Endocrine neoplasms of the pancreas: pathologic and genetic features.
Pancreatic endocrine neoplasms (PENs) are epithelial tumors with endocrine differentiation. They account for approximately 2% of all pancreatic neoplasms and commonly affect adults between the ages of 40 and 60 years with no sex predilection. (1,2) At variance with the fast proliferating and deadly pancreatic ductal adenocarcinoma, the typical PEN grows slowly and impairs patient quality of life only very late in the course of the disease, even when metastatic. It is thus important to distinguish PEN from ductal adenocarcinoma, because its prognosis is largely more favorable. (1,2)
Pancreatic endocrine neoplasms are usually sporadic but may be part of hereditary syndromes mostly including multiple endocrine neoplasia type 1 (MEN-1) and, more rarely, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). Sporadic PENs are solitary, whereas the hereditary forms may be multifocal.
Patients seek medical assistance because of symptoms resulting from either hormonal hypersecretion or mass. Thus, PENs are clinically defined as functioning (syndromic) (F-PENs) or nonfunctioning (nonsyndromic) (NF-PENs), depending on the presence of a syndrome related to inappropriate hormone secretion. The clinical syndromes associated with the different types of F-PENs are summarized in Table 1. The patients presenting with metastatic or mass-related symptoms are those with NF-PENs and report abdominal pain, nausea, weight loss or, exceptionally, jaundice. Half of clinically observed PENs and more than 50% of surgically resected cases are NF-PENs. (1-5)
Imaging procedures address the diagnosis by recognizing the characteristic hypervascular pattern of these lesions, which is present in about 70% of cases (Figure 1). Large size and smooth regular margins with lack of dilation of the biliary and main pancreatic ducts contribute to the differentiation of PEN from adenocarcinoma. Most PENs express receptors for somatostatin and can be easily identified by somatostatin receptor scintigraphy. (4,6-8) Moreover, the current and more sensitive imaging techniques increasingly detect small and asymptomatic tumors, the so-called pancreatic endocrine incidentalomas. (9-11)
Most F-PENs, with the exception of insulinomas, are diagnosed when they are already malignant diseases, and liver metastases are common. (12-15) Nonfunctioning PENs are also frequently malignant, as more than 50% of patients have liver metastases at diagnosis and almost 40% are not candidates for radical surgery because of either locally advanced disease or unresectable metastases. (16-18) Patients with well-differentiated NF-PENs have a 5-year survival rate of approximately 65% and a 10-year survival rate of 45%. (2,19)
Pancreatic endocrine neoplasms can be located anywhere within the pancreas.
Common Type.--Pancreatic endocrine neoplasms usually present as solitary, solid, homogeneous masses, usually from 1 to 5 cm in diameter, with rounded and sharp borders (Figure 2), rarely surrounded by a fibrotic pseudocapsule. Their expansive pattern of growth differs from the infiltrative pattern of the ductal adenocarcinoma. When located in the pancreatic head, they usually compress and deviate, but not infiltrate, the main pancreatic and biliary ducts. Also, PENs extending outside the pancreas usually displace rather than invade the adjacent structures including large vessels. Their color and consistency depend on the amount of stroma and vascularization; the usual PEN is rich in small vessels and poor in fibrotic stroma. The color varies from brown to reddish and the consistency is slightly firmer than that of the surrounding parenchyma. Rare masses appear hemorrhagic. Necrotic yellowish foci can be observed in large masses. Features of malignancy evident at macroscopic examination include involvement of perivisceral fat, mainly as satellite nodules, and invasion of duodenal wall or adjacent organs, common bile duct, spleen, or large vessels (Figure 3). Involvement of splenic vessels with thrombosis can cause splenic infarctions.
Uncommon Types.--Pancreatic endocrine neoplasms may have unusual macroscopic aspects. They may mimic cystic or fibrotic tumors (Figure 4, A and B). Pancreatic endocrine neoplasms with cystic appearance may be either unilocular or multilocular and are filled with a clear or hemorrhagic fluid (20-23) (Figure 4, A). These tumors are most difficult to diagnose preoperatively and are often mistakenly interpreted as being cystic neoplasia. Pancreatic endocrine neoplasms with fibrotic appearance have considerable fibrosis that results in firm consistency, whitish color, and ill-defined borders (Figure 4, B). These PENs look like a ductal adenocarcinoma. Cases of black or yellow PENs have been described. The "pigmented black PEN" (24) is composed of cells with abundant intracytoplasmic lipofuscin. This tumor may mimic metastatic melanoma. The yellow "lipid-rich PEN" can mimic adrenal cortical neoplasia. (25)
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PEN and the Main Pancreatic Duct.--Pancreatic endocrine neoplasms rarely grow within the duct itself and, even more rarely, infiltrate the duct and cause strictures. Intraductal PENs are NF-PENs that grow within the main pancreatic duct without invading its epithelium and may be connected to an extraductal lesion. They have been described in case reports (26-29) in which most cases were malignant. Pancreatic endocrine neoplasms causing duct strictures are lesions growing around the main pancreatic duct with extensions into its wall that cause abrupt-type strictures (30,31) (Figure 5, A and B).
Most PENs are well-differentiated tumors whose highly characteristic histologic features permit the recognition of their endocrine nature. Broad variations in the architectural and cytological aspects can be encountered, particularly in larger tumors. Tumors smaller than 0.5 cm are called microadenomas, generally show a trabecular pattern, and are observed more frequently in patients with genetic disease. (32,33)
The Architectural Aspects.--Pancreatic endocrine neoplasm typically has an organoid pattern of growth, characterized by solid nests and macrotrabecular or microtrabecular/ gyriform patterns with cords, festoons, and ribbons (Figure 6, A). Glandular (Figure 6, B), acinar, and cribriform features can also be observed. Although one pattern is generally prevalent, more than one can be seen in different regions of the same tumor. A rich vascularization characterizes most PENs and is responsible for their hyperdense radiologic appearance. Typically, numerous small vessels encircle the neoplastic nests. These vessels are embedded in a variable amount of stroma (Figure 6, C), which rarely forms sclerohyaline bands and only occasionally shows calcified foci. The presence of amyloid is frequent in insulinomas. Necrosis can be present either as large and confluent areas ("infarctlike"), especially in large tumors, or as punctate foci recognized at microscopic observation in the center of neoplastic nests. No conclusion may ever be reached by tumor histologic analysis alone concerning the functional state or hormone type produced. The 2 exceptions are the stroma with amyloid deposits identifying insulinoma and the glandular pattern with psammoma bodies identifying somatostatinoma.
The Cytologic Aspects.--Regardless of the growth pattern, the neoplastic cells have similar cytologic features. The classic PEN is composed of small- to medium-sized cells with eosinophilic to amphophilic and finely granular cytoplasm. The nuclei are usually centrally located, round or oval, uniform in size and show finely stippled "endocrine chromatin" referred to as salt-and-pepper (Figure 7). Nucleoli are inconspicuous or absent; rarely, they are prominent and incorrectly suggest an acinar cell carcinoma (Figure 8, A). In some tumors, the neoplastic cells show a plasmacytoid appearance due to peripherally located nuclei. When the tumor is made up of small cells with minimal cytoplasm, PEN may be confused with a high-grade small cell endocrine carcinoma, but the mitotic activity is low and necrosis is undetected. Sometimes nuclei show variable shapes and atypia (Figure 8, B), which is not a criterion for aggressiveness as it is in adenocarcinomas, where it correlates with prognosis. (34)
Unusual cytologic features can be occasionally seen in otherwise conventional PENs; when they become prevalent, the tumor is considered a morphologic variant. Oncocytic, lipid-rich, clear cell, and rhabdoid variants, as well as tumors with marked nuclear pleomorphism, have been reported (2) (Figure 9, A and B). The clinical outcome of these tumors does not differ significantly from that of conventional PENs. The main reason for recognizing these variants is to avoid misdiagnosis with other pancreatic or extrapancreatic neoplasms. In fact, these unusual morphologies may obscure the endocrine nature of the neoplasm that can be readily established by immunohistochemistry, provided that the possibility of a PEN has been considered.
The Morphologic Signs of Malignancy.--Tumoral infiltration of the duodenum and/or the biliary duct wall and lymph node metastases identify the malignant forms, and they should be carefully searched because they are not always evident macroscopically. The involvement of the peripancreatic fat can be more difficult to evaluate when the tumor has expansive growth margins and a pseudocapsule. Perineural and vascular invasion are most easily recognized in the peritumoral nerves and vessels within or adjacent to the pseudocapsule, if present; these are prognostic parameters included in the World Health Organization (WHO) classification (1) (Table 2). The slowly growing tumor may entrap normal pancreatic structures such as ducts and acini, giving the false impression that the neoplastic cells have taken multiple differentiation paths; these aspects should never be considered as evidence of aggressive behavior.
