tumours are well visualized on T1-weighted MR images due to the high intrinsic contrast between the hypointense tumours and the hyperintense pancreas particularly on fat-suppressed images. Moreover the commonly hypervascular nature of these tumours makes them more conspicuous as highly enhancing lesions relative to the moderate enhancement of the normal pancreas on contrast-enhanced images (Fig.8). Most endocrine tumours display an increased signal intensity on T2-weighted images. This holds particularly true for gastrinomas. However, the MRI features of the different types of islet cell tumours may be variable. Some islet cell tumours display iso- or hypointensity on T2-weighted images (Fig.9). Moreover, islet cell tumours may not be detected on contrast enhanced MRI, because they are isointense relative to the adjacent normal pancreas. More and more evidence is now available suggesting that MRI study including contrast enhancement is at least as sensitive as contrast enhanced spiral CT for the detection of endocrine tumours of the pancreas (Fig.10) and that a combination of both modalities can provide a higher sensitivity than that of each of them separately.

Transhepatic venous sampling

This technique consists in percutaneous catheterization of the right portal vein, followed by selective catheterization of the splenic vein and the smaller pancreatic veins. Serial blood samples for hormone assay are taken at the different sites and the site marked on a "map" drawn from the splenoportogram. Superselective catheterization of the numerous pancreatic veins requires great technical expertise and is time consuming. The results can be difficult to interpret. There is some dispute in the literature as to how much of a hormonal gradient is necessary for accurate tumour localization. It has been shown that up to threefold variations in hormonal concentration can occur simply by repeating sampling at the same site in large venous trunks, possibly due to lamellar flow. The method is not without risk. Complications include: pneumo- and haemothorax, accidental puncture of the inferior vena cava, the biliary system or the gastrointestinal tract and intraperitoneal bleeding. Indications for transhepatic venous sampling are:

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