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Neoplasms of the Neuroendocrine Pancreas

An Update in the Classification, Definition, and Molecular Genetic Advances

Guilmette, Julie M., MD; Nosé, Vania, MD, PhD

Advances in Anatomic Pathology: January 2019 - Volume 26 - Issue 1 - p 13–30
doi: 10.1097/PAP.0000000000000201
Review Articles

This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of “well-differentiated high-grade NET (G3)” to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.

Departments of Pathology, Massachusetts General Hospital, Boston, MA

The authors have no conflicts of interest to disclose.

Reprints: Vania Nosé, MD, PhD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (e-mail: vnose@mgh.harvard.edu).All figures can be viewed online in color at www.anatomicpathology.com.

Neoplasms of the neuroendocrine pancrea (panNEN) are a rare group of neuroendocrine tumors, arising from the precursor cells in the ductal epithelium of the pancreas.1 PanNEN comprises about 1% to 2% of all clinically detected pancreatic tumors, reaching an incidence of 0.43 per 100,000 people per year in the United States.2,3 Over the last decades, the panNEN incidence is undergoing a persistent increase due to the early detection of localized and asymptomatic tumors made possible by highly sensitive and specific imaging modalities.4,5 Although >90% of panNEN are sporadic, few tumors can arise in the setting of hereditary genetic syndromes, most frequently multiple endocrine neoplasia type 1 (MEN1).6–9 Whether sporadic or syndrome-associated, panNEN initial presentation varies widely, with more than half of patients having distant metastatic disease at the time of diagnosis. PanNENs capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes, are known as functioning panNEN. Nonfunctioning (N-F) panNEN may secrete peptide hormones and other biogenic substances, but at levels insufficient to cause symptoms. On a diagnostic standpoint, the 2017 WHO classification and grading of pancreatic neuroendocrine neoplasms now separates panNEN into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), while adding a new subcategory of “well-differentiated high-grade NET (G3)” to the well-differentiated NET category. The purpose of this new classification is to improve the prediction of clinical outcomes and determines better therapeutic strategies and patient care.10 Even with advanced multimodality therapies, surgical resection of the tumor remains the cornerstone of therapy and the only curative treatment. Curative surgical approach should be pursued for localized neoplasms and for metastatic disease amenable to resection.

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UPDATES ON CLASSIFICATION

In 2017, a new WHO classification: Tumors of Endocrine Organs and grading system has been proposed for pancreatic neuroendocrine tumors (Table 1). This new system simplifies the comparison and assessment of clinical, pathologic, prognostic features, and treatment options for panNENs.2,10,11

TABLE 1

TABLE 1

The 2017 WHO classification relies mainly on histopathologic criteria, including ki-67 proliferative index and mitotic index to predict the tumor’s grade and biological behavior (Table 2). Using this stratification system, panNENs are classified as well-differentiated NET and poorly differentiate NEC. In addition, well-differentiated NET is further subdivided into “well-differentiated low-grade NET (G1),” “well-differentiated intermediate-grade NET (G2),” or “well-differentiated high-grade NET (G3).”10

TABLE 2

TABLE 2

The integration of a new subcategory of a well-differentiated high-grade NET (G3) is based on recent publications. In regards to the previous WHO classification of panNEN, Basturk et al12 have reported some discordances between the mitotic rate and ki-67 index when evaluating G2 and G3 panNENs. These specific cases involved panNENs with a ki-67 index in the G3 range (>20%), but a mitotic rate in the G2 range (2 to 20 mitoses per 10 high-power fields). It has been found that panNENs with a ki-67 proliferative index >20%, if well-differentiated, are more aggressive than G2 but significantly less aggressive than NEC with poorly differentiated features, large or small cell type.12 In addition, poorly differentiated NEC are often associated to a worse biological behavior and rapid clinical progression, while well-differentiated NET generally have a better survival. Nevertheless, well-differentiated panNENs remain a heterogenous group with a variable spectrum of aggressive biological behavior. This new available data requested modification to the 2010 WHO classification for G3 NEC and promoted the emergence of 2 distinct categories: well-differentiated high-grade NET (G3) and poorly differentiated NEC.12–17

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Well-differentiated panNET (G1, G2, and G3)

Well-differentiated panNETs are usually slow-growing tumors with equal sex preference occurring over a broad age range, highest incidence peak between third and sixth decade. Clinically, these neoplasms present with variable symptoms related to their different clinical secretory syndromes, genetic syndromes or obstructive behaviors.18,19 All grades included, well-differentiated panNET accounts for >90% of pancreatic neuroendocrine neoplasia.20 These tumors can show a variety of gross appearances but are usually well-circumscribed neoplasms partially and completely surrounded by a thin capsule. Their color ranges from light yellow to reddish tan and may present with occasional cystic changes, and hemorrhage. Necrosis is uncommon in well-differentiated tumors (Fig. 1). These tumors demonstrate variable architectural patterns and wide cytomorphologic appearance both between and within tumors. The tumor may show solid, trabecular, gyriform, organoid, tubuloacinar or glandular growth patterns, with or without pseudorosettes formation and usually no associated necrosis (Fig. 2). The nuclei are relatively uniform and homogenous, featuring low-to-moderate atypia, with characteristic salt and pepper chromatin, and finely granular cytoplasm. The tumor cells also vary in shapes ranging from round polygonal to plasmacytoid and spindled. The underlying stroma can reveal areas of fibrosis and hyalinization and occasionally, can be richly vascularized. In slow-growing tumors, calcifications can be observed. In addition, amyloid deposits and psammoma bodies are sometimes encountered in insulinoma and somatostatinoma, respectively. Immunophenotypically, panNET stains with specific markers of general neuroendocrine differentiation, such as synaptophysin, chromogranin A, neuron-specific enolase (NSE), CD56, and CD57.1,11,18–25

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

The 2017 WHO classification grades well-differentiated NET based on their proliferative activity. PanNETs, graded as G1, have <2 mitoses per 10 high-power fields and a ki-67 proliferation index <3% (Fig. 3). PanNETs, graded as G2, have between 2 and 20 mitoses per 10 high-power fields or a ki-67 proliferation index ranging between 3% and 20%. Finally, panNETs, graded as G3, present with >20 mitoses per 10 high-power fields or a ki-67 proliferation index >20% and do not present poorly differentiated small cell or large cell features (Fig. 4).10,16,26,27

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

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Molecular of Well-differentiated panNETs

Molecular analysis of panNET G1 and G2 has revealed several genetic alterations with MEN1, DAXX, and ATRX, being the most common somatic inactivating mutations in these tumors.28–30 MEN1 genetic mutation can be inherited as part of MEN1 syndrome; however, in >35% of cases, MEN1 mutation occurs as a somatic disorder.20,28,29 MEN1 gene encodes a protein, menin, a histone methyltransferase complex, which acts a tumor suppressor. Recent advances have shown that the tumor-suppressing pathway mediated by MEN1 is dependent on the Pi3K-Akt-mTOR pathway mediated by PHLDA3, a novel tumor suppressor gene that inhibits Akt activation. The inactivation of both PHLDA3 and MEN1 the emergence of panNET.31,32

Both DAXX (death-domain-associated protein) and ATRX (α thalassemia/mental retardation syndrome X-linked) genes encode proteins implicated in the chromatin remodeling at the telomeric and pericentromeric regions, with the unique function of incorporating the histone variant H3.3 at the telomeric ends of chromosomes. More than 45% of panNET have been found to have mutation in one of the 2 genes, strengthening the idea that these 2 genes are mutually exclusive and act as a DAXX/ATRX complex in the same molecular pathway.29 Thus, mutations in these encoding proteins result in alternative lengthening of the telomeres (ALT) phenotype and chromosomal instability. Although the ALT phenotype has been described in several different malignancies, certain cancer types have shown a specific correlation between ALT and tumor aggressiveness.29,30,33,34 Recent advances have shown that panNETs with somatic inactivating mutation in DAXX/ATRX gene acts as a potential independent prognostic factor and may be associated with an overall poor prognosis.28,33 Still, further research is needed to understand the function and association of DAXX/ATRX complex and tumor aggressiveness in panNETs.