Poorly differentiated endocrine carcinomas present with ill-defined solid masses and extensive necrosis, and histologically resemble small cell carcinomas or large cell endocrine carcinomas of others organs2 (Figure 10, A and B). They typically have a high mitotic rate, with a proliferative activity of more than 20%, and frequently stain for p53 protein. (1,2)
Immunohistochemistry serves primarily to confirm the endocrine nature of the neoplasia and thus to differentiate PENs from other pancreatic, extrapancreatic, and metastatic neoplasms. It is also useful for determining the type of hormones produced by the neoplastic cells. In addition, immunohistochemical markers are used or, at least, have been proposed for assessment of prognosis.
General Endocrine Markers.--Although examination of hematoxylin-eosin sections in general allows the diagnosis of endocrine tumor, the endocrine differentiation has to be proved by immunohistochemical labeling with antibodies to at least 1 general endocrine marker, synaptophysin35 or chromogranin A (CgA), (36) which are located in small neurotransmitter-storing synaptic vesicles and in neurosecretory granules, respectively (Figure 11, A and B). The cytosolic neuron-specific enolase (37) and protein gene product 9.5 (38) are less specific, and their diagnostic utility is limited.
Chromogranin A stain is proportional to the content of neurosecretory granules and may be patchy and of variable intensity. Up to 20% of PENs show only focal CgA positivity, in contrast with the generally diffuse labeling for synaptophysin. Poorly differentiated endocrine tumors are usually negative for CgA, while synaptophysin persists in the neoplastic cells. Circulating CgA is also used as a tumor marker for PENs. It is elevated in 60% to 80% of cases and correlates with disease burden, and, as such, is very useful for diagnosis, follow-up, and monitoring of response to therapy. (4,39,40)
Additional Markers for Differential Diagnosis.--Different cytokeratins show variable immunoreactivities in PENs. Cytokeratins 8 and 18 are constantly positive, whereas cytokeratins 7 and 20 are usually negative; cytokeratin AE1/AE3 labels 50% of PENs. (41) [beta]-Catenin displays a membranous pattern of staining, in contrast with the abnormal nuclear positivity observed in solid-pseudopapillary neoplasm. (42) Neural markers CD56 and S100 protein can be expressed in PENs. The first is a cell adhesion molecule and is identified in most cases, whereas S100 immunoreactivity is present in only a few tumors. (34)
Pancreatic endocrine neoplasms may focally express trypsin, a marker of acinar differentiation; if more than 25% of the neoplastic cells are positive, the neoplasm should be classified as a mixed acinar-endocrine carcinoma. (43-45) Labeling for glycoproteins DUPAN-2 or carbohydrate antigen 19-9, markers of ductal differentiation, (16,45) can be evident in cases with pseudoglandular pattern, but this is not sufficient for a diagnosis of mixed ductal-endocrine carcinoma, unless a typical adenocarcinoma component is recognized.
Identification of Hormones Produced by the Neoplasia.--Pancreatic endocrine neoplasms may express normally produced pancreatic hormones (insulin, glucagon, somatostatin, pancreatic polypeptide), hormones of ectopic origin (gastrin, vasoactive intestinal polypeptide, adrenocorticotrophic hormone), and bioamines (serotonin). The pattern of labeling for these hormones varies widely; some PENs show strong and diffuse positivity, while others only show focal and faint staining; the positivity for more than one hormone is common. In F-PENs, the hormone responsible for the clinical syndrome can be demonstrated, but staining intensity or the number of positive cells does not correlate with the severity of symptoms because of impairment in the storage and secretion capability of the cells. Nonfunctioning PENs produce and secrete a wide range of hormones whose serum levels are elevated. The potential reasons for the lack of a syndrome include inadequate secretion of hormone (eg, amount is too small to cause symptoms) or secretion of a hormone in an inactive, functionally inert form. However, the type of hormone produced may be useful as a serologic marker for the early recognition of relapse or metastases.
Prognostic Markers.--Several recent studies have suggested a prognostic significance for a variety of immunohistochemical markers, such as COX2, (46) p27, (47) and CD99 (48) or some expressed by normal islet cells, like progesterone receptors. (49) However, these results need to be verified in independent patient cohorts. (50,51) The expression of cytokeratin 19, regarded as a marker of ductal epithelium, has been suggested as a marker of aggressiveness (48,52,53) that gives prognostic information independently from that obtained by WHO criteria. (54) As proliferative activity has a recognized prognostic value, (1,55) its assessment by Ki-67 immunostaining is a routine practice in several institutions, including ours. The WHO classification considers a Ki-67 labeling index of 2% as a discriminant, among well-differentiated PENs, between those with benign and those with uncertain behavior. (1)
The differential diagnosis of PENs includes the other "solid cellular" pancreatic neoplasms, some extrapancreatic tumors, and, more rarely, cystic tumors and nonneoplastic lesions of the pancreas.
Solid Cellular Pancreatic Neoplasms.--These are acinar cell carcinomas, (56,57) pancreatoblastomas, (58) and solid-pseudopapillary neoplasms, (59,60) which frequently share the clinical scenario with PENs because of the presence of a slow-growing, pushing mass. However, each of these neoplasms can be differentiated from PENs because of its distinctive clinicopathologic features. Acinar cell carcinoma generally affects adults; solid-pseudopapillary neoplasm is more common in young females; pancreatoblastoma mostly arises in children. Pancreatic endocrine neoplasms often show a wide variety of different organoid patterns that generally are not present in the other solid cellular tumors, and their cells exhibit the classic salt-andpepper chromatin. An acinar pattern, prominent nucleoli, and a high mitotic rate should suggest acinar cell carcinoma; degenerative pseudopapillae, cells with clear cytoplasm, cytoplasmic hyaline globules, and oval nuclei with longitudinal grooves are diagnostic for solid pseudopapillary tumor. Squamoid nests are a hallmark of pancreatoblastoma. Immunohistochemistry is needed to demonstrate the endocrine (chromogranin and synaptophysin) or acinar (trypsin) differentiation. Solid-pseudopapillary neoplasms generally do not express specific cell-lineage markers and only focally express keratin in a minority of cases. They express nonspecific markers such as vimentin, neuron-specific enolase, and CD56, but typically they show abnormal nuclear positivity for [beta]-catenin, and the cells immunolabel with CD10 but never with chromogranin.
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Other Pancreatic and Extrapancreatic Neoplasms.--Tumors that may be confused with PENs include solid serous adenoma, (61,62) PEComa (clear cell "sugar" tumor), (63) and paraganglioma. (64)
Differential Diagnosis of the Morphologic Variants of PEN.--The morphologic variants of PENs are prone to be misdiagnosed for more aggressive neoplasms. Biopsy or cytologic material represents the greatest diagnostic challenge for the surgical pathologist in these cases, particularly in the case of hepatic metastatic disease.
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Clear cell PENs should be differentiated from all the clear cell lesions occurring in the pancreas. Among metastatic neoplasms, (65) renal cell carcinoma is by far the most relevant (66-68); immunohistochemical analysis demonstrating coexpression of [CD10.sup.+], vimentin, and cytokeratin, together with lack of endocrine markers, allows its identification. Less frequent primary pancreatic lesions to be considered include tumors rich in lipid, glycogen, or mucin foamygland adenocarcinoma, (69) ductal adenocarcinoma with clear cell features, (70,71) serous adenoma, especially its solid variant, clear cell variant of solid-pseudopapillary neoplasm, (72) and clear cell sugar tumor. (63) Those occurring in the peripancreatic region comprise adrenal tumors, steroid-secreting tumors of the ovary, clear cell hepatocellular carcinoma, and clear cell sarcoma or melanoma. (73)
Oncocytic (74) and lipid-rich PENs (25) may resemble hepatocellular and adrenal cortical tumors. Nuclear pleomorphism, glandular formation, glassy cytoplasmic inclusions ("rhabdoid features"), and occasional abundance of fibrotic stroma are features erroneously suggesting a diagnosis of pancreatic adenocarcinoma or metastatic carcinoma. Pleomorphic PEN (34,75) is frequently diagnosed as ductal adenocarcinoma and rhabdoid PEN (76-78) as anaplastic carcinoma (79,80) or metastases with rhabdoid phenotype, particularly of melanoma. The absence of necrosis and a low mitotic rate should suggest a low-grade neoplasm.
Pancreatic endocrine neoplasms presenting as cystic lesions, (21-23,81) either macrocystic or microcystic, are difficult to diagnose preoperatively. Most are nonfunctioning tumors and the identification of their endocrine nature is usually delayed until the histopathologic examination of the surgical specimen.
Ductuloinsular tumor of the pancreas (82) is an endocrine tumor that may be misdiagnosed as mixed ductal-endocrine neoplasm. It is characterized by the presence of several small, cytologically bland ductules intimately admixed with the endocrine component. It has been suggested that this neoplasm be named pancreatic endocrine tumor with entrapped ductules (83) to describe the nonneoplastic nature of the ductules. The clinical behavior of this neoplasm is similar to typical well-differentiated PEN.
