Well-Differentiated Pancreatic Nonfunctioning Tumors/Carcinoma

Abstract

Nonfunctioning pancreatic neuroendocrine tumors (NET) are defined by their histopathological differentiation. Neuroendocrine cells are characterized by the expression of marker molecules like neuron-specific enolase (NSE), an unspecific cytosolic marker or vesicle proteins like chromogranin A or synaptophysin, indicating large and dense hormone-storing core vesicles and neuropeptides- or small neurotransmitter-storing synaptic vesicles, respectively [1,2,3,4]. These proteins define the neuroendocrine origin of the tumor cells. The term ‘nonfunctioning’ refers to the absence of clinical symptoms of hormonal hypersecretion. However, nonfunctioning tumors may well show immunohistochemical positivity for hormones, neuropeptides or neurotransmitters. The WHO classifies nonfunctioning pancreatic NETs according to the uniform classification scheme for endocrine tumors, independent of the site of the primary: (1) well-differentiated endocrine tumor, with benign or uncertain behavior at the time of diagnosis; (2) well-differentiated endocrine carcinoma, with low-grade malignant behavior, and (3) poorly differentiated endocrine carcinoma, with high-grade malignant behavior [5] (table 1). Most (60–100%, according to the series) are classified as well-differentiated endocrine carcinomas [6, 7].Due to new and more sensitive imaging techniques, the number of neuroendocrine pancreatic incidentalomas has increased. The autoptic incidence is 1.6–10% per year [8], while the clinical incidence is 3.5–4/million/year [9]. Pancreatic endocrine tumors represent about 2–10% of all pancreatic tumors [9, 10]. In earlier series the percentage of nonfunctioning tumors out of all pancreatic endocrine tumors was estimated to be 18–66% [11,12,13,14,15,16,17]. In contrast, recent, large monocentric [7, 18, 19] or multicentric studies [20] classify 68–80% as nonfunctioning pancreatic neuroendocrine tumors. The peak incidence is during the fifth decade [6], with equal distribution among the sexes.Nonfunctioning pancreatic neuroendocrine tumors are defined by the absence of a hormone hypersecretion syndrome. The classification of the tumor as of neuroendocrine origin refers to the immunohistochemical positivity of chromogranin A and/or synaptophysin. Pathological grading is done according to the WHO classification of endocrine tumors; the majority are well-differentiated carcinomas. Pancreatic neuroendocrine tumors are rare.Due to the lack of symptoms related to hormonal hypersecretion, nonfunctioning pancreatic neuroendocrine tumors are diagnosed late in the course of the disease. The clinical signs and symptoms are due to the tumor mass, with local invasion and/or distant metastases. Abdominal pain is the major presenting symptom (35–78%), followed by weight loss (20–35%), anorexia and nausea (45%). The patient may present with intra-abdominal hemorrhage (4–20%), jaundice (17–50%) or a palpable mass (7–40%) [21,22,23,24,25]. Fifty-nine percent to 80% of the patients present with synchronous liver metastases at diagnosis [10, 25]. Given the mostly large primary (>5 cm), localizing the tumor at the head of the pancreas, followed by the body and tail, is straightforward [26].Most neuroendocrine pancreatic tumors are well-differentiated (WHO group 2) endocrine carcinomas (table 1) [27]. Overall 5-year survival is 30–63%, with a median survival from diagnosis of 72 months [12, 25, 28, 29]. Actuarial 5- and 10-year survival rates after diagnosis of liver metastases were 46 and 38%, respectively. [10]. However, aggressive treatment may increase 5-year survival to 63 or 82% [25, 30]. Rapid progression of liver metastases (more than 25% volume increase within 6–12 months) and the development of bone metastases confer a poor prognosis [10]. Histopathological staging (table 1), including tumor differentiation, tumor size, proliferation marker and angioinvasion, correlates with survival. All patients with low-risk tumors were alive after 47 months, 10% of those with intermediate-risk tumors had died after 94 months, while 35% of patients with low-grade malignant tumors died after a period of 42 months. Few patients with a high-grade malignant tumor were alive after 4 months [27].Nonfunctioning pancreatic neuroendocrine tumors present as large tumors, with signs and symptoms related to the tumor burden. At diagnosis, the prevalence of synchronous metastases is 80%. Prognosis depends on the presence or absence of liver/bone metastases and histopathological classification. Overall 5-year survival is 60%. MEN-1. Multiple endocrine neoplasia type 1 (MEN-1) is a hereditary tumor syndrome with autosomal inheritance and high penetrance. The main manifestations of the disease are primary hyperparathyroidism, pituitary adenomas and pancreatic neuroendocrine tumors. Nonfunctioning pancreatic neuroendocrine tumors occur besides functional tumors. MEN-1-related tumors occur at an earlier age and demonstrate a more benign course than do sporadic tumors. They may be multiple and vary in size from small microadenomas to large tumors. The malignant potential is related to the size of the tumor [31]. Recent data indicate a prevalence of 55% for nonfunctioning pancreatic neuroendocrine tumors in MEN-1 patients [32]. However, only a small number of patients (8%) with nonfunctioning pancreatic neuroendocrine tu- mors have MEN-1 syndrome [17]. Von Hippel-Lindau Disease (VHL). VHL is an autosomal-dominant disease with almost complete penetrance, characterized by the development of several types of neoplasia. Nonfunctioning pancreatic neuroendocrine tumors are part of the syndrome in up to 16% of the patients; frequently coexist with pheochromocytomas and may even precede the manifestation of other lesions [33,34,35,36].Tuberous Sclerosis. An association of nonfunctioning pancreatic NETs with tuberous