Other less frequently encountered mutations, ∼15% of panNET, include PTEN, TSC2, TSC1, DEPDC5, and PIK3CA, which are parts of the mTOR (mammalian target of rapamycin) pathway.20,29,31,35–38 PTEN mutations are mutually exclusive with both TSC1 and TSC2 mutations, which encodes negative regulators of the mTOR pathway.20 DEPDC5, a recently discovered mutation in panNET, act as a tumor suppressor and appears to be mutually exclusive to PTEN and TSC2 mutations.20 These mutations are of significant clinical interest as these patients may be eligible for therapy with mTOR pathway inhibitors, which has been shown to improve the progression-free survival.29,32,36,39–42 In addition, these tumors often present with other genetic alterations, such as HIF1A, ATM, AKT1, and VHL mutations.35,38

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FUNCTIONING panNEN

PanNENs can also be classified based on their cell of origin as functioning or N-F tumors. Functioning panNENs abnormally secrete large amounts of peptide hormones and other bioactive compounds leading to hypersecretion clinical syndromes. N-F panNEN, as it names implies, may or may not secrete peptide hormones but at levels insufficient to cause clinical symptoms. Most functioning and N-F panNENs are graded as well-differentiated. Clinicians must be aware of the numerous presentations of these tumors, as the first step to management of these uncommon malignancies is to initially suspect the diagnosis.

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Insulinoma

Insulinomas are the most common functioning panNET and account for >35% to 40% of this category.2,43 They are composed of insulin-producing and proinsulin-producing β cells actively secreting large amount of insulin resulting in episodic hyperinsulinemia.2,10 These episodic hyperinsulinemias are referred to as Whipple’s triad. Clinically, patients present with various symptoms related to hypoglycemia, including: weakness, tremors, sweating, confusion, blurred vision, and palpitation, which occur during fasting or exercise. They have documented hypoglycemia at time of symptoms with plasma glucose levels <40 to 50 mg/dL. And, their symptoms are resolved with the administration of glucose administration.2,43–47 Other laboratory analysis is needed for the diagnosis of insulinoma, such as prolonged fasting (2 h) with blood glucose measurement, C-peptide, serum insulin and proinsulin.2,47 Insulinomas share the same morphologic and molecular features of panNET at the exception of stromal amyloid deposits, amylin, specific to insulinomas and insulin immunohistochemical labeling (Fig. 5).48 Most insulinomas, >90%, are benign and often cured by surgical resection.45 These benign insulinomas are usually well-differentiated, G1, panNETs with a ki-67 proliferative index <2% and confined to the pancreas. Malignant insulinomas are more often G2 panNETs with a greater ki-67 proliferative index and are characterized by local invasion, lymph node or liver metastasis.10,47,49 In addition to the proliferation index, the most important prognostic factors for panNETs is tumor size.50,51 Insulinomas <2 cm in largest diameter have a 10-year survival rate close to 100%; whereas, those >2 cm see their 10-year survival rate dropped to nearly 30%. Less than 10% of patients have metastasis, usually hepatic, at the time of diagnosis.46

FIGURE 5

FIGURE 5

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Glucagonoma

Glucagonoma is a rare pancreatic α-islet tumor and it accounts for up to 5% of panNETs making it the fourth most common functioning panNET, after insulinoma, gastrinoma, and VIPoma.44,52–54 Glucagonomas are well-differentiated panNETs composed of glucagon-producing cells secreting uncontrolled quantities of glucagon in the bloodstream resulting in the glucagonoma syndrome. This syndrome is characterized by clinical triad featuring necrolytic migratory erythema (NME), diabetes mellitus, and weight loss.53,55–57 NME, a zinc deficiency dermatosis, is often the hallmark initial presenting symptom of this disorder and is characterized by histologic necrolysis of the upper epidermis with vacuolated keratinocytes.54,58 NME usually involves the intertriginous areas of the perineum and buttocks then migrates toward the distal extremities and can be associated with angular stomatitis, cheilitis, and atrophic glossitis.54 Other reported clinical features of this syndrome are vulvovaginitis, urethritis, amino acid deficiency, anemia, depression, and venous thrombosis with pulmonary embolism.54,56,59–61 The diagnosis of a glucagonoma requires laboratory validation elevated serum glucagon level, 500 to 1000 pg/mL, and imaging confirming a pancreatic neoplasm.54 On a histomorphologic standpoint, glucagonoma shares the same features as any panNETs. Immunohistochemical stains for glucagon highlights the glucagon-producing neoplastic cells.55 Although most glucagonomas are sporadic, 3% of these tumors are associated with MEN1 syndrome.62

These neoplasms are slow-growing tumors and often diagnosed at an advance stage. More than 70% to 90% are malignant and present with metastases at time of diagnosis, usually involving the liver.55,63,64 Their prognosis depends on stage and grades.52,65 Tumor size and ki-67 proliferative index do not seem to correlate with biological behavior, as most are diagnosed large.52,63,66 Despite the malignant potential of these tumors, the overall 5-year survival rate is estimated close to 70% with tumor growth and mass effect being the main cause of mortality.55,57,63

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Somatostatinoma

Somatostatinomas account for <5% of functioning panNETs44,67 and are made up of somatostatin-secreting D cells leading to uncontrolled hypersecretion of this particular hormone. Besides the pancreas, they have been known to occur in the duodenum, especially the periampullary region, and the jejunum. Although most are found incidentally, the main presenting symptoms are usually related to mass effect. True somatostatinomas are quite rare and found in <10% of patients.3 Most will commonly present with variable somatostatin hypersecretion symptoms ranging from diabetes mellitus, hypochlorhydria, gallbladder disease (cholelithiasis), diarrhea, steatorrhea, anemia, to weight loss.2,44,67,68 Serum analysis reveals a markedly elevated somatostatin levels. Except for occasional paraganglioma-like growth pattern and psammoma bodies, somatostatinomas are morphologically identical to panNETs (Fig. 6).68,69 Most demonstrate immunolabelling for somatostatin marker, with variable degree and intensity. Somatostatinoma has been identified in certain syndromes including neurofibromatosis type 1 and MEN1. A recent somatic mutation, HIF2A, a gene involved in the control of cellular response to hypoxia has been discovered for this particular panNET. Dysregulation of HIF2A leads to polycythemia, paraganglioma, and somatostatinoma syndrome.69–72 Approximately 60% to 70% of these tumors are malignant at time of diagnosis with two-thirds revealing lymph nodes or liver metastasis.67,68,73 The overall 5-year survival is estimated close to 75% and drops significantly, from 15% to 60% if distant metastasis are identified.67,73–76

FIGURE 6

FIGURE 6

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Gastrinoma

Gastrinomas are the second most common functioning panNETs and account as many as 20% of cases.77–79 These neoplasms are found in an anatomic location called the gastrinoma triangle, a region between the junctions of cystic and common bile ducts, second and third parts of the duodenum, and neck and body of the pancreas. Gastrinomas are composed of gastrin-producing G cells resulting in excessive gastrin production and a high gastric acid output leading to a clinical syndrome called Zollinger-Ellison syndrome (ZES).80,81 Patients with this syndrome present with severe and extensive peptic ulcer disease, dyspepsia, nausea, vomiting, abdominal pain, and ulcer complications.44,80,82,83 An increased fasting serum gastrin level at basal state or after stimulation is helpful in establishing the diagnosis.44,81,84 As other functioning neuroendocrine tumors, gastrinomas are histologically and molecularly identical in addition to showing diffuse apical immunostaining for gastrin (Fig. 7).85,86 On a prognostic standpoint, >90% of gastrinomas are malignant with one-third presenting metastasis at the time of diagnosis, with liver and bone being common spread site.3,80

FIGURE 7

FIGURE 7

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VIPoma

VIPomas are a rare tumor accounting for 3% to 5% of functioning panNETs and arise from non-β islet cells of the pancreas that secrete vasoactive intestinal polypeptide.3,44,45 VIP-secreting neoplasms can occur in many regions of the body, including the colon, adrenal glands, liver and bronchus. Nevertheless, >85% are found in the pancreas, predominantly the tail.87 VIPomas are known to produce hypersecretion syndrome, called by many names including Verner-Morrison, watery diarrhea, hypokalemia, and achlorhydria (WDHA), or VIPoma syndrome.3,88,89 WDHA syndrome is characterized watery diarrhea (up to 10 to 15 L), flushing, hyperglycemia, hypocalcemia, and paralytic ileus. Patients suffering from severe secretory watery diarrhea can develop secondary electrolyte disturbances, such as hypokalemia, hypophosphatemia, hypomagnesemia, and metabolic acidosis.90 VIP-secreting neoplasms also inhibit gastric acid production leading to hypochlorhydria or achlorhydria in ∼75% of cases.3,44,90,91 In the absence of a radiologically visible tumor, an increased serum VIP level (>500 pg/mL or >80 pmol/L) and suggestive clinical symptoms, the diagnosis of VIPoma can be established.80,89–91 In addition to routine neuroendocrine markers, about 90% of VIPomas are immunoreactive with VIP immunohistochemical stain. Certain VIPomas can also cross react with additional markers, such as peptide histidine methionine, pancreatic polypeptide, GHRH, α-HCG, insulin, and others.92–95 Most VIPomas, ranging from 70% to 90%, are malignant with 40% to 70% having metastasized at time of diagnosis, especially to the, liver, lymph nodes or bone.90 Although VIPomas are often diagnoses at an advanced stage, the overall 5-year survival rate has been documented as high as 94% in certain studies and drops significantly to <68% in patients with metastases.89,91,96