Nonneoplastic Conditions.--The aggregation of nonneoplastic islets in chronic pancreatitis may be mistaken for a PEN. In this case, endocrine elements are grouped in vaguely insular structures characterized by the persistence and normal distribution of the 4 cell types normally present in the pancreatic insulae. (84) The presence of endocrine elements in perineural spaces, observed in rare cases of severe chronic pancreatitis, must not be considered a sign of neoplasia.
The WHO classification, proposed in 2000 and modified in 2004 (Table 2), identifies 3 main categories of PENs: well-differentiated endocrine tumor, well-differentiated endocrine carcinoma, and poorly differentiated endocrine carcinoma. (1)
Morphology allows the distinction between poorly differentiated carcinomas and well-differentiated neoplasms. The former are invariably high-grade malignancies. The latter include more than 90% of PENs, whose clinical behavior, varying from indolent to malignant, cannot be predicted by their tissue architecture or cytologic features. Well-differentiated endocrine carcinomas are morphologically similar to well-differentiated endocrine tumors and are identified only when there is either invasion of adjacent structures or metastasis. As a number of well-differentiated endocrine tumors may eventually metastasize, the WHO classification has introduced 2 subcategories--benign and of uncertain behavior--that are assigned to a tumor according to the presence of a series of pathologic parameters, widely recognized as prognostic factors (Table 2). The presence of vascular and perineural invasion, a tumor size larger than 2 cm, a mitotic rate higher than 2 mitoses per 10 high-power fields, and a Ki-67 proliferative index above 2% are considered a sign of potential aggressive behavior. (16,55,85-89)
In our experience, an accurate examination of the peripancreatic adipose tissue to search for lymph node metastasis is mandatory to avoid the erroneous assignment of a number of well-differentiated endocrine carcinomas to the well-differentiated endocrine tumor category. In fact, metastasis does not always cause an increase in nodal size (Figure 12). In this respect, a recent study demonstrated that tumor size was not associated with the probability of lymph node metastasis, and positive nodes were identified in 5 of 19 patients with tumors smaller than 2 cm. (90) Recent studies by our group and others have validated the WHO classification and demonstrated that it is a useful tool for clinical purposes. (18,54,87,90-95) The WHO criteria efficiently discriminate PENs into different categories that show a statistically significant different outcome and permit the planning of surgical or medical strategies.
STAGING AND GRADING FOR PROGNOSTIC STRATIFICATION
The WHO classification has defined the features that discriminate benign behavior or low-risk, well-differentiated endocrine tumors from low-grade, malignant, well-differentiated endocrine carcinomas. This has been an important step and several recent publications have proven its effectiveness. (18,54,87,90-95) However, the WHO classification does not allow a prognostic stratification of patients affected by well-differentiated endocrine carcinomas, which represent the true clinical challenge among PENs.
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As the traditional TNM staging system does not include endocrine neoplasms, the European Neuroendocrine Tumor Society (ENETS) has proposed a TNM-based staging system for gastroenteropancreatic endocrine tumors. The TNM classification proposal reported in Table 3 is the result of a consensus conference that included 62 experts in the field of digestive endocrine tumors from 20 countries. (96) The TNM system is based on the evaluation of the following parameters: size, extrapancreatic invasion, and lymph node and liver metastasis. These are the very same parameters used in the WHO classification to assign a tumor to a benign or malignant category, whereas in the TNM system they are independently evaluated and scored. Each of these parameters has a diverse weight in the assignment of the stage grouping, which results in a measure for the extent of the disease with prognostic significance.
However, the clinical need to differentiate between carcinomas belonging to the same stage is not solved by the TNM assignment. Therefore, in the same conference, the potential role of a grading system applied to PENs that would provide this information was widely discussed. Cytologic criteria were considered of no help in this matter, so it was decided to use the proliferation activity as a grading system based on mitotic count and/or Ki-67 index (Table 4).
Both the TNM staging and grading systems have been shown to be valid tools for prognostic stratification of PENs in clinical practice. (93,97) The TNM staging of PENs for 274 patients observed at our institution in the last 15 years has allowed the assignment of a relative risk of death proportional to the TNM stage at the time of diagnosis. Patients with stages II, III, and IV disease showed a respective risk of death of 7, 29, and 58 times higher than did patients with stage I tumors (A.S., unpublished data, 2008). Moreover, grading is useful for therapeutic decisions, particularly in patients with advanced stage disease, as we have recently reported in a prospective single center study.98 Also, Aparicio et al (99) reported that a slow tumor growth rate is the only predictive factor for response to therapy with somatostatin analogues.
A different proposal for a staging and grading system applied to PENs, which is reported to provide more accurate prognostic information than that of the WHO, comes from a group at the Memorial Sloan-Kettering Cancer Center (New York, New York). (90) This combined system uses tumor size and metastasis to stage PENs into 3 categories (<2 cm, primary; [greater than or equal to] 2 cm, primary; or metastases) and uses mitosis and necrosis to grade PENs into 2 categories (low grade, no necrosis with <2 mitoses per 50 HPFs; or intermediate grade with necrosis and/or [greater than or equal to] 2 mitoses per 50 HPFs).
The therapy of choice for PENs is surgical resection with curative intent. The issue of which is the best treatment for advanced, well-differentiated endocrine carcinomas not suitable for radical surgery remains controversial (3,98) and consensus guidelines have been proposed. (4,13-15) As most cases express receptors for somatostatin, somatostatin analogues have been used and shown to achieve frequent stabilization of the disease. The therapeutic options for the more aggressive diseases include either chemotherapy, usually based on doxorubicin and streptozotocin, or peptide receptor radionuclide therapy. The open question is how we can best identify which patients to treat with somatostatin analogues and which will benefit from more aggressive therapies as first-line treatment.
Pancreatic endocrine neoplasms may arise in the context of 4 hereditary cancer syndromes, the most common of which is MEN-1, where PENs occur at an earlier age than they do in sporadic forms, may precede other manifestations of the syndrome, and determine the prognosis. Nonfunctioning PENs are also a rare, yet well recognized part of VHL (Figure 13), whereas they seldom occur in NF1 and TSC. However, most PENs occur as sporadic diseases.
Multiple Endocrine Neoplasia Type 1.--Multiple endocrine neoplasia type 1 is an autosomal dominant disease with greater than 95% penetrance, characterized by multifocal endocrine tumors affecting multiple organs. MEN1 gene encodes a 68-kDa protein of 610 amino acids named menin. MEN1 germline mutations generally cause the inactivation of menin and, consistent with the role of MEN1 as a tumor suppressor gene, most MEN-1-associated tumors show somatic loss of the second wild-type allele (loss of heterozigosity). The pancreas is involved in roughly 60% of cases with multiple endocrine tumors of variable size, mostly NF-PEN, either synchronous or metachronous. (100,101)
The finding of "pancreatic microadenomatosis" in more than 80% of patients with MEN-1, that is, the presence of numerous microadenomas, suggests that the latter are precursor lesions of MEN-1-associated PENs. (33) A microadenoma is a lesion up to 5 mm in diameter with the following typical features: (1) a trabecular growth pattern, (2) a distinct stromal component, and (3) immunopositivity for 1 hormone, with prevalence of glucagon. Microadenomatosis is often associated with 1 or more macrotumors (>5 mm) with frequent immunohistochemical expression of glucagon and pancreatic polypeptide or, rarely, somatostatin, and never causes hormonal syndromes. (32,100) Moreover, the detection of loss of heterozygosity in the so-called monohormonal isletlike endocrine cell clusters found in MEN-1 pancreas, has identified these as forerunners of microadenomas. (102) The single enlarged islets with an increased number of glucagon cells found in MEN-1 pancreas are also a potential precursor of microadenomas. However, retention of the normal MEN1 allele in these cells indicates that they are still nonneoplastic in nature. Although pancreatic microadenomatosis is a feature of MEN-1 syndrome, this condition is not specific, as multiple glucagon- or insulin-producing microadenomas have also been found in patients with no evidence of hereditary syndromes. (33)
von Hippel-Lindau Disease.--von Hippel-Lindau syndrome is an autosomal dominant disease with age-dependent penetrance and a marked phenotypic variability,103 characterized by predisposition to a variety of malignant and benign neoplasms in various organs, including central nervous system hemangioblastomas, renal cell carcinomas, and pheochromocytomas. The VHL tumor suppressor gene is located on chromosome 3p25. The VHL protein is a component of a complex involved in the degradation of hypoxia-inducible factor, a transcription factor that plays a central role in the regulation of gene expression by oxygen. (104) In up to 77% of cases, the pancreas is involved by serous microcystic adenomas and in up to 16% of cases, by PENs. (101,103) Pancreatic endocrine neoplasms are multiple in about 40% of cases and most are nonfunctioning. Two histological variants of PEN occur in VHL: the conventional type and, more commonly, the clear cell type that appears to be specific for the disease. (105) The latter type can be differentiated from metastatic renal cell carcinoma by using immunohistochemical staining for [CD10.sup.+], vimentin, and cytokeratin together with endocrine markers. Combined PEN/serous cystadenomas also occur, sometimes involving the whole pancreas. von Hippel-Lindau-related PENs grow as slowly as their sporadic counterpart and no precursor lesions have yet been identified. (101)
Neurofibromatosis Type 1.--Neurofibromatosis type 1 is an autosomal dominant disease with high penetrance (106) caused by mutations of the NF1 gene, localized on chromosome 17q11.2, which encodes neurofibromin that acts as a negative regulator of the Ras-related G-proteins by increasing Ras GTPase activity. Our knowledge of NF1-associated intestinal neuroendocrine tumors (NETs) is based on case reports and small series. (101) They occur in 1% of patients with NF1 and most arise in the region of the ampulla of Vater, show glandular structures containing periodic acid-Schiff-positive psammoma bodies, and consistently express somatostatin (SOM-NETs). Neurofibromatosis type 1-related SOM-NETs may be associated with gastrointestinal stromal tumors. Rare intrapancreatic SOM-NETs or insulinomas have been reported in patients with NF1. (107,108) Precursor lesions of NF1-associated endocrine neoplasms have not been identified.
