Pancreatic Endocrine Tumors

Modern Pathology (2011) 24, S66–S77 S66 & 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00 Pancreatic endocrine tumors Sylvia L Asa Department of Pathology and Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, ON, Canada The endocrine cells of the pancreas and their related cells throughout the gastrointestinal tract give rise to a variety of tumors that pose a diagnostic challenge. There has been progress in understanding their histogenesis, morphology, immunohistochemistry, molecular biology and classifications. This review will focus on nomenclature/terminology, classification, the role of immunohistochemistry, molecular advances, including genetic predisposition, and potential therapeutic targets to define the role of pathology in the application of prognostic and predictive markers for this disease. Modern Pathology (2011) 24, S66–S77; doi:10.1038/modpathol.2010.127 Keywords: classification; endocrine tumor; molecular genetics; pancreas; predictive markers; staging The endocrine pancreas is a component of the nancy. Thus, the term ‘carcinoid’ has led to the dispersed endocrine system, a complex group of misunderstanding of the malignant potential of peptide hormone-secreting or ‘neuroendocrine’ cells these tumors and the use of the term has been that are dispersed singly and in small clusters increasingly discouraged in favor of more precise throughout the pancreas, gut, lung and other sites, terminology. including prostate and ovary.1 The neoplasms that Endocrine tumors in the pancreas were originally arise from these cells range from small benign thought to derive from the islets of Langerhans, incidental findings to functional hormone-secreting hence the previous terminology ‘islet cell tumors.’ tumors to aggressive malignancies. More recent evidence indicates that they actually derive from precursors in the ductal epithelium, so this terminology has been abandoned in favor of Nomenclature/terminology ‘pancreatic endocrine tumors (PETs).’ The term ‘carcinoid’ meaning ‘carcinoma like’ was The controversy continued with discussions of originally introduced by Oberndorfer in 1907 to the appropriateness of ‘endocrine’ or ‘neuroendo- describe these peculiar tumors that resembled crine’ to describe these tumors. The cells that cancers, but had unusual clinical behavior.2 Use comprise these lesions, such as their normal of the term carcinoid has become entrenched in counterparts, express several antigens that are the medical literature, but has been applied to commonly expressed by neuronal elements: neuron- different entities by pathologists and clinicians. specific enolase (NSE), protein gene product 9.5 (PGP 9.5), chromogranin A, B and C and synapto- Pathologists have traditionally classified well-differ- 3 entiated endocrine tumors of the lung, gut and physin. For this reason ‘neuroendocrine’ has pancreas as ‘carcinoid tumors,’ whereas clinicians become the preferred designation and the term ‘neuroendocrine tumor’ (NET) is becoming preva- have restricted the use of the term to describe 4 the syndrome caused by serotonin excess. Moreover, lent for tumors outside the pancreas. However, in the pancreas the term ‘PET’ has been recommended it became apparent that a ‘carcinoid tumor’ in one 5 site was not equivalent to a similar tumor in by the World Health Organization (WHO). another site and that these tumors, initially The mature pancreas contains at least four thought to be benign, display the full histopatholo- characteristic neuroendocrine cell types that are gical spectrum from very low- to high-grade malig- usually found together in small clusters within the islets of Langerhans (Figure 1). There are at least 15 discrete neuroendocrine cell types distributed Correspondence: Dr SL Asa, Department of Pathology, University throughout the gastrointestinal tract. There is ex- Health Network, 200 Elizabeth Street, 11th floor, Eaton wing, Toronto, ON, Canada M5G 2C4. tensive overlap, for example somatostatin-produ- E-mail: [email protected] cing cells are present in both, and during Received 21 May 2010; accepted 31 May 2010 development, gastrin is produced in the pancreas, www.modernpathology.org Pancreatic endocrine tumors SL Asa S67 Figure 1 The normal endocrine pancreas. The endocrine pancreas is composed of the islets of Langerhans, small unencapsulated clusters of endocrine cells in a vascular connective tissue (top left). Although they appear homogeneous, the endocrine cells are actually of distinct types arranged in a specific pattern. Insulin-containing B cells (top right) comprise the majority, forming solid tubular structures that are wound into the round islet. They are surrounded by glucagon-containing A cells (bottom right) that form the outer lining of the tubules. Between the