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Serotonin-producing Tumors

Serotonin-producing panNETs are extremely rare and ∼100 cases have been documented in literature.97–102 These neoplasms are composed of serotonin-producing cells, which are believed to arise from either enterochromaffin cells, Kulchitsky cells, or from multipotent precursor cells along the pancreatic ducts.97,100 Because of their small number, serotonin-producing tumors or serotonomas are diagnosed based on positive immunoreactivity to serotonin markers, elevated serum serotonin levels or high urine levels of its metabolite 5-hydroxyindoleacetic acid.99,100 Serotonin hypersecretion can cause a carcinoid syndrome, which has been documented predominantly in advanced metastatic disease.99,103–105 In a carcinoid syndrome, patients present with a classic triad of cutaneous flushing, diarrhea, and valvular disease.104,105 Additional symptoms such as asthma, abdominal pain, and weight loss are also common findings.99,105 The overall 1-year survival rate for patients with local disease is up to 84%; however, if metastatic disease is identified, their prognosis significantly drops to 37.5% over the course of 5 years.99,106

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ACTH-producing Tumors

ACTH-producing tumors of the pancreas are rare and <150 cases have been reported in literature.107–111 These neoplasms are composed of ACTH-hypersecreting cells, causing ectopic Cushing syndrome. Cushing syndrome involves a wide range of clinical symptoms including significant weight gain with centripetal fat distribution, hypertension, purplish-red skin striae, lower limb edema, and others.112–114 Besides symptoms of Cushing syndrome, patients diagnosed with ACTH-secreting pancreatic neoplasms were also found with additional clinical features of ZES (34.5%), insulinoma syndrome (5%), and carcinoid syndrome (1 patient), caused by concomitant release of gastrin, insulin, and serotonin, respectively.9,107,110 High level of serum ACTH and β-endorphin may help in the diagnosis. Morphologically, these tumors are identical to well-differentiated panNETs and often demonstrate vascular and perineural invasion, which are frequently found in grade 2. Immunohistochemical expression of ACTH, with variable degree and intensity, has been found in most cases, in occasional CD117 immunopositivity which can be associated to a worse prognosis (Fig. 8).107 An extensive literature review performed by Maragliano et al107 has compared the survival rate of ACTH-secreting panNETs to other functioning panNETs. The overall 5-year survival rate of ACTH-secreting panNETs is quite poor and estimated at 35%, compared with 97% for insulinomas,72% for gastrinomas, and 75.2% for somatostatinomas, and 80% for N-F panNETs.107

FIGURE 8

FIGURE 8

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N-F panNEN

As previously stated, the term N-F panNEN is reserved for neuroendocrine neoplasms occurring in patients with no paraneoplastic symptoms related to tumor hormone hypersecretion. Recent advances in imaging modalities are responsible for an important increased number in the diagnosis of incidental N-F panNEN causing its relative frequency, in some studies, to reach as high as 70% to 90% of panNENs.17,115–119 Excluding incidental cases, N-F panNEN symptomatology is usually related to its mass-related burden of the primary disease or metastasis. Most of these tumors are located in the head of the pancreas resulting in biliary obstruction, gastric outlet obstruction, pancreatitis, postobstructive jaundice, and nonspecific abdominal pain. Immunomorphologic features of N-F panNENs are consistent with those of well-differentiated panNETs, as these tumors demonstrate positive expression of neuroendocrine markers. Although not associated with hypersecretory syndromes, N-F tumors may express various peptide hormones on immunohistochemical studies, such as glucagon, somatostatin, and serotonin.120–122 Most N-F panNENs occur sporadically, nearly 10% are associated with predisposing genetic syndromes, including MEN1, von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC).123 N-F panNENs are a heterogenous group of disease and range from slow-growing noninfiltrative tumors to rapidly metastasizing malignancies. Because of their lack of paraneoplastic symptoms, many N-F panNENs are generally diagnosed at more advanced stages.51,115,116,124,125 As consequence, N-F panNEN presents with distant metastases in up to 50% of patients.126 Metastatic disease primarily occurs in the liver, although other sites including bone, peritoneum, adrenal, brain, and spleen have been documented.127 Surgery should be considered for all patients for whom complete resection is possible, while liver directed therapies are useful for managing hepatic metastases.125,128

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SYNDROME-ASSOCIATED PANCREATIC NEUROENDOCRINE NEOPLASMS

Neuroendocrine pancreatic cancers can occur as part of inherited tumor syndromes.129,130 There are 4 well-established syndromes associated with inherited panNETs. These include MEN1, VHL, NF1, and TSC, and altogether, these syndromes account for ∼10% to 20% of well-differentiated panNETs (Table 3).1,20,129,131–135 Unlike their sporadic counterparts, syndromic panNENs are usually diagnosed as a multifocal disease.

TABLE 3

TABLE 3

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MEN1

MEN1 is an inherited autosomal dominant disorder characterized by mutations in the MEN1 gene mapped to chromosome region 11q13 and encoding for the nuclear protein menin. MEN1 gene is classified as a gatekeeper tumor suppressor and directly controls cellular proliferation, regulation and death.131,133,136–143 Patients with MEN1 syndrome are at higher risk to develop several endocrine tumors at a young age, over 90% by the age of 40 years old.129 These endocrine neoplasms frequently arise in the parathyroid glands (95%), anterior pituitary (up to 40%), and pancreatic islet and duodenum (40% to 80%).129,144,145 In the pancreas, these tumors are usually multicentric, occur in any parts, head or tail, and range in size from microadenomas to macroadenomas. Their biological behavior also varies from benign to invasive and metastatic carcinomas.146,147 The most commonly encountered panNENs in MEN1 are N-F panNENs; however, insulinomas, gastrinomas, glucaconomas, and rarely VIPomas and somatostatinomas are also observed.78,133,134,137,147–150 In addition to their typical neuroendocrine morphology, MEN1-associated panNENs may present with foci of nesidioblastosis in addition to ductuloinsular complexes. As any other neuroendocrine tumors, these tumors reveal positive immunolabeling for neuroendocrine markers and their respective pancreatic hormone polypeptide markers.133

Compared with their sporadic counterpart, some MEN1-associated panNENs exhibit a more aggressive potential behavior with metastatic disease reported in 23% to 33% of cases.77,151–153 For these MEN1 syndromic tumors, tumor size at time of presentation is an important prognostic factor shown to influence both progression and overall survival, as tumors with a diameter larger than >1.5 to 2 cm are associated with a higher risk of malignant involvement.147,153 Even in presence of metastatic disease, long-term survival has been documented in MEN1 patients, suggesting a slow progression in this disease. Nevertheless, pancreatic cancer remains the main cause of disease-related death in MEN1, with a probability of death of 50% by the age of 50 years, if not treated.147,151,153–155 Early panNEN diagnosis is essential in patients with MEN1 syndrome, as these neoplasm have a significant impact on life expectancy and morbidity.

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VHL

VHL syndrome is an inherited autosomal dominant condition caused by mutations in VHL gene, a tumor suppressor, mapped on chromosome region 3p25. VHL gene function involves the oxygen-sensing pathway through hypoxia-inducible factors.129,133,156–159 Mutations in this gene lead to the emergence of several tumors in various organs, including hemangioblastomas of the retina and craniospinal region (>70%), pancreatic lesions (35% to 72%), renal tumors (up to 60%) pheochromocytomas (10% to 20%), and endolymphatic sac tumors (10%).133,159–161 Presence of VHL-associated panNEN has been described in about 10% to 17% of syndromic patients. Most neoplasms are diagnosed at a young age, mean of 38 years and present usually as multifocal lesions dispersed along the pancreas.161–165 N-F panNETs are the most frequently identified type with rare cases of insulinoma, glucagonoma, VIPoma, and somatostatinoma reported.162,166–168 In addition to classic neuroendocrine morphology, these tumors may present with a trabecular, glandular and/or solid architecture and other histological features, such as hypervascularity, nuclear atypia, and clear/multivacuolated cell changes. These distinctive findings are attributed to the pseudohypoxia state caused by the activation of HIF in VHL syndrome.169 Compared with sporadic panNENs, resected VHL-associated panNENs reveal a better long-term outcome with recurrences observed in patients with large tumors, ≥5.0 cm, or with aggressive grade 3 tumors.158,170