Tuberous Sclerosis Complex.--Tuberous sclerosis complex is an autosomal dominant disorder with almost complete penetrance, characterized by hamartomatous lesions caused by inactivating mutations in either the TSC1 gene at 9q34 or the TSC2 gene at 16p13.3. These genes encode the proteins hamartin and tuberin, respectively, which form a complex that participates in the regulation of cell proliferation, growth, and differentiation. (109) The TSC1/ TSC2 dimer mediates a key step in the phosphoinositide 3-kinase (PI3K) signaling pathway. Thus, the TSC1/TSC2 complex is involved in the regulation of mTOR activity, a master controller of protein translation that integrates information on growth stimuli, cellular energy levels, nutrient availability, hypoxia, and cell growth. (109) The few cases of PENs described in patients with TSC were insulinomas or NF-PENs, some of which were malignant. (101)
The genetic aberrations associated with PENs include anomalies in the "anatomy" and function of DNA. The anatomic lesions consist of chromosomal alterations (numerical and structural) and epigenetic changes that regulate gene transcription. The latter changes include DNA methylation and acetylation or other modifications of DNA-associated histones. The third anatomic lesion of DNA is mutation in single genes. The functional genomic alterations are those found at the gene expression level and involve 2 main types of RNAs: protein-coding mRNAs and regulatory small RNAs known as "noncoding RNAs" (microRNAs and small noncoding RNAs or sncRNAs). (110)
Chromosomal Anomalies.--Chromosomal analysis has identified numerous regions of chromosome loss and gain in sporadic PENs,111 suggesting the existence of 2 subgroups: those showing frequent allelic imbalances and those showing a low number of allelic imbalances. (112,113) It has been suggested that these 2 molecular subgroups, which correspond to aneuploid or near-diploid tumors, respectively, have prognostic value. (113) More recent studies based on comparative genomic hybridization array technology confirmed the previous observation that the total number of genomic changes per tumor appears to be associated with both tumor burden and stage of the disease, suggesting that genetic alterations accumulate during tumor progression. (112) A recent study concluded that the DNA copy number status is the most sensitive and efficient marker of clinical outcome in insulinomas and is of potential interest in noninsulinoma PENs. (114)
These findings point to chromosomal instability as an important mechanism associated with tumor progression. In particular, comparative genomic hybridization and microsatellite analysis (loss of hetrozygosity) have shown that chromosomal losses occur more frequently than gains, whereas amplifications are seemingly uncommon. (112,113) The most frequent gains are on chromosomes 5q (25%), 7pq (41%), 9q (28%), 14q (32%), 17pq (31%), and 20q (27%). The most frequent losses include 1p (21%), 3p (19%), 6q (28%), 11q (30%), Y (31%), and X (31%). An important observation from these studies is that the alterations are not randomly distributed on chromosomes but are particularly common in distinct chromosomal regions. Furthermore, genomic alterations including losses of chromosomes 1 and 11q, as well as gains of 9q, are already present in many small tumors (<2 cm), thus suggesting that these may be early events in the development of PENs. (115-118) A strong correlation has been found between sex chromosome loss and aggressive behavior of PEN, namely, the presence of local invasion or metastasis. (119)
Microsatellite instability, that is, the occurrence of widespread mutations in microsatellite sequences, due to inactivation or silencing of mutator genes, is a very rare phenomenon; it was not found in 76 published cases of PENs, (120) and was found in only 1 of 113 PENs in our institution (A.S., unpublished data, 2008).
Epigenetic Anomalies.--Epigenetic abnormalities occur in PENs, but as yet, genes targeted by these changes and with a definite role in PEN tumorigenesis have not been identified.
Two studies on the methylation status of several candidate tumor suppressor genes have been published to date.120,121 The first analyzed 11 genes in 46 PENs and revealed hypermethylation in the following 8 genes: RASSF1A (75%), P16/INK4A (40%), MGMT (40%), MLH1 (23%), APC (21%), E-cadherin (23%), P73 (17%), and RARB (25%); no methylation was found in TIMP3, P14, and GST.121 The second study also included 46 PENs that were analyzed for 11 genes, 7 of which were common to both reports and showed the following methylation rates: RASSF1A (80%), P16/INK4A (0%), MGMT (17%), MLH1 (0%), APC (48%), E-cadherin (2%), TIMP3 (0%); the remaining 4 genes were MEN1 (19%), HIC-1 (93%), RUNX3 (7%), and PTEN (0%). (120,121)
Two findings were consistent in the analysis of the 7 genes common to both studies: the first is the lack of methylation in the TIMP3 gene, a finding that contrasts with a report showing that methylation is associated with loss of expression of TIMP3 in 8 of 18 PENs (44%) (122); the second is the high rate of methylation in the RASSF1A gene, a finding confirmed in other PEN series in which the reported rate ranged from 60% to 100% of cases. (121,123-125)
Because RASSF1A inhibits tumor growth in both in vitro and in vivo systems, (123) it has been suggested that its inactivation may be a crucial event in PEN pathogenesis. (120,123-125) However, this assumption has never been confirmed by data demonstrating the loss of RASSF1A expression in the presence of gene methylation. Although RASSF1A has been considered a RAS inhibitor, and, as such, its inactivation is considered to result in the indirect activation of the RAS pathway in PENs, recent studies assign a more complex role to this gene in cell life. (126)
Beyond methylation studies regarding single genes, 10 PENs have also been evaluated for the global methylation status of DNA by analysis of long interspersed nucleotide elements (LINE) 1 and ALU sequences. (127) In particular, PENs were found to have a global hypomethylation with respect to normal pancreas, but less commonly than is seen in intestinal endocrine tumors versus normal intestine.
