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