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NF1

NF1 is an inherited autosomal dominant disorder caused by mutations in NF1 gene, encoding a protein called neurofibromin, mapped to chromosome region 17q11.2.67,129–131,133,171 NF1 gene acts as a tumor suppressor and its inactivation leads to increased signaling by the RAS oncogenes, commonly known as RASopathy gene.172,173 This loss of function leads to the development of cardinal neoplasms encountered in this syndrome, neurofibromas, café-au-lait spots, Lisch nodules, freckles, and optic glioma, needed for the clinical diagnosis.174–177 PanNENs are not included as part of NF1 diagnostic criteria, account for <10% of documented cases, and are almost exclusively duodenal somatostatinomas.133,178 Histologically, these tumors often demonstrate a glandular architecture and scattered psammoma bodies. Altogether, NF1-associated duodenal and pancreatic somatostatinomas differ from sporadic pancreatic somatostatinomas in several aspects. Syndromic somatostatinomas are less likely cause clinical hypersecretory state, ≤2% versus 66%, are diagnosed with a smaller tumor size, 2.8 versus 5.9 cm, and are less likely to present with metastatic disease, 30% versus 71%.178

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TSC

TSC is a rare inherited autosomal dominant syndrome caused by mutations in 2 tumor suppressor genes, TSC1 mapped to chromosome 9q34 and TSC2 mapped to chromosome 16p13.3, encoding for the proteins hamartin and tuberin, respectively.133,179,180 The protein tuberin-hamartin complex involves multiple intracellular signaling pathways regulating both cell growth and proliferation.179,181 Patients with TSC are characterized mainly by multiorgans hamartomatous lesions, disabling neurologic features (epilepsy, mental retardation) and cutaneous lesions, typically facial angiofibroma, hypomelanocytic macules and ungula fibromas.181,182 Although there is limited data linking TSC to an increased risk of panNENs, both functioning (gastrinomas and insulinomas) and N-F tumors have been reported in patients with this syndrome, especially those with TSC2 mutation.183–188 Potential malignant behavior has been documented in rare cases.189,190 Consequently, careful clinical surveillance and appropriate surgical treatment should be considered on a case-to-case basis.

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Glucagon Cell Hyperplasia and Neoplasia (GCHN)

GCHN is a rare inherited recessive syndrome with an estimated ten cases documented in literature.191,192 Germline mutation of the GCGR gene, located on chromosome 17q25, has been identified in half of these syndromic patients giving a potential insight into the pathophysiology of this uncommon disorder. It is believed that GCGR mutation alters its overall protein function and expression causing an abnormal feedback mechanism between glucagon signaling in the liver and the glucagon cells of the pancreas.191,193,194 This deficient communication pathway results in an increased glucagon serum level and multifocal pancreatic glucagon cell hyperplasia, microadenomas and macroadenomas.191,192 These pancreatic lesions show well-differentiated panNET morphology with occasional cystic changes and calcifications in larger tumors and positive expression for glucagon immunohistochemistry. Although most GCHN followed a benign course post partial pancreatectomy, metastatic lymph node disease has been reported.191

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panNEC

Poorly differentiated panNECs are rare and account for ∼2% to 3% of pancreatic neuroendocrine cancers.12,115,195 PanNECs have a slight male predominance with an incidence peak in the sixth to seventh decade and frequently involve the head of the pancreas. Their clinical presentation is very similar to exocrine pancreatic tumors and are related to their location, large size and both obstructive and somewhat invasive nature. As a result, postobstructive jaundice, back pain, and/or nonspecific abdominal complaints are the only signs and symptoms available to suspect the diagnosis.12,13,196 On histologic assessment, panNECs usually present with a nested, organoid, or solid growth-like pattern composed of highly atypical small to large polygonal cells with large vesicular nuclei and often prominent nucleoli. The small cell type has a more infiltrative growth pattern. The large cell type is more commonly observed, accounting for ∼60% of cases.12,197 Areas of geographic necrosis, vascular invasion, and mitoses are easily identifiable (Fig. 9). Both tumors are reminiscent of small and large cell carcinoma of the lungs. Because of its high-grade histologic features, immunohistochemical studies are needed to confirm the diagnosis. Like its well-differentiated counterpart, panNEC immunostains demonstrate neuroendocrine differentiation. The tumor cells should express diffuse or focal, sometimes only dot-like, synaptophysin staining in variable intensity. Chromogranin A, although a useful specific marker, can occasionally be negative. In addition, less specific markers such as CD56 and NSE, which are interpreted in conjunction with both synaptophysin and/or chromogranin A positivity, may or may not be expressed in the tumor, but are still helpful tools in the diagnosis of more difficult cases.12,13,196,197 On a morphologic standpoint, the distinction between panNET, well-differentiated (G3) and panNEC, poorly differentiated (G3), can be challenging. To facilitate the distinction, both p53 and Rb markers are good and reliable immunostains to use, which have been identified in 95% and 74% of panNECs, respectively. PanNEC is characterized by strong and diffuse p53 nuclear expression in at least >20% of the tumors, in addition to complete loss of Rb expression.16,26

FIGURE 9

FIGURE 9

By definition, panNECs are graded based on their proliferative activity evaluation as >20 mitoses per 10 high-power fields or ki-67 proliferation index >20%.10 Nevertheless, most panNECs are very mitotically active and cases with >40 to 50 mitoses per high-power fields or ki-67 proliferation index >50% are frequently observed.12,13,197

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Molecular of panNECs

Targeted molecular sequencing of panNECs has identified somatic genetic alterations involving predominantly: TP53, KRAS, PIK3CA/PTEN, and BRAF.198,199 At a lesser frequency, other genes such as RB1, CDKN2A/p16, APC, FBXW7, WNT, BCL2, and CTNNB1 can be mutated.198 Molecular abnormalities encountered in panNETs (MEN1, DAXX, and ATRX) and ductal pancreatic adenocarcinoma (SMAD4/DPC4) are not common features of panNEC.200,201 TP53 is a well-known tumor suppressor gene with multiple functions including cell division, apoptosis, and DNA repair and its mutation has been documented in more than half of cases.198,200,201 TP53 mutation usually leads to nuclear accumulation of the protein characterized as strong nuclear staining seen on immunohistochemical studies. Few cases of nonsense mutation in the TP53 gene were identified resulting in the absence of protein accumulation objectified on immunohistochemical stains as complete absence of nuclear p53 labeling.200 Abnormal immunostaining pattern for p53 and the Rb indicates that inactivation of these 2 pathways is a central feature for panNEC development. Additional correlations suggest that loss of Rb protein is mutually exclusive with the loss of p16 protein, supporting the known relationship of Rb and CDKN2A/p16 pathways in cell cycle regulation.199,200 KRAS mutations, although mainly described in colorectal cancers, were documented in different proportions in panNECs ranging from 0% to 50% in some studies.198,200–203

Although several mutations are identified in panNECs, only few of them (TP53, BRAF, PIK3CA, PTEN, WNT, and CTNNB1) are potentially actionable mutations for gene targeted therapies.198

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Mixed Ductal-neuroendocrine Carcinoma

Mixed ductal-neuroendocrine carcinomas are a rare and aggressive neoplasm accounting for <0.5% of all pancreatic ductal adenocarcinomas.10,204–206 More than 70% of these mixed cancers are located in the head of the pancreas and present with symptoms related to their mass effect, although one case of ZES and another with the WDHA syndrome have been reported.10,207–210 They are usually quite large at time of presentation, measuring 1.4 to 19.0 cm in largest diameter, with a mean of 7.0 cm.208 Both mixed components are confined to a solitary, well-demarcated, white-to-yellow mass with occasional hemorrhagic or necrotic foci. This tumor exhibits morphologic characteristics of non-neuroendocrine carcinoma, usually an adenocarcinoma, admixed with a neuroendocrine neoplasm. Histologically, 2 different architectural patterns are described. In the first one, malignant ductal and neuroendocrine cells are intertwined together to form glandular, trabecular and various architectures. In the other pattern, separate ductal and neuroendocrine components are combined to form one tumors (Fig. 10).208,211,212 Immunohistochemical makers are strongly recommended to highlight both cell populations. For a diagnosis of mixed ductal-neuroendocrine carcinoma to be rendered, it is recommended for each tumor cell-type to account for ≥30% of the overall tumor cell population.10,213 Normally, both tumors are graded as poorly differentiated high-grade neoplasms (G3); however, well-differentiated endocrine neoplasms, G1/G2, are possible.210,212–214

FIGURE 10

FIGURE 10

Despite few documented cases, this mixed tumor seems to have similar or slightly better prognosis than pure ductal pancreatic adenocarcinoma but worse prognosis than pure endocrine carcinoma, likely contributed by the ductal adenocarcinoma component.205,208,215–218

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Mixed Acinar-neuroendocrine Carcinoma (MANEC)