A recent report by our group has suggested that chromatin remodeling by histone acetylation might play a role in pancreatic endocrine neoplasms, as the histone-deacetylase inhibitor trichostatin A strongly inhibits cell growth of different pancreatic endocrine carcinoma cell lines. (128)
Single-Gene Mutations.--To date, mutation of MEN1 and allelic loss of chromosome 11q, which encompasses the region containing the MEN1 locus, are the most common genetic alterations found in PENs. These occur in NF-PENs and gastrinomas with a frequency higher than that in insulinomas. (102,129,130) Indeed, mutations are detected in about 30% of NF-PENs, whereas insulinomas, gastrinomas, glucagonomas, and VIPomas show a mutation rate of 7%, 36%, 67%, and 44%, respectively. (129)
In contrast to the low rate of MEN1 mutations, more than 50% of all PENs exhibit losses at 11q13 and/or more distal parts of the long arm of chromosome 11. This implies that a haploinsufficiency of the MEN1 gene may be sufficient as an initiating factor, which is possibly backed by the loss of additional oncosuppressor genes lying distally on this chromosomal arm. (131-133)
Promoter methylation has been suggested as an additional mechanism of inactivation of MEN1, but the existing data are controversial. (120,121)
Menin associates with and modulates the histone methyltransferase activity of a nuclear protein complex that regulates gene expression. Menin-dependent histone H3 lysine-4 methylation maintains the in vivo expression of cyclin-dependent kinase inhibitors to prevent pancreatic islet tumors. Therefore, menin activates an epigenetic mechanism of tumor suppression by promoting histone modifications and maintaining transcription at multiple loci encoding cell cycle regulators, essential for endocrine growth control. (134) Interestingly, tumors of Men1 [beta]-cell mutant mice exhibit deregulation of genes involved in cell proliferation and cell cycle control. (135)
Mutations of the VHL tumor suppressor gene have been detected only in rare sporadic PENs, despite a high loss-of-heterozygosity rate of this chromosomal region, suggesting the involvement of potential tumor suppressor genes telomeric to the VHL locus. (129,136)
Other tumor suppressor genes or oncogenes including P16, PTEN, KRAS, DPC4, and P53 are only occasionally mutated, mostly in malignant tumors. (2,129,137-140)
Aberrant expression of both [beta]-catenin and E-cadherin correlated strongly with lymph node spread and liver metastases in gastrointestinal endocrine tumors, but only 4 of the 165 PENs displayed nuclear staining and had a higher Ki-67 proliferation index. (141,142) No mutation was detected in the [beta]-catenin gene. (142)
Gene Expression Alterations: Protein-Coding RNAs.--Gene expression profiling with microarray-based technology has produced a long list of differentially expressed genes in PENs that may, in the future, lead to the identification of prognostic markers and therapeutic targets. (143-146) One study has suggested Serpine10 and BIN1 as potential markers and BST2 and LCK as potential therapeutic molecular targets. (146) Another study has compared benign and metastatic PENs and has identified differentially expressed genes involved in pathways related to angiogenesis and remodeling, signal transduction through tyrosine kinases, calcium-dependent cell signaling, and response to drugs. (145) A third study with 19 PENs has suggested the existence of "benign" and "malignant" clusters, corresponding to the WHO categories of well-differentiated endocrine tumor and well-differentiated endocrine carcinoma, respectively. Moreover, because the platelet-derived growth factor receptor [beta] (PDGFR-[beta]) is in the active, phosphorylated state in 83% of all PENs, it has been suggested as a candidate therapeutic target. (147)
Several studies have addressed the analysis of expression levels of particular genes in PENs. Some factors like VEGF-C, MAGE-1, P27/KIP1, thrombomodulin, and SRC kinases have been described as being involved in metastatic spread of PEN, thus suggesting new therapeutic approaches. (47,148-150) Other molecules recently proposed as possible targets for novel therapies of PENs are CDK4, PDGFR-[beta], CLDN3, and CXCL-12. (151-154) Finally, the expression of ARHI seems to be a prognostic factor for disease outcome in pancreatic endocrine neoplasms, (155) whereas expression of clusterin, ghrelin receptor, utrophin, and cyclin D1 do not relate to tumor aggressiveness. (156-158)
Gene Expression Alterations: Regulatory MicroRNAs. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies. (110) An investigation of global microRNA expression patterns in normal pancreas, PENs, and acinar cell carcinomas showed that a particular pattern of microRNA expression distinguishes PEN from normal pancreas and acinar carcinoma, suggesting that this set of microRNAs might be involved in PEN tumorigenesis. This study also showed that miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin and that the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and the presence of liver metastases. These results suggest that alteration in microRNA expression is related to endocrine neoplastic transformation and progression of malignancy and might prove useful in distinguishing tumors with different clinical behavior. (159)
An accurate pathology report must include the necessary information to allow a correct classification, staging, and grading of the disease for prognostic evaluation, which will drive therapeutic choices.
At variance with many other tumor types, the genes and pathways involved in hereditary neoplastic syndromes, whose spectrum comprise PENs, do not seem to be involved in the genesis of the sporadic PENs. The exception is MEN1 gene inactivation. The degree of genomic instability, as measured by the number of chromosomal anomalies or changes in DNA copy number, correlates with the aggressiveness of the neoplasm.
The differentially expressed genes on the lists produced by expression profiling studies are pieces of the fascinating puzzle of PEN pathogenesis, a puzzle that awaits the discovery of keystone findings to be constructed.
Supported by the European Community Grant FP6 MolDiagPaca and by the Fondazione Cariverona, Verona, Italy.
Accepted for publication November 13, 2008.
(1.) Heitz PU, Komminoth P, Perren A, et al. Pancreatic endocrine tumours. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004.World Health Organization Classification of Tumours.
(2.) Hruban RH, Bishop Pitman M, Klimstra DS. Endocrine neoplasms. In: Silverberg SG, Sobin LH, eds. Tumors of the Pancreas. Vol 6. Washington, DC: Armed Forces Institute of Pathology; 2007:251-304.
(3.) Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. 2005;19:753-781.
(4.) Falconi M, Plockinger U, Kwekkeboom DJ, et al. Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology. 2006;84:196-211.
(5.) Vagefi PA, Razo O, Deshpande V, et al. Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. Arch Surg. 2007;142:347-354.
(6.) Lamberts SW, Bakker WH, Reubi JC, Krenning EP. Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med. 1990;323:1246-1249.
(7.) Reubi JC, Krenning E, Lamberts SW, Kvols L. Somatostatin receptors in malignant tissues. J Steroid Biochem Mol Biol. 1990;37:1073-1077.
(8.) O'Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. Eur J Surg Oncol. 2008;34:324-332.
(9.) Fitzgerald TL, Smith AJ, Ryan M, et al. Surgical treatment of incidentally identified pancreatic masses. Can J Surg. 2003;46:413-418.
(10.) Winter JM, Cameron JL, Lillemoe KD, et al. Periampullary and pancreatic incidentaloma: a single institution's experience with an increasingly common diagnosis [discussion in: Ann Surg. 2006;243:680-683]. Ann Surg. 2006;243:673-680.
(11.) Bruzoni M, Johnston E, Sasson AR. Pancreatic incidentalomas: clinical and pathologic spectrum [discussion in: Am J Surg. 2008;195:332]. Am J Surg. 2008; 195:329-332.
(12.) Anlauf M, Garbrecht N, Henopp T, et al. Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features. World J Gastroenterol. 2006;12:5440-5446.
(13.) de Herder WW, Niederle B, Scoazec JY, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84:183-188.
(14.) Jensen RT, Niederle B, Mitry E, et al. Gastrinoma (duodenal and pancreatic). Neuroendocrinology. 2006;84:173-182.
(15.) O'Toole D, Salazar R, Falconi M, et al. Rare functioning pancreatic endocrine tumors. Neuroendocrinology. 2006;84:189-195.
(16.) Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol. 2002;20:2633-2642.
(17.) Gullo L, Migliori M, Falconi M, et al. Nonfunctioning pancreatic endocrine tumors: a multicenter clinical study. Am J Gastroenterol. 2003;98:2435-2439.
(18.) Bettini R, Boninsegna L, MantovaniW, et al. Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours. Ann Oncol. 2008;19:903-908.
(19.) Kloppel G, Rindi G, Anlauf M, Perren A, Komminoth P. Site-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors. Virchows Arch. 2007;451(suppl 1):9S-27S.
(20.) Iacono C, Serio G, Fugazzola C, et al. Cystic islet cell tumors of the pancreas: a clinico-pathological report of two nonfunctioning cases and review of the literature. Int J Pancreatol. 1992;11:199-208.
(21.) Ligneau B, Lombard-Bohas C, Partensky C, et al. Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases. Am J Surg Pathol. 2001;25:752-760.
(22.) Kosmahl M, Pauser U, Peters K, et al. Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Arch. 2004;445:168-178.
(23.) Bordeianou L, Vagefi PA, Sahani D, et al. Cystic pancreatic endocrine neoplasms: a distinct tumor type? J Am Coll Surg. 2008;206:1154-1158.
(24.) Smith AE, Levi AW, Nadasdy T, Campbell KA, Fishman EK, Hruban RH. The pigmented "black" neuroendocrine tumor of the pancreas: a question of origin. Cancer. 2001;92:1984-1991.
(25.) Singh R, Basturk O, Klimstra DS, et al. Lipid-rich variant of pancreatic endocrine neoplasms. Am J Surg Pathol. 2006;30:194-200.
(26.) Shimizu K, Shiratori K, Toki F, et al. Nonfunctioning islet cell tumor with a unique pattern of tumor growth. Dig Dis Sci. 1999;44:547-551.
(27.) Kitami CE, Shimizu T, Sato O, et al. Malignant islet cell tumor projecting into the main pancreatic duct. J Hepatobiliary Pancreat Surg. 2000;7:529-533.
(28.) Akatsu T, Wakabayashi G, Aiura K, et al. Intraductal growth of a nonfunctioning endocrine tumor of the pancreas. J Gastroenterol. 2004;39:584-588.
(29.) Kawakami H, Kuwatani M, Hirano S, et al. Pancreatic endocrine tumors with intraductal growth into the main pancreatic duct and tumor thrombus within the portal vein: a case report and review of the literature. Intern Med. 2007;46: 273-277.
(30.) Heller SJ, Ferrari AP, Carr-Locke DL, Lichtenstein DR, Van Dam J, Banks PA. Pancreatic duct stricture caused by islet cell tumors. Am J Gastroenterol. 1996;91:147-149.
(31.) Powell AC, Hajdu CH, Megibow AJ, Shamamian P. Nonfunctioning pancreatic endocrine neoplasm presenting as asymptomatic, isolated pancreatic duct stricture: a case report and review of the literature. Am Surg. 2008;74:168-171.
(32.) Klimstra DS, Perren A, Oberg K, Komminoth P, Bordi C. Non-functioning tumours and microadenomas. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours.
(33.) Anlauf M, Schlenger R, Perren A, et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol. 2006;30:560-574.
(34.) Zee SY, Hochwald SN, Conlon KC, Brennan MF, Klimstra DS. Pleomorphic pancreatic endocrine neoplasms: a variant commonly confused with adenocarcinoma. Am J Surg Pathol. 2005;29:1194-2000.