two, somatostatin-containing D cells are randomly distributed. PP cells that contain pancreatic polypeptide are found mainly in islets in the head of the pancreas (not shown). so that any discussion of pancreatic NETs has reflect biases in clinical practice referrals. The implications for gastrointestinal NETs. incidence in autopsy studies has been reported as high as 1.5%; these studies usually identify clinically unrecognized, often asymptomatic and usually Epidemiology small (o1 cm) lesions. The tumors show no significant gender predilection and occur at all ages, PETs are rare, with an incidence of 1 in 100 000 with a peak incidence between 30 and 60 years.5–7 people. They represent approximately 1–2% of all Approximately 1–2% of patients with these tumors pancreatic neoplasms, but in some series that have familial syndromes of predisposition, and the number is higher, reaching up to 15%; this may genetics of these disorders are discussed below. Modern Pathology (2011) 24, S66–S77 Pancreatic endocrine tumors S68 SL Asa Clinical and biochemical features solitary, well-demarcated, tan to pink soft tumors, but they may be hard and gray-white nodules The clinical manifestations of PETs vary depending when they exhibit fibrosis or amyloid deposition on whether they are clinically ‘functioning,’ giving (Figure 2). Well-differentiated tumors can manifest a rise to signs and symptoms of hormone excess, or diverse range of histological appearances including ‘non-functioning,’ that is, creating no clinical fea- the common solid nesting pattern (Figure 3a), a tures that prompt a search for hormone production. trabecular/gyriform pattern (Figure 3b), glandular The clinical syndromes caused by inappropriate formations (Figure 3c), tubular-acinar and mixed secretion of hormones are different for each hor- patterns. Stromal fibrosis (Figure 3d) and amyloid mone produced. Insulinomas that secret excess deposition are seen, the latter mainly in insulino- insulin result in hypoglycemia. Glucagonomas mas. The presence of calcification is sometimes cause a spectrum of features including dia- noted and when psammomatous in nature is diagno- betes mellitus and occasionally a characteristic rash stic of a somatostatin-producing tumor. Less com- known as ‘necrolytic migratory erythema.’ The monly, cystic, papillary and so-called angiomatoid/ somatostatinoma syndrome is a well described but angiomatous patterns may also be seen. Another poorly recognized syndrome that includes diabetes, morphological variant is a pancreatic NET with cholelithiasis and borborygmi. Gastrinomas are ductules.9,10 This is not a mixed neuroendocrine- associated with the Zollinger–Ellison syndrome, epithelial tumor, but a NET with ductules that are and VIPomas give rise to the disorder known as either entrapped as the tumor grows into surround- ‘pancreatic cholera.’ Other less common tumors can ing normal pancreatic tissue (Figure 3e) or as a result secrete hormones that result in acromegaly, Cush- of secondary ductular proliferation occurring as a ing’s syndrome and other unusual disorders. reactive phenomenon. Approximately 30–40% of PETs are classified as The cells have readily recognizable cytological ‘non-functioning’ or ‘non-syndromic’ because they features: round to ovoid cells with eosinophilic, are not associated with distinct clinical manifesta- slightly granular cytoplasm and nuclei with a tions of hormone alterations. These lesions may still dispersed chromatin pattern (‘salt and pepper’) produce hormones that are detected by immuno- and, not infrequently, discernible nucleoli (Figure histochemistry or by measurement of circulating 3). Occasionally, nuclear pseudoinclusions may be levels in the blood. Non-functioning tumors usually seen. Oncocytic change results in the development become clinically apparent when they reach a size of abundant granular eosinophilic cytoplasm be- that causes compression or invasion of adjacent cause of accumulation of mitochondria (Figure 3f). organs, or when they metastasize. They may be Clear cell change may be seen focally in oncocytic detected incidentally on abdominal imaging for lesions, or may be diffuse due to extreme lipid other reasons. Rarely, they cause pancreatitis. accumulation. Unusual tumors may have spindle- cell morphology or so-called ‘rhabdoid’ features that are actually due to perinuclear aggresomes com- Diagnosis and classification posed of keratin filaments rather than rhabdoid 11,12 Morphology differentiation. Large cell and small cell endocrine carcinomas The initial diagnosis of a PET is based on morpho- are high-grade malignancies with high mitotic and logical features.8 Grossly, these lesions are usually Ki-67-labeling indices. Mixed tumors with exocrine Figure

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