MANEC is a rare malignancy representing up to 20% of acinar cell carcinomas.219,220 These tumors are usually >5.0 cm at presentation with a slight preferential location in the head of the pancreas. Patients complain of jaundice, weight loss, and vague abdominal pain. Tumors are well-circumscribed, solid, whitish mass with occasional necrosis and cystic degenerative features.221–225 Their diagnosis is performed on histological assessment of both acinar and neuroendocrine component. Both cell-types are generally intermingled and quite challenging to identify on routine evaluation, as they morphologically resemble one another. Immunohistochemistry for both acinar and neuroendocrine markers is necessary.212,213 As in mixed ductal-neuroendocrine carcinoma, the diagnosis of MANEC also requires each tumor cell-type to represent ≥30% of the overall tumor cell population. The neuroendocrine component is usually a poorly differentiated NEC, G3, but few cases of well-differentiated neuroendocrine tumors, G2, are observed.221,226,227

Despite the small number of cases, the prognosis of MANEC seems similar to that of pure acinar carcinoma. Patients with surgically resectable disease have a favorable prognosis with a 5-year survival of 30% to 50%.212,221,228,229 While patients with nonresectable malignancies usually do not survive beyond 5 years.221

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CONCLUSIONS

PanNENs are a heterogenous group of tumors representing only 1% to 2% of all pancreatic cancers. They encompass tumors with a wide spectrum of potential pathologic behaviors. Their clinical presentation varies from nonspecific mass-related symptoms to hypersecretory state and inherited syndromes, making their identification a diagnostic challenge.

The new WHO 2017 classification categorized panNENs into 3 groups based predominantly on histopathologic criteria, including ki-67 proliferative index and mitotic index, in addition to diagnostic immunohistochemical markers to further stratify each tumors into their respective categories. The purpose of this new system is to provide strong diagnostic and prognostic tools to better assess clinical outcomes and to determine optimal therapeutic strategies and patient care.