(35.) Wiedenmann B, Franke WW, Kuhn C, Moll R, Gould VE. Synaptophysin: a marker protein for neuroendocrine cells and neoplasms. Proc Natl Acad Sci U S A. 1986;83:3500-3504.
(36.) Lloyd RV, Mervak T, Schmidt K,Warner TF,Wilson BS. Immunohistochemical detection of chromogranin and neuron-specific enolase in pancreatic endocrine neoplasms. Am J Surg Pathol. 1984;8:607-614.
(37.) Bishop AE, Polak JM, Facer P, Ferri GL, Marangos PJ, Pearse AG. Neuron specific enolase: a common marker for the endocrine cells and innervation of the gut and pancreas. Gastroenterology. 1982;83:902-915.
(38.) Rode J, Dhillon AP, Doran JF, Jackson P, Thompson RJ. PGP 9.5, a new marker for human neuroendocrine tumours. Histopathology. 1985;9:147-158.
(39.) Eriksson B, Arnberg H, Lindgren PG, et al. Neuroendocrine pancreatic tumours: clinical presentation, biochemical and histopathological findings in 84 patients. J Intern Med. 1990;228:103-113.
(40.) Dixon E, Pasieka JL. Functioning and nonfunctioning neuroendocrine tumors of the pancreas. Curr Opin Oncol. 2007;19:30-35.
(41.) Hoefler H, Denk H, Lackinger E, Helleis G, Polak JM, Heitz PU. Immunocytochemical demonstration of intermediate filament cytoskeleton proteins in human endocrine tissues and (neuro-) endocrine tumours. Virchows ArchA Pathol Anat Histopathol. 1986;409:609-626.
(42.) El-Bahrawy MA, Rowan A, Horncastle D, et al. E-cadherin/catenin complex status in solid pseudopapillary tumor of the pancreas. Am J Surg Pathol. 2008;32:1-7.
(43.) Klimstra DS, Rosai J, Heffess CS. Mixed acinar-endocrine carcinomas of the pancreas. Am J Surg Pathol. 1994;18:765-778.
(44.) Yantiss RK, Chang HK, Farraye FA, Compton CC, Odze RD. Prevalence and prognostic significance of acinar cell differentiation in pancreatic endocrine tumors. Am J Surg Pathol. 2002;26:893-901.
(45.) Kamisawa T, Tu Y, Egawa N, et al. Ductal and acinar differentiation in pancreatic endocrine tumors. Dig Dis Sci. 2002;47:2254-2261.
(46.) Ohike N, Morohoshi T. Immunohistochemical analysis of cyclooxygenase (COX)-2 expression in pancreatic endocrine tumors: association with tumor progression and proliferation. Pathol Int. 2001;51:770-777.
(47.) Rahman A, Maitra A, Ashfaq R, Yeo CJ, Cameron JL, Hansel DE. Loss of p27 nuclear expression in a prognostically favorable subset of well-differentiated pancreatic endocrine neoplasms. Am J Clin Pathol. 2003;120:685-690.
(48.) Ali A, Serra S, Asa SL, Chetty R. The predictive value of CK19 and CD99 in pancreatic endocrine tumors. Am J Surg Pathol. 2006;30:1588-1594.
(49.) Viale G, Doglioni C, Gambacorta M, Zamboni G, Coggi G, Bordi C. Progesterone receptor immunoreactivity in pancreatic endocrine tumors: an immunocytochemical study of 156 neuroendocrine tumors of the pancreas, gastrointestinal and respiratory tracts, and skin. Cancer. 1992;70:2268-2277.
(50.) Canavese G, Azzoni C, Pizzi S, et al. p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior. Hum Pathol. 2001;32:1094-1101.
(51.) Guo SS, Wu X, Shimoide AT, Wong J, Sawicki MP. Anomalous overexpression of p27(Kip1) in sporadic pancreatic endocrine tumors. J Surg Res. 2001; 96:284-288.
(52.) La Rosa S, Rigoli E, Uccella S, Novario R, Capella C. Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours. Histopathology. 2007;50:597-606.
(53.) Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol. 2004;28:1145-1153.
(54.) Schmitt AM, Anlauf M, Rousson V, et al. WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors. Am J Surg Pathol. 2007;31:1677-1682.
(55.) Pelosi G, Bresaola E, Bogina G, et al. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Hum Pathol. 1996;27:1124-1134.
(56.) Ordonez NG. Pancreatic acinar cell carcinoma. Adv Anat Pathol. 2001;8: 144-159.
(57.) Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar cell carcinoma of the pancreas: a clinicopathologic study of 28 cases. Am J Surg Pathol. 1992;16:815-837.
(58.) Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma: a clinicopathologic study and review of the literature. Am J Surg Pathol. 1995;19:1371-1389.
(59.) Klimstra DS, Wenig BM, Heffess CS. Solid-pseudopapillary tumor of the pancreas: a typically cystic carcinoma of low malignant potential. Semin Diagn Pathol. 2000;17:66-80.
(60.) Kloppel G, Solcia E, Longnecker DS, Capella C, Sobin L. Histological Typing of Tumours of the Exocrine Pancreas. 2nd ed. Berlin, Germany: SpringerVerlag; 1996. World Health Organization International Histological Classification of Tumours.
(61.) Perez-Ordonez B, Naseem A, Lieberman PH, Klimstra DS. Solid serous adenoma of the pancreas: the solid variant of serous cystadenoma? Am J Surg Pathol. 1996;20:1401-1405.
(62.) Machado MC, Machado MA. Solid serous adenoma of the pancreas: an uncommon but important entity. Eur J Surg Oncol. 2008;34:730-733.
(63.) Zamboni G, Pea M, Martignoni G, et al. Clear cell "sugar" tumor of the pancreas: a novel member of the family of lesions characterized by the presence of perivascular epithelioid cells. Am J Surg Pathol. 1996;20:722-730.
(64.) Tsukada A, Ishizaki Y, Nobukawa B, Kawasaki S. Paraganglioma of the pancreas: a case report and review of the literature. Pancreas. 2008;36:214-216.
(65.) Adsay NV, Andea A, Basturk O, Kilinc N, Nassar H, Cheng JD. Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature. Virchows Arch. 2004;444:527-535.
(66.) Thompson LD, Heffess CS. Renal cell carcinoma to the pancreas in surgical pathology material. Cancer. 2000;89:1076-1088.
(67.) Bassi C, Butturini G, Falconi M, Sargenti M, Mantovani W, Pederzoli P. High recurrence rate after atypical resection for pancreatic metastases from renal cell carcinoma. Br J Surg. 2003;90:555-559.
(68.) Zerbi A, Ortolano E, Balzano G, Borri A, Beneduce AA, Di Carlo V. Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection? Ann Surg Oncol. 2008;15:1161-1168.
(69.) Adsay V, Logani S, Sarkar F, Crissman J,VaitkeviciusV. Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant. Am J Surg Pathol. 2000;24:493-504.
(70.) Ray S, Lu Z, Rajendiran S. Clear cell ductal adenocarcinoma of pancreas: a case report and review of the literature. Arch Pathol Lab Med. 2004;128:693-696.
(71.) Luttges J, Vogel I, Menke M, Henne-Bruns D, Kremer B, Kloppel G. Clear cell carcinoma of the pancreas: an adenocarcinoma with ductal phenotype. Histopathology. 1998;32:444-448.
(72.) Albores-Saavedra J, Simpson KW, Bilello SJ. The clear cell variant of solid pseudopapillary tumor of the pancreas: a previously unrecognized pancreatic neoplasm. Am J Surg Pathol. 2006;30:1237-1242.
(73.) Ekfors TO, Kujari H, Isomaki M. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) in the duodenum: the first visceral case. Histopathology. 1993;22:255-259.
(74.) Gotchall J, Traweek ST, Stenzel P. Benign oncocytic endocrine tumor of the pancreas in a patient with polyarteritis nodosa. Hum Pathol. 1987;18:967-969.
(75.) Taniguchi K, Tomioka T, Komuta K, et al. Pleomorphic nonfunctioning islet cell tumor of the pancreas. Int J Pancreatol. 1995;17:83-89.
(76.) Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the "rhabdoid" inclusions seen in pancreatic endocrine neoplasms. Am J Surg Pathol. 2004;28:271-273.
(77.) Nappi O, Ferrara G, Wick MR. Neoplasms composed of eosinophilic polygonal cells: an overview with consideration of different cytomorphologic patterns. Semin Diagn Pathol. 1999;16:82-90.
(78.) Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with 'rhabdoid' features. Am J Surg Pathol. 2003;27:642-649.
(79.) Nishihara K, Katsumoto F, Kurokawa Y, Toyoshima S, Takeda S, Abe R. Anaplastic carcinoma showing rhabdoid features combined with mucinous cystadenocarcinoma of the pancreas. Arch Pathol Lab Med. 1997;121:1104-1107.