sclerosis has also been suggested [37, 38].Nonfunctioning pancreatic neuroendocrine tumors are part of the MEN-1 syndrome. They occur at an earlier age than do sporadic pancreatic NETs, may precede other manifestations of the syndrome and determine the prognosis of the patients. Nonfunctioning pancreatic NET are a rare, but recognized part of von Hippel-Lindau disease and may be seen in patients with tuberous sclerosis.SRS has a sensitivity and specificity for pancreatic neuroendocrine tumors of 90 and 80%, respectively [39, 40]. SRS is the central modality for localization of the primary and definition of the extent of the disease. Whole-body imaging allows for detection of distant metastases and thus influences therapeutic decisions [41]. SRS is indicated as the first staging procedure and whenever the demonstration of extrahepatic metastases is necessary for therapeutic decisions. The following details indicate the recommended standard procedure: a double or triple head gamma-camera and a medium energy, parallel hole collimator, peaks at 172 and 245 keV with a window of 20%. 111In-octreotide 200 MBq for planar, 200–220 MBq for SPECT images. At an acquisition time of 15 min and 4 h post injection (p.i.) anterior and posterior abdominal views, at 24 h p.i. anterior and posterior views of the upper abdomen, head, chest and pelvis, as well as left and right lateral, anterior and posterior oblique views of the upper abdomen. Optional delayed images at 30– 48 h p.i. are recommended. Whole body imaging should be performed with a scanning speed of 3 cm/min. SPECT images should be acquired at 24 h p.i. with a 6° step rotation for 360°/40–60 s [42].Positron emission tomography (PET) and/or PET CT, using Ga-DOTATOC to visualize somatostatin receptors is a promising new tool. However sufficient data are still lacking [43,44,45]. Additional tracers used so far (11C-labelled L-Dopa, 18F-labelled L-Dopa and 11C-5-hydroxytryptophan) are not useful in nonfunctioning pancreatic NET [46, 47].With US, most, especially small lesions, appear hypoechoic [48,49,50], while larger lesions are more heterogeneous, due to the different degree of hyalinized stroma, hemorrhage and cystic degeneration [48, 50]. Cystic areas are hypoechoic to anechoic.Non-contrast-enhanced computed tomographic images (NCE-CT) display iso- or hypodense lesions compared to the adjacent pancreatic parenchyma. In addition, calcification and hemorrhage are accurately depicted on NCE-CT. With contrast enhancement, the hypervascularity of endocrine tumors is apparent and characteristic [48, 51, 52]. In addition areas of cystic degeneration are visualized as regions of reduced vascularity by contrast-enhanced CT. Images should be obtained with multidetector CT (2.5 mm section thickness) at the peak arterial phase of contrast enhancement and reconstructed at 1.25 mm thickness [42, 53, 54].MRT displays hypointense or hyperintense lesions compared to the adjacent pancreatic parenchyma on T1- or T2-weighted MRT images, respectively. Fat-saturated T1-weighted images during the injection of gadolinium chelates demonstrate the hypervascularity of endocrine tumors [48, 55, 56]. The hyperintensity is best depicted on fat-suppressed T2-weighted images. High-resolution, fat-saturated T2-weighted images, acquired during breath-hold acquisition, and volumetric T1-weighted images (3 mm slice thickness) at the peak arterial phase of contrast enhancement, using a high-field (1.5 T) MRT, employing high-performing gradients and phased array surface coils, are recommended. Injection rates of contrast material for the evaluation of hypervascular lesions average 3–5 ml/s. MRT with a hepatocyte-specific contrast agent may depict small (<1 cm) liver metastases and thus influence decision-making with respect to surgical therapy.To differentiate the hypervascular pancreatic neuroendocrine tumor from hypovascular pancreatic adenocarcinoma, contrast-enhanced techniques (multidetector CT or MRT) [53, 54, 57, 58] are useful. In addition, T2-weighted MR images differentiate the hyperintense neuroendocrine pancreatic tumor from the frequently scirrous, and thus hypointense, adenocarcinoma. Other helpful signs of differentiation are the mean larger volume, the occasionally cystic component and the lack of infiltration of peripancreatic fat and vessels of neuroendocrine tumors in comparison to the more aggressive growing adenocarcinoma [59, 60].In patients with a high degree of clinical suspicion but negative non-invasive imaging studies (US, CT and/or MRT), further diagnostic investigations may include contrast-enhanced US (sensitivity and specificity 94 and 96%, respectively) [61] or endoscopic ultrasound (EUS) with biopsies (sensitivity 82–86%) [62,63,64]. The sensitivity of CT and MR imaging is in the range of 75–79%, using comparable technical standards and equipment [65]. For follow-up, the technique which best visualizes the individual tumor should be used. However, with progressive disease and before therapeutic decisions, a thorough staging (SRS, US and CT/MRT) is recommended.US combined with state of the art contrast-enhanced CT/ MR imaging (including MRCP) is recommended. The decision whether to use CT or MRT depends on the preference, skill and expertise of the radiologist and the availability of the different techniques at each institution. Somatostatin receptor scintigraphy is the most sensitive, single screening method for extrahepatic disease manifestation. A possible algorithm is provided in figure 1.Chromogranin A (CgA) is a general tumor marker for neuroendocrine tumors [66]. Its concentration is supposed to correlate with the tumor mass. This correlation may be lost during SSA therapy [67]. In addition, basal and meal-stimulated pancreatic polypeptide (PP) may be useful for early detection of pancreatic involvement in MEN-1. 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