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REFERENCES

1. Asa SL. Pancreatic endocrine tumors. Mod Pathol. 2011;24 (suppl 2):S66–S77.
2. McKenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. Gland Surg. 2014;3:258–275.
3. Anderson CW, Bennett JJ. Clinical presentation and diagnosis of pancreatic neuroendocrine tumors. Surg Oncol Clin N Am. 2016;25:363–374.
4. Fraenkel M, Kim MK, Faggiano A, et al. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26:691–703.
5. Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:1–18.
6. Paniccia A, Edil BH, Schulick RD. Pancreatic neuroendocrine tumors: an update. Indian J Surg. 2015;77:395–402.
7. Burns WR, Edil BH. Neuroendocrine pancreatic tumors: guidelines for management and update. Curr Treat Options Oncol. 2012;13:24–34.
8. Rubinstein WS. Endocrine cancer predisposition syndromes: hereditary paraganglioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, and hereditary thyroid cancer. Hematol Oncol Clin North Am. 2010;24:907–937.
9. Oberg K. Pancreatic endocrine tumors. Semin Oncol. 2010;37:594–618.
10. Klöppel G, Couvelard A, Hruban RH, et alLloyd RV, Osamura RY, Klöppel G, Rosai J. Tumours of the endocrine pancreas. WHO Classification of the Tumours of Endocrine Organs, 4th ed. Lyon, France: International Agency for Research on Cancer; 2017:175–207.
11. Kasajima A, Yazdani S, Sasano H. Pathology diagnosis of pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2015;22:586–593.
12. Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39:683–690.
13. Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657–664.
14. Fazio N, Milione M. Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: new insights and treatment implications. Cancer Treat Rev. 2016;50:61–67.
15. Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer. 2013;20:649–657.
16. Tang LH, Untch BR, Reidy DL, et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res. 2016;22:1011–1017.
17. Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103:186–194.
18. Cetinkaya RB, Aagnes B, Thiis-Evensen E, et al. Trends in incidence of neuroendocrine neoplasms in Norway: a report of 16,075 cases from 1993 through 2010. Neuroendocrinology. 2016;104:1–10.
19. Franko J, Feng W, Yip L, et al. Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2,158 patients. J Gastrointest Surg. 2010;14:541–548.
20. Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543:65–71.
21. Lloyd RV, Mervak T, Schmidt K, et al. Immunohistochemical detection of chromogranin and neuron-specific enolase in pancreatic endocrine neoplasms. Am J Surg Pathol. 1984;8:607–614.
22. Shi C, Klimstra DS. Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. Semin Diagn Pathol. 2014;31:498–511.
23. Baudin E, Gigliotti A, Ducreux M, et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer. 1998;78:1102–1107.
24. Kasprzak A, Zabel M, Biczysko W. Selected markers (chromogranin A, neuron-specific enolase, synaptophysin, protein gene product 9.5) in diagnosis and prognosis of neuroendocrine pulmonary tumours. Pol J Pathol. 2007;58:23–33.
25. Klöppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract. 1988;183:155–168.
26. Tang LH, Basturk O, Sue JJ, et al. A practical approach to the classification of WHO Grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40:1192–1202.
27. Sun J. Pancreatic neuroendocrine tumors. Intractable Rare Dis Res. 2017;6:21–28.
28. Park JK, Paik WH, Lee K, et al. DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors. Oncotarget. 2017;1:1–10.
29. Pea A, Hruban RH, Wood LD. Genetics of pancreatic neuroendocrine tumors: implications for the clinic. Expert Rev Gastroenterol Hepatol. 2015;9:1407–1419.
30. Ohmoto A, Rokutan H, Yachida S. Pancreatic neuroendocrine neoplasms: basic biology, current treatment strategies and prospects for the future. Int J Mol Sci. 2017;18:e143–e159.
31. Ohki R, Saito K, Chen Y, et al. PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A. 2014;111:E2404–E2413.
32. Takikawa M, Ohki R. A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors. Cancer Sci. 2017;108:1101–1108.
33. Marinoni I, Kurrer AS, Vassella E, et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology. 2014;146:453–460.
34. De Wilde RF, Heaphy CM, Maitra A, et al. Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol. 2012;25:1033–1039.
35. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203.
36. Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28:245–255.
37. Perren A, Komminoth P, Saremaslani P, et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol. 2000;157:1097–1103.
38. Chou WC, Lin PH, Yeh YC, et al. Genes involved in angiogenesis and mTOR pathways are frequently mutated in Asian patients with pancreatic neuroendocrine tumors. Int J Biol Sci. 2016;12:1523–1532.
39. Kulke MH, Bendell J, Kvols L, et al. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. J Hematol Oncol. 2011;4:29–37.
40. Wolin EM. PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors. Cancer Lett. 2013;335:1–8.
41. Raymond E, Hammel P, Dreyer C, et al. Sunitinib in pancreatic neuroendocrine tumors. Target Oncol. 2012;7:117–125.
42. Wiedenmann B, Pavel M, Kos-Kudla B. From targets to treatments: a review of molecular targets in pancreatic neuroendocrine tumors. Neuroendocrinology. 2011;94:177–190.
43. Lee DW, Kim MK, Kim HG. Diagnosis of pancreatic neuroendocrine tumors. Clin Endosc. 2017;50:537–545.
44. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–1492.
45. De Wilde RF, Edil BH, Hruban RH, et al. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol. 2012;9:199–208.
46. Doi R. Determinants of surgical resection for pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2015;22:610–617.
47. Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol. 2013;19:829–837.
48. Bhatti TR, Ganapathy K, Huppmann AR, et al. Histologic and molecular profile of pediatric insulinomas: evidence of a paternal parent-of-origin effect. J Clin Endocrinol Metab. 2016;101:914–922.
49. Wang L, Yang M, Zhang Y, et al. Prognostic validation of the WHO 2010 grading system in pancreatic insulinoma patients. Neoplasma. 2015;62:484–490.
50. Klöppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2011;18(suppl 1):S1–S16.
51. Falconi M, Bartsch DK, Eriksson B, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95:120–134.
52. Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007;14:3492–3500.
53. Song X, Zheng S, Yang G, et al. Glucagonoma and the glucagonoma syndrome. Oncol Lett. 2018;15:2749–2755.
54. Halvorson SAC, Gilbert E, Hopkins RS, et al. Putting the pieces together: necrolytic migratory erythema and the glucagonoma syndrome. J Gen Intern Med. 2013;28:1525–1529.
55. Wermers RA, Fatourechi V, Wynne AG, et al. The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Medicine (Baltimore). 1996;75:53–63.
56. Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci. 2001;321:306–320.
57. Eldor R, Glaser B, Fraenkel M, et al. Glucagonoma and the glucagonoma syndrome—cumulative experience with an elusive endocrine tumour. Clin Endocrinol (Oxf). 2011;74:593–598.
58. van Beek AP, de Haas ERM, van Vloten WA, et al. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. 2004;151:531–537.
59. McGevna L, McFadden D, Ritvo J, et al. Glucagonoma-associated neuropsychiatric and affective symptoms: diagnostic dilemmas raised by paraneoplastic phenomena. Psychosomatics. 2009;50:548–549.
60. Guilarte Lopez-Manas J, Bellot Garcia V, Fernandez Perez R, et al. Pancreatic glucagonoma and deep vein thrombosis. Gastroenterol Hepatol. 1998;21:483–485.
61. Alexander EK, Robinson M, Staniec M, et al. Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome. Clin Endocrinol (Oxf). 2002;57:827–831.
62. Lévy-Bohbot N, Merle C, Goudet P, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol. 2004;28:1075–1081.
63. Kindmark H, Sundin A, Granberg D, et al. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years. Med Oncol. 2007;24:330–337.
64. Soga J, Yakuwa Y. Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. J Hepatobiliary Pancreat Surg. 1998;5:312–319.
65. Bilimoria KY, Bentrem DJ, Merkow RP, et al. Application of the pancreatic adenocarcinoma staging system to pancreatic neuroendocrine tumors. J Am Coll Surg. 2007;205:558–563.
66. Kim JY, Kim MS, Kim KS, et al. Clinicopathologic and prognostic significance of multiple hormone expression in pancreatic neuroendocrine tumors. Am J Surg Pathol. 2015;39:592–601.
67. Nesi G, Marcucci T, Rubio CA, et al. Somatostatinoma: clinico-pathological features of three cases and literature reviewed. J Gastroenterol Hepatol. 2008;23:521–526.
68. Moayedoddin B, Booya F, Wermers RA, et al. Spectrum of malignant somatostatin-producing neuroendocrine tumors. Endocr Pract. 2006;12:394–400.
69. Toyoda H, Hirayama J, Sugimoto Y, et al. Polycythemia and paraganglioma with a novel somatic HIF2A mutation in a male. Pediatrics. 2014;133:e1787–e1791.
70. Lorenzo FR, Yang C, Ng Tang, et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med. 2013;91:507–512.
71. Yang C, Sun MG, Matro J, et al. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood. 2013;121:2563–2566.
72. Buffet A, Smati S, Mansuy L, et al. Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab. 2014;99:e396–e473.
73. Garbrecht N, Anlauf M, Schmitt A, et al. Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: Incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocr Relat Cancer. 2008;15:229–241.
74. Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005;16:1806–1810.
75. Halfdanarson TR, Rubin J, Farnell MB, et al. Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer. 2008;15:409–427.
76. Fendrich V, Langer P, Celik I, et al. An aggressive surgical approach leads to long-term survival in patients with pancreatic endocrine tumors. Ann Surg. 2006;244:845–851.
77. Gibril F, Venzon DJ, Ojeaburu JV, et al. Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. J Clin Endocrinol Metab. 2001;86:5282–5293.
78. Nikou GC, Toubanakis C, Nikolaou P, et al. Gastrinomas associated with MEN-1 syndrome: new insights for the diagnosis and management in a series of 11 patients. Hepatogastroenterology. 2005;52:1668–1676.
79. 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.
80. Grozinsky-Glasberg S, Mazeh H, Gross DJ. Clinical features of pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2015;22:578–585.
81. Berna MJ, Hoffmann KM, Serrano J, et al. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the national institutes of health and comparison with 2229 cases from the literature. Medicine (Baltimore). 2006;85:295–330.
82. Metz DC. Diagnosis of the Zollinger-Ellison syndrome. Clin Gastroenterol Hepatol. 2012;10:126–130.