(80.) Kuroda N, Sawada T, Miyazaki E, et al. Anaplastic carcinoma of the pancreas with rhabdoid features. Pathol Int. 2000;50:57-62.
(81.) Adsay NV. Cystic neoplasia of the pancreas: pathology and biology. J Gastrointest Surg. 2008;12:401-404.
(82.) Reid JD, Yuh SL, Petrelli M, Jaffe R. Ductuloinsular tumors of the pancreas: a light, electron microscopic and immunohistochemical study. Cancer. 1982;49: 908-915.
(83.) van Eeden S, de Leng WW, Offerhaus GJ, et al. Ductuloinsular tumors of the pancreas: endocrine tumors with entrapped nonneoplastic ductules. Am J Surg Pathol. 2004;28:813-820.
(84.) Nguyen GK, Rayani NA. Hyperplastic and neoplastic endocrine cells of the pancreas in aspiration biopsy. Diagn Cytopathol. 1986;2:204-211.
(85.) Phan GQ, Yeo CJ, Hruban RH, Lillemoe KD, Pitt HA, Cameron JL. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. 1998;2:472-482.
(86.) Capella C, Heitz PU, Hofler H, Solcia E, Kloppel G. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch. 1995; 425:547-560.
(87.) Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer. 2005;12:1083-1092.
(88.) Heymann MF, Joubert M, Nemeth J, et al. Prognostic and immunohistochemical validation of the Capella classification of pancreatic neuroendocrine tumours: an analysis of 82 sporadic cases. Histopathology. 2000;36:421-432.
(89.) La Rosa S, Sessa F, Capella C, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Arch. 1996;429:323-333.
(90.) Ferrone CR, Tang LH, Tomlinson J, et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J Clin Oncol. 2007;25:5609-5615.
(91.) Artale S, Giannetta L, Cerea G, et al. Treatment of metastatic neuroendocrine carcinomas based on WHO classification. Anticancer Res. 2005;25:4463-4469.
(92.) Bajetta E, Catena L, Procopio G, et al. Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? Ann Oncol. 2005;16:1374-1380.
(93.) Fischer L, Kleeff J, Esposito I, et al. Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas. Br J Surg. 2008;95:627-635.
(94.) Panzuto F, Di Fonzo M, Iannicelli E, et al. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol. 2006;17:461-466.
(95.) Schindl M, Kaczirek K, Kaserer K, Niederle B. Is the new classification of neuroendocrine pancreatic tumors of clinical help? World J Surg. 2000;24:1312-1318.
(96.) Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395-401.
(97.) Pape UF, Jann H, Muller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer. 2008;113:256-265.
(98.) Butturini G, Bettini R, Missiaglia E, et al. Predictive factors of efficacy of the somatostatin analogue octreotide as first line therapy for advanced pancreatic endocrine carcinoma. Endocr Relat Cancer. 2006;13:1213-1221.
(99.) Aparicio T, Ducreux M, Baudin E, et al. Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer. 2001; 37:1014-1019.
(100.) Calender A, Morrison C, Komminoth P, Scoazec K, Sweet K, Teh B. Multiple endocrine neoplasia type 1. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC press; 2004. World Health Organization Classification of Tumours.
(101.) Anlauf M, Garbrecht N, Bauersfeld J, et al. Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Archiv. 2007;451:S29-S38.
(102.) Perren A, Anlauf M, Henopp T, et al. Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas. J Clin Endocrinol Metab. 2007;92:1118-1128.
(103.) Maher E, Nathanson K, Komminoth P, et al. von Hippel-Lindau syndrome (VHL). In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours.
(104.) Paltoglou S, Roberts BJ. HIF-1alpha and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases. Oncogene. 2007;26:604-609.
(105.) Hoang MP, Hruban RH, Albores-Saavedra J. Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel-Lindau disease. Am J Surg Pathol. 2001;25:602-609.
(106.) Evans D, Komminoth P, Scheithauer B, Peltonen J. Neurofibromatosis type 1. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC; 2004. World Health Organization Classification of Tumours.
(107.) Fujisawa T, Osuga T, Maeda M, et al. Malignant endocrine tumor of the pancreas associated with von Recklinghausen's disease. J Gastroenterol. 2002; 37:59-67.
(108.) Perren A, Wiesli P, Schmid S, et al. Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient. Am J Surg Pathol. 2006;30:1047-1051.
(109.) Jozwiak J, Jozwiak S, Wlodarski P. Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol. 2008;9:73-79.
(110.) Barbarotto E, Schmittgen T, Calin G. MicroRNAs and cancer: profile, profile, profile. Int J Cancer. 2008;122:969-977.
(111.) Chung DC, Brown SB, Graeme-Cook F, et al. Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res. 1998;58:3706-3711.
(112.) Nagano Y, Kim do H, Zhang L, et al. Allelic alterations in pancreatic endocrine tumors identified by genome-wide single nucleotide polymorphism analysis. Endocr Relat Cancer. 2007;14:483-492.
(113.) Rigaud G, Missiaglia E, Moore PS, et al. High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications. Cancer Res. 2001;61:285-292.
(114.) Jonkers YM, Claessen SM, Perren A, et al. DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients. Endocr Relat Cancer. 2007;14:769-779.
(115.) Zhao J, de Krijger RR, Meier D, et al. Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids): marked differences indicating diversity in molecular pathogenesis. Am J Pathol. 2000;157:1431-1438.
(116.) Stumpf E, Aalto Y, Hoog A, et al. Chromosomal alterations in human pancreatic endocrine tumors. Genes Chromosomes Cancer. 2000;29:83-87.
(117.) Speel EJ, Richter J, Moch H, et al. Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol. 1999;155:1787-1794.
(118.) Speel EJ, Scheidweiler AF, Zhao J, et al. Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: gain of 9Q34 is an early event in insulinomas. Cancer Res. 2001;61:5186-5192.
(119.) Missiaglia E, Moore PS, Williamson J, et al. Sex chromosome anomalies in pancreatic endocrine tumors. Int J Cancer. 2002;98:532-538.
(120.) Arnold CN, Sosnowski A, Schmitt-Graff A, Arnold R, Blum HE. Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-enteropancreatic system. Int J Cancer. 2007;120:2157-2164.
(121.) House MG, Herman JG, Guo MZ, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms [discussion in: Ann Surg. 2003;238:431-432]. Ann Surg. 2003;238:423-431.
(122.) Wild A, Ramaswamy A, Langer P, et al. Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumors. J Clin Endocrinol Metab. 2003;88:1367-1373.
(123.) Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet. 2000;25:315-319.
(124.) Liu L, Broaddus RR, Yao JC, et al. Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Mod Pathol. 2005;18:1632-1640.
(125.) Pizzi S, Azzoni C, Bottarelli L, et al. RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. J Pathol. 2005;206:409-416.
(126.) Liu L, Guo C, Dammann R, Tommasi S, Pfeifer GP. RASSF1A interacts with and activates the mitotic kinase Aurora-A. Oncogene. 2008;27:6175-6186.
(127.) Choi IS, Estecio MR, Nagano Y, et al. Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors). Mod Pathol. 2007;20:802-810.
(128.) Cecconi D, Donadelli M, Rinalducci S, et al. Proteomic analysis of pancreatic endocrine tumor cell lines treated with the histone deacetylase inhibitor trichostatin A. Proteomics. 2007;7:1644-1653.
(129.) Moore PS, Missiaglia E, Antonello D, et al. Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes Chromosomes Cancer. 2001;32:177-181.
(130.) Vortmeyer AO, Huang S, Lubensky I, Zhuang Z. Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab. 2004;89:1934-1938.
(131.) Gortz B, Roth J, Krahenmann A, et al. Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. Am J Pathol. 1999;154:429-436.
(132.) Yu F, Jensen RT, Lubensky IA, et al. Survey of genetic alterations in gastrinomas. Cancer Res. 2000;60:5536-5542.
(133.) Goebel SU, Heppner C, Burns AL, et al. Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. J Clin Endocrinol Metab. 2000;85:116-123.
(134.) Karnik SK, Hughes CM, Gu X, et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci U S A. 2005;102:14659-14664.
(135.) Fontaniere S, Tost J, Wierinckx A, et al. Gene expression profiling in insulinomas of Men1 beta-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic beta-cell tumorigenesis. Endocr Relat Cancer. 2006; 13:1223-1236.
(136.) Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A. A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest. 1997;100:404-410.
(137.) Serrano J, Goebel SU, Peghini PL, Lubensky IA, Gibril F, Jensen RT. Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas. J Clin Endocrinol Metab. 2000;85:4146-4156.
(138.) Lohmann DR, Funk A, Niedermeyer HP, Haupel S, Hofler H. Identification of p53 gene mutations in gastrointestinal and pancreatic carcinoids by nonradioisotopic SSCA. Virchows Arch B Cell Pathol Incl Mol Pathol. 1993;64:293-296.
(139.) Komminoth P, Roth J, Muletta-Feurer S, Saremaslani P, Seelentag WK, Heitz PU. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab. 1996;81:2041-2046.
(140.) Beghelli S, Pelosi G, Zamboni G, et al. Pancreatic endocrine tumours: evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p. J Pathol. 1998;186:41-50.
(141.) Chetty R, Serra S, Asa SL. Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors. Am J Surg Pathol. 2008;32:413-419.
(142.) Hervieu V, Lepinasse F, Gouysse G, et al. Expression of beta-catenin in gastroenteropancreatic endocrine tumours: a study of 229 cases. J Clin Pathol. 2006;59:1300-1304.
(143.) Maitra A, Hansel DE, Argani P, et al. Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clin Cancer Res. 2003;9:5988-5995.
(144.) Hansel DE, Rahman A, House M, et al. Met proto-oncogene and insulinlike growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin Cancer Res. 2004;10:6152-6158.
(145.) Couvelard A, Hu J, Steers G, et al. Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors. Gastroenterology. 2006;131:1597-1610.
(146.) Capurso G, Lattimore S, Crnogorac-Jurcevic T, et al. Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr Relat Cancer. 2006;13:541-558.
(147.) Duerr EM, Mizukami Y, Ng A, et al. Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. Endocr Relat Cancer. 2008;15:243-256.
(148.) Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene. 2000;19: 5598-5605.
(149.) Hansel DE, House MG, Ashfaq R, Rahman A, Yeo CJ, Maitra A. MAGE1 is expressed by a subset of pancreatic endocrine neoplasms and associated lymph node and liver metastases. Int J Gastrointest Cancer. 2003;33:141-147.
(150.) Di Florio A, Capurso G, Milione M, et al. Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells. Endocr Relat Cancer. 2007;14:111-124.
(151.) Takahashi Y, Akishima-Fukasawa Y, Kobayashi N, et al. Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumors. Clin Cancer Res. 2007; 13:187-196.
(152.) Borka K, Kaliszky P, Szabo E, et al. Claudin expression in pancreatic endocrine tumors as compared with ductal adenocarcinomas. Virchows Arch. 2007;450:549-557.
(153.) Fjallskog ML, Hessman O, Eriksson B, Janson ET. Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas. Acta Oncol. 2007;46:741-746.
(154.) Lindberg D, Hessman O, Akerstrom G, Westin G. Cyclin-dependent kinase 4 (CDK4) expression in pancreatic endocrine tumors. Neuroendocrinology. 2007;86:112-118.
(155.) Dalai I, Missiaglia E, Barbi S, et al. Low expression of ARHI is associated with shorter progression-free survival in pancreatic endocrine tumors. Neoplasia. 2007;9:181-183.
(156.) Ekeblad S, Lejonklou MH, Grimfjard P, et al. Co-expression of ghrelin and its receptor in pancreatic endocrine tumours. Clin Endocrinol (Oxf). 2007; 66:115-122.
(157.) Mourra N, Couvelard A, Tiret E, Olschwang S, Flejou JF. Clusterin is highly expressed in pancreatic endocrine tumours but not in solid pseudopapillary tumours. Histopathology. 2007;50:331-337.
(158.) Chang MC, Xiao S, Nose V. Clinicopathologic and immunohistochemical correlation in sporadic pancreatic endocrine tumors: possible roles of utrophin and cyclin D1 in malignant progression. Hum Pathol. 2007;38:732-740.
(159.) Roldo C, Missiaglia E, Hagan JP, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24:4677-4684.
(160.) Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13-27.
(161.) Alexakis N, Neoptolemos JP. Pancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2008;22:183-205.
(162.) Komminoth P, Perren A, Oberg K, et al. Gastrinoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours.
(163.) Lechago J, Speel EJ, Perren A, Papotti M. VIPoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours.
(164.) Dayal Y, Oberg K, Perren A, Komminoth P. Somatostatinoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours.
(165.) Osamura RY, Oberg K, Perren A. ACTH and other ectopic hormone producing tumours. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004.World Health Organization Classification of Tumours.
(166.) Osamura RY, Oberg K, Speel EJ,Volante M, Perren A. Serotonin-sectreting tumour. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours.
Paola Capelli, MD; Guido Martignoni, MD; Federica Pedica, MD; Massimo Falconi, MD; Davide Antonello, PhD; Giorgio Malpeli, PhD; Aldo Scarpa, MD, PhD
From the Departments of Pathology (Drs Capelli, Martignoni, Pedica, Antonello, and Scarpa) and Surgical and Gastroenterological Sciences (Drs Falconi and Malpeli), University of Verona, Verona, Italy.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Paola Capelli, MD, Department of Pathology, Section of Anatomical Pathology, Policlinico G. B. Rossi, 37134 Verona, Italy (e-mail: firstname.lastname@example.org).
Table 1. Main Clinicopathologic Characteristics of Functioning Pancreatic Endocrine Neoplasms (PENs) Insulinoma (2,13,19,160,161) Hypoglycemic syndrome: confusion, behavioral changes, blurred vision, fatigue, seizures, coma Most common F-PEN Solitary in 95% of cases (<2 cm in size in >80% of cases) 5%-10% in MEN-1, usually multiple (40%-90%) Surgical resection is the treatment of choice; enucleation is sufficient in most cases Benign in 90% of cases; most of the malignant cases occur in the older age group Gastrinoma (2,12,14,19,161,162) "Zollinger-Ellison syndrome": peptic ulcer disease, gastroesophageal reflux disease, diarrhea Second most common F-PEN Located in the "gastrinoma triangle" (common bile duct, duodenal and pancreatic head area) Pancreas is the less common site, the duodenum is affected in >50% of sporadic cases and >90% of hereditary cases 20%-30% in MEN-1, where it is the most common functional pancreatico-duodenal endocrine neoplasm Malignant in about 80% of cases, with liver metastasis more frequent in pancreatic gastrinomas 10-y survival rate of approximately 50% and >90% in absence of liver metastasis Glucagonoma (2,15,19,160,161) "4Ds disease": diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis, depression Solitary, large Most frequent in the tail More than 50% have liver metastases at presentation VIPoma (2,15,19,161,163) Verner-Morrison syndrome: watery diarrhea, hypokalemia, and achlorhydria/hypochlorhydria Solitary, large Most frequent in the tail of the pancreas Somatostatinoma (2,15,19,161,164) Diabetes mellitus, diarrhea or steatorrhea, anemia, malabsorption, and cholelithiasis Very rare Solitary, usually large (>4 cm) More than 50% have liver metastases at presentation 5-y survival rate is about 60% Ectopic hormone-producing PEN (2,15,19,161,165,166) Adrenocorticotropic hormone (Cushing syndrome), serotonin (atypical carcinoid syndrome), growth hormone Releasing factor (acromegaly), parathyroid hormone (paraneoplastic hypercalcemia) Usually malignant Solitary, generally large Abbreviations: F-PEN, functioning pancreatic endocrine neoplasm; MEN-1, multiple endocrine neoplasia type 1. Table 2. World Health Organization Classification of Pancreatic Endocrine Neoplasms (a) Well-Differentiated Endocrine Tumor Confined to the Pancreas Benign behavior No angioinvasion No perineural invasion <2 cm in size <2 mitoses/10 HPFs <2% Ki-67 Uncertain behavior Angioinvasion and/or Perineural invasion and/or [greater than or equal to] 2cm in size and/or 2-10 mitoses/10 HPFs and/or [greater than or equal to] 2% Ki-67 Well-Differentiated Endocrine Carcinoma Low-grade malignancy Gross local invasion and/or metastases Poorly Differentiated Endocrine Carcinoma High-grade malignancy >10 mitoses/10 HPFs Abbreviation: HPFs, high-power fields. (a) Data from Calender et al. (100) Table 3. TNM Classification and Staging Proposed by the European Neuroendocrine Tumor Society (a) T--Primary Tumor Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor limited to the pancreas and size <2 cm T2 Tumor limited to the pancreas and size 2-4 cm T3 Tumor limited to the pancreas and size >4 cm or invading duodenum or bile duct T4 Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland, or the wall of large vessels) N--Regional Lymph Nodes Nx Regional lymph node cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases M--Distant Metastases Mx Distant metastases cannot be assessed M0 No distant metastases M1 Distant metastases TNM Stage Groupings Stage I T1 N0 M0 Stage IIA T2 N0 M0 Stage IIB T3 N0 M0 Stage IIIA T4 N0 M0 Stage IIIB Any T N1 M0 Stage IV Any T Any N M1 (a) Data from Rindi et al. (96) Table 4. Grading System Proposed by the European Neuroendocrine Tumor Society (a) Mitotic Count/10 HPFs Ki-67 Index, % G1 <2 [less than or equal to] 2 G2 2-20 3-20 G3 >20 >20 Abbreviation: HPFs, high-power fields. (a) Data from Rindi et al. (96)
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|Author:||Capelli, Paola; Martignoni, Guido; Pedica, Federica; Falconi, Massimo; Antonello, Davide; Malpeli, G|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Mar 1, 2009|
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