83. Roy PK, Venzon DJ, Shojamanesh H, et al. Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore). 2000;79:379–411.
84. Roy PK, Venzon DJ, Feigenbaum KM, et al. Gastric secretion in Zollinger-Ellison syndrome: correlation with clinical expression, tumor extent and role in diagnosis—a prospective NIH study of 235 patients and a review of 984 cases in the literature. Medicine (Baltimore). 2001;80:189–222.
85. Bonnavion R, Teinturier R, Jaafar R, et al. Islet cells serve as cells of origin of pancreatic gastrin-positive endocrine tumors. Mol Cell Biol. 2015;35:3274–3283.
86. Lewis RB, Lattin GE, Paal E. Pancreatic endocrine tumors: radiologic-clinicopathologic correlation. Radiographics. 2010;30:1445–1464.
87. Friesen SR. Update on the diagnosis and treatment of rare neuroendocrine tumors. Surg Clin North Am. 1987;67:379–393.
88. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958;25:374–380.
89. Ghaferi AA, Chojnacki KA, Long WD, et al. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. 2008;12:382–393.
90. Adam N, Lim SS, Ananda V, et al. VIPoma syndrome: challenges in management. Singapore Med J. 2010;51:1–6.
91. Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res. 1998;17:389–400.
92. Song S, Shi R, Li B, et al. Diagnosis and treatment of pancreatic vasoactive intestinal peptide endocrine tumors. Pancreas. 2009;38:811–814.
93. Rudholm T, Wallin B, Theodorsson E, et al. Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats. Regul Pept. 2009;152:8–12.
94. Vinik A, Casellini C, Perry RR, et al. Diagnosis and management of pancreatic neuroendocrine tumors (PNETS). Endotext. 2000. Available at: www.ncbi.nlm.nih.gov/pubmed/25905300. Accessed February 10, 2018.
95. Vinik A. Vasoactive intestinal peptide tumor (VIPoma). Endotext. 2000. Available at: www.ncbi.nlm.nih.gov/books/NBK278960/. Accessed February 10, 2018.
96. Strosberg JR, Cheema A, Weber J, et al. Prognostic validity of a Novel American Joint Committee on Cancer staging classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011;29:3044–3049.
97. La Rosa S, Franzi F, Albarello L, et al. Serotonin-producing enterochromaffin cell tumors of the pancreas: clinicopathologic study of 15 cases and comparison with intestinal enterochromaffin cell tumors. Pancreas. 2011;40:883–895.
98. Maurer CA, Glaser C, Reubi JC, et al. Carcinoid of the pancreas. Digestion. 1997;58:410–414.
99. Maurer CA, Baer HU, Dyong TH, et al. Carcinoid of the pancreas: clinical characteristics and morphological features. Eur J Cancer. 1996;32:1109–1116.
100. Tsoukalas N, Chatzellis E, Rontogianni D, et al. Pancreatic carcinoids (serotonin-producing pancreatic neuroendocrine neoplasms): report of 5 cases and review of the literature. Medicine (Baltimore). 2017;96:e6201–e6204.
101. Mao CY, El Attar A, Domenico DR, et al. Carcinoid tumors of the pancreas—status report based on two cases and review of the world’s literature. Int J Pancreatol. 1998;23:153–164.
102. McCall CM, Shi C, Klein AP, et al. Serotonin expression in pancreatic neuroendocrine tumors correlates with a trabecular histologic pattern and large duct involvement. Hum Pathol. 2012;43:1169–1176.
103. Gettenberg G, Zimbalist E, Marini C. Chronic pancreatitis and pseudocyst formation secondary to carcinoid tumor of the pancreas. Gastroenterology. 1988;94(pt 1):1222–1224.
104. Prasad S, Patankar T, Joshi A, et al. Pancreatic carcinoid: an unusual tumour in an uncommon location. J Postgr Med. 1998;44:97–98.
105. Zavras N, Schizas D, Machairas N, et al. Carcinoid syndrome from a carcinoid tumor of the pancreas without liver metastases: a case report and literature review. Oncol Lett. 2017;13:2373–2376.
106. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934–959.
107. Maragliano R, Vanoli A, Albarello L, et al. ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J Surg Pathol. 2015;39:374–382.
108. Vaduganathan M, Nagarur A, Kerr DA, et al. Metastatic pancreatic neuroendocrine tumor with ectopic adrenocorticotropic hormone production. Proc (Bayl Univ Med Cent). 2015;28:46–49.
109. Lee T, Karl M, Solorzano CC. Adrenocorticotropic hormone-secreting pancreatic islet cell carcinoma. J Am Coll Surg. 2004;199:336–337.
110. Zhu L, Domenico DR, Howard JM. Metastatic pancreatic neuroendocrine carcinoma causing Cushing’s syndrome. ACTH secretion by metastases 3 years after resection of nonfunctioning primary cancer. Int J Pancreatol. 1996;19:205–208.
111. Surace A, Ferrarese A, Benvenga R, et al. ACTH-secreting neuroendocrine pancreatic tumor: a case report. Int J Surg. 2014;12(suppl 1):S222–S224.
112. Buliman A, Tataranu LG, Paun DL, et al. Cushing’s disease: a multidisciplinary overview of the clinical features, diagnosis, and treatment. J Med Life. 2016;9:12–18.
113. Duan K, Gomez Hernandez K, Mete O. Clinicopathological correlates of adrenal Cushing’s syndrome. J Clin Pathol. 2015;68:175–186.
114. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281–293.
115. Halfdanarson TR, Rabe KG, Rubin J, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–1733.
116. Jung JG, Lee KT, Woo YS, et al. Behavior of small, asymptomatic, nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs). Medicine. 2015;94:e983–e990.
117. 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.
118. Rindi G, Falconi M, Klersy C, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012;104:764–777.
119. Scarpa A, Mantovani W, Capelli P, et al. Pancreatic endocrine tumors: Improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol. 2010;23:824–833.
120. Kapran Y, Bauersfeld J, Anlauf M, et al. Multihormonality and entrapment of islets in pancreatic endocrine tumors. Virchows Arch. 2006;448:394–398.
121. Konukiewitz B, Enosawa T, Klöppel G. Glucagon expression in cystic pancreatic neuroendocrine neoplasms: an immunohistochemical analysis. Virchows Arch. 2011;458:47–53.
122. 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.
123. Kuo JH, Lee JA, Chabot JA. Nonfunctional pancreatic neuroendocrine tumors. Surg Clin North Am. 2014;94:689–708.
124. Lee LC, Grant CS, Salomao DR, et al. Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery. 2012;152:965–974.
125. Cloyd JM, Poultsides GA. Non-functional neuroendocrine tumors of the pancreas: advances in diagnosis and management. World J Gastroenterol. 2015;21:9512–9525.
126. Keutgen XM, Nilubol N, Glanville J, et al. Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors. Surgery. 2016;159:311–318.
127. Zerbi A, Falconi M, Rindi G, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol. 2010;105:1421–1429.
128. Bar-Moshe Y, Mazeh H, Grozinsky-Glasberg S. Non-functioning pancreatic neuroendocrine tumors: surgery or observation? World J Gastrointest Endosc. 2017;9:153–161.
129. Crona J, Skogseid B. GEP-NETS UPDATE: genetics of neuroendocrine tumors. Eur J Endocrinol. 2016;174:R275–R290.
130. Chen M, Van Ness M, Guo Y, et al. Molecular pathology of pancreatic neuroendocrine tumors. J Gastrointest Oncol. 2012;3:182–188.
131. Zhang Y, Nosé V. Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 2011;18:206–218.
132. Wood LD, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms. Cancer J. 2012;18:492–501.
133. Jensen RT, Berna MJ, Bingham DB, et al. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113:1807–1843.
134. Carrera S, Sancho A, Azkona E, et al. Hereditary pancreatic cancer: related syndromes and clinical perspective. Hered Cancer Clin Pract. 2017;15:9–18.
135. Connor AA, Gallinger S. Hereditary pancreatic cancer syndromes. Surg Oncol Clin N Am. 2015;24:733–764.
136. Balogh K, Rácz K, Patócs A, et al. Menin and its interacting proteins: elucidation of menin function. Trends Endocrinol Metab. 2006;17:357–364.
137. Larsson C, Skogseid B, Oberg K, et al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 1988;332:85–87.
138. Dreijerink KMA, Lips CJM, Timmers HTM. Multiple endocrine neoplasia type 1: a chromatin writer’s block. J Intern Med. 2009;266:53–59.
139. Dreijerink KM, Höppener JW, Timmers HM, et al. Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation. Nat Clin Pract Endocrinol Metab. 2006;2:562–570.
140. Lemmens I, Van de Ven WJ, Kas K, et al. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997;6:1177–1183.
141. Carroll RW. Multiple endocrine neoplasia type 1 (MEN1). Asia Pac J Clin Oncol. 2013;9:297–309.
142. Brewer JJChu Q, Gibbs J, Zibary G. Multiple endocrine neoplasia (MEN) syndromes. Surgical Oncology A Practical and Comprehensive Approach. Springer, New York. 2015:573–584.
143. Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med. 2007;58:253–265.
144. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–5671.
145. Vasen HFA, Lamers CBHW, Lips CJM. Screening for the multiple endocrine neoplasia syndrome type I. A study of 11 kindreds in the Netherlands. Arch Intern Med. 1989;149:2717–2722.
146. Le Bodic MF, Heymann MF, Lecomte M, et al. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. Am J Surg Pathol. 1996;20:1378–1384.
147. Chiloiro S, Lanza F, Bianchi A, et al. Pancreatic neuroendocrine tumors in MEN1 disease: a mono-centric longitudinal and prognostic study. Endocrine. 2017;2:1–6.
148. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012;26:737–753.
149. Norton JA, Krampitz G, Jensen RT. Multiple endocrine neoplasia: genetics and clinical management. Surg Oncol Clin N Am. 2015;24:795–832.
150. 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.
151. Åkerström G, Hessman O, Skogseid B. Timing and extent of surgery in symptomatic and asymptomatic neuroendocrine tumors of the pancreas in MEN 1. Langenbecks Arch Surg. 2002;386:558–569.
152. Andrén-Sandberg A. Pancreatic endocrine tumors. N Am J Med Sci. 2011;3:164–166.
153. Conemans EB, Brosens LAA, Raicu-Ionita GM, et al. Prognostic value of WHO grade in pancreatic neuro-endocrine tumors in multiple endocrine neoplasia type 1: results from the DutchMEN1 Study Group. Pancreatology. 2017;17:766–772.
154. Casadei R, Ricci C, Pezzilli R, et al. Are there prognostic factors related to recurrence in pancreatic endocrine tumors? Pancreatology. 2010;10:33–38.
155. Gaztambide S, Vazquez F, Castaño L. Diagnosis and treatment of multiple endocrine neoplasia type 1 (MEN1). Minerva Endocrinol. 2013;38:17–28.
156. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19:617–623.
157. Chittiboina P, Lonser RR. Von Hippel-Lindau disease. Handb Clin Neurol. 2015;132:139–156.
158. De Mestier L, Hammel P. Pancreatic neuroendocrine tumors in von Hippel-Lindau disease. Scand J Gastroenterol. 2015;50:1054–1055.
159. Shuin T, Yamasaki I, Tamura K, et al. Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol. 2006;36:337–343.
160. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361:2059–2067.
161. Hough DM, Stephens DH, Johnson CD, et al. Pancreatic lesions in von Hippel-Lindau disease: prevalence, clinical significance, and CT findings. AJR Am J Roentgenol. 1994;162:1091–1094.
162. Hammel PR, Vilgrain V, Terris B, et al. Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d’Etude de la Maladie de von Hippel-Lindau. Gastroenterology. 2000;119:1087–1095.
163. Blansfield JA, Choyke L, Morita SY, et al. Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery. 2007;142:814–818.
164. Libutti SK, Choyke PL, Bartlett DL, et al. Pancreatic neuroendocrine tumors associated with von Hippel Lindau disease: diagnostic and management recommendations. Surgery. 1998;124:1153–1159.
165. Libutti SK, Choyke PL, Alexander HR, et al. Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease. Surgery. 2000;128:1022–1030.
166. Horton WA, Wong V, Eldridge R. Von Hippel-Lindau Disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med. 1976;136:769–777.
167. Probst A, Lotz M, Heitz P. Von Hippel-Lindau’s disease, syringomyelia and multiple endocrine tumors: a complex neuroendocrinopathy. Virchows Arch A Pathol Anat Histol. 1978;378:265–272.
168. Cornish D, Pont A, Minor D, et al. Metastatic islet cell tumor in von Hippel-Lindau disease. Am J Med. 1984;77:147–150.
169. Gucer H, Szentgyorgyi E, Ezzat S, et al. Inhibin-expressing clear cell neuroendocrine tumor of the ampulla: an unusual presentation of von Hippel-Lindau disease. Virchows Arch. 2013;463:593–597.
170. De Mestier L, Gaujoux S, Cros J, et al. Long-term prognosis of resected pancreatic neuroendocrine tumors in von hippel-lindau disease is favorable and not influenced by small tumors left in place. Ann Surg. 2015;262:384–388.
171. Reynolds RM, Browning GGP, Nawroz I, et al. Von Recklinghausen’s neurofibromatosis: neurofibromatosis type 1. Lancet. 2003;361:1552–1554.
172. Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015;15:290–301.
173. Bhoj EJ, Yu Z, Guan Q, et al. Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing. Genet Med. 2017;19:715–718.
174. DeBella K, Szudek J, Friedman JM. Use of the National Institutes of Health Criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105:608–614.
175. Kresak J, Walsh M. Neurofibromatosis: a review of NF1, NF2, and Schwannomatosis. J Pediatr Genet. 2016;5:98–104.
176. Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017;3:1–12.
177. García-Romero MT, Parkin P, Lara-Corrales I. Mosaic neurofibromatosis type 1: a systematic review. Pediatr Dermatol. 2016;33:9–17.
178. Mao C, Shah A, Hanson DJ, et al. Von recklinghausen’s disease associated with duodenal somatostatinoma: contrast of duodenal versus pancreatic somatostatinomas. J Surg Oncol. 1995;59:67–73.
179. Dworakowska D, Grossman AB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocr Relat Cancer. 2009;16:45–58.
180. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243–254.
181. Leung AKC, Robson WLM. Tuberous sclerosis complex: a review. J Pediatr Health Care. 2007;21:108–114.
182. Randle SC. Tuberous sclerosis complex: a review. Pediatr Ann. 2017;46:e166–e171.
183. Arva NC, Pappas JG, Bhatla T, et al. Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis-case report and review of the literature. Am J Surg Pathol. 2012;36:149–153.
184. Schwarzkopf G, Pfisterer J. Metastasizing gastrinoma and tuberous sclerosis complex. Association or coincidence? Zentralbl Pathol. 1994;139:477–481.
185. Kim H, Kerr A, Morehouse H. The association between tuberous sclerosis and insulinoma. AJNR Am J Neuroradiol. 1995;16:1543–1544.
186. Eledrisi MS, StuartCA, Alshanti M. Insulinoma in a patient with tuberous sclerosis: is there an association? Endocr Pract. 2002;8:109–112.
187. Davoren PM, Epstein MT. Insulinoma complicating tuberous sclerosis. J Neurol Neurosurg Psychiatry. 1992;55:1209–1216.
188. Merritt JL, Davis DME, Pittelkow ME, et al. Extensive acrochordons and pancreatic islet-cell tumors in tuberous sclerosis associated with TSC2 mutations. Am J Med Genet A. 2006;140:1669–1672.
189. Verhoef S, Van Diemen-Steenvoorde R, Akkersdijk WL, et al. Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur J Pediatr. 1999;158:284–287.
190. Francalanci P, Diomedi-Camassei F, Purificato C, et al. Malignant pancreatic endocrine tumor in a child with tuberous sclerosis. Am J Surg Pathol. 2003;27:1386–1389.
191. Sipos B, Sperveslage J, Anlauf M, et al. Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. J Clin Endocrinol Metab. 2015;100:E783–E788.
192. Henopp T, Anlauf M, Schmitt A, et al. Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. J Clin Endocrinol Metab. 2009;94:213–217.
193. Zhou C, Dhall D, Nissen NN, et al. Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas. 2009;38:941–946.
194. Ouyang D, Dhall D, Yu R. Pathologic pancreatic endocrine cell hyperplasia. World J Gastroenterol. 2011;17:137–143.
195. Ilett E, Langer S, Olsen I, et al. Neuroendocrine carcinomas of the gastroenteropancreatic system: a comprehensive review. Diagnostics. 2015;5:119–176.
196. Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014;120:2814–2823.
197. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38:437–447.
198. Vijayvergia N, Boland PM, Handorf E, et al. Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study. Br J Cancer. 2016;115:564–570.
199. Ohtani1 N, Yamakoshi1 K, Takahashi1 EH A. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest. 2004;51:146–153.
200. Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36:173–184.
201. Girardi DM, Silva ACB, Rêgo JFM, et al. Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: a systematic review. Cancer Treat Rev. 2017;56:28–35.
202. Sahnane N, Furlan D, Monti M, et al. Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer. 2015;22:35–45.
203. Hijioka S, Hosoda W, Mizuno N, et al. Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? J Gastroenterol. 2015;50:564–572.
204. Cubilla A, Fitzgerald P. Cancer of the exocrine pancreas: the pathologic aspects. CA Cancer J Clin. 1985;35:2–18.
205. Ohike N, Jürgensen A, Pipeleers-Marichal M, et al. Mixed ductal-endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells. Virchows Arch. 2003;442:258–265.
206. Fernandez-del Castillo M. Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer—UpToDate. 2016. Available at: www-uptodate-com.ezproxy.uniandes.edu.co:8443/contents/clinical-manifestations-diagnosis-and-staging-of-exocrine-pancreatic-cancer?source=search_result&search=pancreaticcancer&selectedTitle=1~150. Accessed February 10, 2018.
207. Terada T, Matsunaga Y, Maeta H, et al. Mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome: an autopsy case with a 24-year survival period. Virchows Arch. 1999;435:606–611.
208. Chatelain D, Parc Y, Christin-Maitre S, et al. Mixed ductal-pancreatic polypeptide-cell carcinoma of the pancreas. Histopathology. 2002;41:122–126.
209. Ordóñez NG, Balsaver AM, Mackay B. Mucinous islet cell (amphicrine) carcinoma of the pancreas associated with watery diarheaand hypokalemia syndrome. Hum Pathol. 1988;19:1458–1461.
210. Ballas KD, Rafailidis SF, Demertzidis C, et al. Mixed exocrine-endocrine tumor of the pancreas. JOP. 2005;6:449–454.
211. Ahmad Z, Mumtaz S, Fatima S, et al. Mixed ductal-endocrine carcinoma of pancreas. BMJ Case Rep. 2011;2:9–15.
212. La Rosa S, Sessa F, Uccella S. Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol. 2016;27:284–311.
213. Klöppel G, Klimstra DS, Hruban RH, et al. Pancreatic neuroendocrine tumors: update on the new World Health Organization classification. Am J Surg Pathol. 2017;22:233–239.
214. Shintaku M, Tado H, Inayama K, et al. Ductulo-insular pancreatic endocrine tumor with amyloid deposition: report of a case. Pathol Int. 2015;65:197–201.
215. Oh EJ, Lee S, Bae JS, et al. TERT promoter mutation in an aggressive cribriform morular variant of papillary thyroid carcinoma. Endocr Pathol. 2017;28:49–53.
216. Tezel E, Nagasaka T, Nomoto S, et al. Neuroendocrine-like differentiation in patients with pancreatic carcinoma. Cancer. 2000;89:2230–2236.
217. Kamisawa T, Fukayama M, Tabata I, et al. Neuroendocrine differentiation in pancreatic duct carcinoma special emphasis on duct-endocrine cell carcinoma of the pancreas. Pathol Res Pract. 1996;192:901–908.
218. Deshpande V, Selig MK, Nielsen GP, et al. Ductulo-insular pancreatic endocrine neoplasms: clinicopathologic analysis of a unique subtype of pancreatic endocrine neoplasms. Am J Surg Pathol. 2003;27:461–468.
219. Klimstra DS, Rosai J, Heffess CS. Mixed acinar-endocrine carcinomas of the pancreas. Am J Surg Pathol. 1994;18:765–778.
220. La Rosa S, Adsay V, Albarello L, et al. Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. Am J Surg Pathol. 2012;36:1782–1795.
221. Ohike N, Bastürk O, Klöppel G, et al. Mixed acinar-endocrine carcinoma of the pancreas. Pathol Case Rev. 2010;15:205–209.
222. Kyriazi MA, Arkadopoulos N, Stafyla VK, et al. Mixed acinar-endocrine carcinoma of the pancreas: a case report and review of the literature. Cases J. 2009;2:6481–6490.
223. Ogbonna OH, Garcon MC, Syrigos KN, et al. Mixed acinar-neuroendocrine carcinoma of the pancreas with neuroendocrine predominance. Case Rep Med. 2013;1:20–27.
224. Liu Z, Dong C, Wang C, et al. Mixed acinar-endocrine carcinoma of pancreas: a case report and brief review of the literature. Onco Targets Ther. 2015;8:1633–1642.
225. Lee L, Bajor-Dattilo EB, Das K. Metastatic mixed acinar-neuroendocrine carcinoma of the pancreas to the liver: a cytopathology case report with review of the literature. Diagn Cytopathol. 2013;41:164–170.
226. Apodaca-Torrez F, Pereira LC, Isaacs R, et al. Mixed acinar-endocrine carcinoma of the pancreas. Int Hepato-Pancreatico-Biliary Assoc. 2016;18:380.
227. Sullivan PS, Clebanoff JL, Hirschowitz SL. Hints to the diagnosis of mixed acinar-endocrine carcinoma on pancreatic fine-needle aspiration: avoiding a potential diagnostic pitfall. Acta Cytol. 2013;57:296–302.
228. Kitagami H, Kondo S, Hirano S, et al. Acinar cell carcinoma of the pancreas: clinical analysis of 115 patients from Pancreatic Cancer Registry Of Japan Pancreas Society. Pancreas. 2007;35:42–46.
229. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell carcinoma of the pancreas in the United States: prognostic factors and comparison to ductal adenocarcinoma. J Gastrointest Surg. 2008;12:2078–2086.
Keywords:

pancreatic neuroendocrine neoplasm; pancreatic neuroendocrine carcinoma; well-differentiated pancreatic tumor; mixed pancreatic tumors

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