section name header

Disease Prologue ⬇

Summary ⬆ ⬇

Cancers Staged Using This Staging System

This staging system applies to well-differentiated neuroendocrine tumors arising in the pancreas.

Cancers Not Staged Using This Staging System

These histopathologic types of cancer…Are staged according to the classification for…and can be found in chapter…
Carcinomas of the pancreas, including high-grade (grade 3), poorly differentiated neuroendocrine carcinomaExocrine pancreas28
Well-differentiated neuroendocrine tumors arising in the duodenum (C17.0) or ampulla of Vater (C24.1)Neuroendocrine tumors of the duodenum and ampulla of Vater30

Summary of Changes

ChangeDetails of ChangeLevel of Evidence
New chapterThis staging system was included in the exocrine and endocrine pancreas chapters in previous editions.N/A
AJCC Prognostic Stage GroupsPancreatic neuroendocrine tumors are now staged using a TNM staging system predominantly based on size; the criterion of peripancreatic soft tissue invasion was eliminated.II
Definition of Primary Tumor (T)The Tis distinction was eliminated.II
Definition of Distant Metastasis (M)M1 is subdivided as follows:

M1a: metastasis confined to the liver

M1b: metastases in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)

M1c: both hepatic and extrahepatic metastases

IV

ICD-O-3 Topography Codes

CodeDescription
C25.0Head of pancreas
C25.1Body of pancreas
C25.2Tail of pancreas
C25.4Islets of Langerhans (endocrine pancreas)
C25.7Other specified parts of pancreas
C25.8Overlapping lesion of pancreas
C25.9Pancreas, NOS

WHO Classification of Tumors

This list includes histology codes and preferred terms from the WHO Classification of Tumors and the International Classification of Diseases for Oncology (ICD-O). Most of the terms in this list represent malignant behavior. For cancer reporting purposes, behavior codes /3 (denoting malignant neoplasms), /2 (denoting in situ neoplasms), and in some cases /1 (denoting neoplasms with uncertain and unknown behavior) may be appended to the 4-digit histology codes to create a complete morphology code.

CodeDescription
8150Non-functioning pancreatic neuroendocrine tumor
8151Insulinoma
8152Glucagonoma
8153Gastrinoma
8155VIPoma
8156Somatostatinoma
8158ACTH-producing tumor
8240Neuroendocrine tumor (NET) G1 (carcinoid)
8249Neuroendocrine tumor (NET) G2

Lloyd RV, Osamura RY, Klöppel G, Rosai J, eds. World Health Organization Classification of Tumours of Endocrine Organs. Lyon: IARC; 2017. Used with permission.

Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. World Health Organization Classification of Tumours of the Digestive System. Lyon: IARC; 2010. Used with permission.

International Agency for Research on Cancer, World Health Organization. International Classification of Diseases for Oncology. ICD-O-3-Online.http://codes.iarc.fr/home. Accessed September 29, 2017. Used with permission.

Introduction ⬆ ⬇

Pancreatic neuroendocrine tumors (NETs) exhibit neuroendocrine differentiation and comprise less than 2% of all pancreatic malignancies. Although these tumors are rare, their relatively indolent nature translates into a relatively high prevalence: approximately 10% of all pancreatic tumors.1 An analysis of the Surveillance, Epidemiology, and End Results (SEER) database, 1973 to 2004, suggests that the incidence of pancreatic NETs is increasing.2 In 1973, the age-adjusted incidence of pancreatic NETs in the US population was 0.18 per 100,000; in 2003, it was 0.30 per 100,000.2 A recent analysis of the national population-based Cancer Registry of Norway revealed a similar trend.3 The age-stand ardized incidence rate of pancreatic NETs in the population overall (1993-2010) was 0.47 per 100,000 (95% CI, 0.43-0.52); in 2006 to 2010, it was 0.71 per 100,000 (95% CI, 0.61-0.82). The estimated annual percentage change was +6.9%. The reason for the increasing incidence likely is multifactorial; it probably is a result, at least in part, of more accurate classification by pathologists and improved diagnostic tools (cross-sectional and functional imaging), the latter of which has led to an increase in incidentally discovered tumors.4 Pancreatic NETs appear to be slightly more common in men (53%).1 They may occur at any age but are most commonly detected in the fifth to eighth decades; the median age at diagnosis is 60.2 With the exception of patients with insulinoma, patients with pancreatic NETs often present with advanced disease.2,5 Increased detection of incidental tumors has led to a reduction in the proportion of patients diagnosed with metastatic disease at presentation.6 Autopsy studies assessing the presence of small (less than 1 cm) NETs reported frequencies ranging from 0.8-10%.7

The grading classification scheme for pancreatic NETs has evolved over the years to encompass all NETs arising in the pancreas and gastrointestinal tract. Developed by the European Neuroendocrine Tumor Society (ENETS) and adopted by the World Health Organization (WHO) in 2010, the most common classification system consists of three grades (G1, G2, and G3), which correspond to well-differentiated (G1 and G2) and poorly differentiated neoplasms (G3).8-11

Grade is a significant and independent predictor of outcome.12,13 Most NETs arising in the pancreas are well differentiated (G1 and G2) tumors, which are termed pancreatic neuroendocrine tumors, pancreatic NETs, or panNETs. Poorly differentiated neoplasms are termed pancreatic neuroendocrine carcinomas or pancreatic NECs. Although this classification implies that all high-grade tumors are poorly differentiated, recent data suggest that a significant fraction of patients with well-differentiated tumors have a ki-67 index greater than 20%, and usually less than 50%. These “well-differentiated, high-grade” tumors represent a favorable prognostic category compared with poorly differentiated NECs.14

Approximately 20% of pancreatic NETs are associated with a clinical syndrome due to hormone excess. These “functional” tumors (F-pancreatic NETs) thus are defined based on the clinical syndrome, as asymptomatic production of hormones also may be detected in nonfunctional tumors (NF-pancreatic NETs).15 Among functional tumors, the most common hormones produced are insulin and gastrin (Table 34.1).16 Overproduction of glucagon, vasoactive intestinal peptide, or proinsulin is less common.17 Other, rarer hormone-mediated syndromes also have been reported, including pancreatic NETs secreting adrenocorticotropic hormone (ACTH), leading to Cushing's syndrome (ACTHomas); pancreatic NETs causing the carcinoid syndrome; and pancreatic NETs causing hypercalcemia (PTHrp-omas).18,19 Pancreatic NETs associated with calcitonin or ACTH production appear to be relatively aggressive, as do those that switch from one functional syndrome to another.

More than 50% of functional tumors are located in the tail of the pancreas, the exception being gastrinomas, which are more likely (63%) to be located in the head of the pancreas (Table 34.1).1 Interestingly, most gastrinomas (60-80%) actually arise in the duodenum; 75-85% are located in the “gastrinoma triangle” involving the duodenum and pancreatic head.17 Insulinomas typically are small, well-circumscribed tumors that are diagnosed at an early stage as the result of symptoms associated with hypoglycemia. The vast majority do not recur after resection. Importantly, F-pancreatic NETs may produce more than one hormone, and hormone production may change over the course of tumor progression.20

34.1 Clinical features of functional pancreatic neuroendocrine tumors

NameBiologically active peptide(s)Incidence(new cases/106 population/year)Tumor locationMost common symptoms/signs
Most common syndromes
InsulinomaInsulin1-3Pancreas (greater than 99%)Hypoglycemic symptoms (Whipple's triad)
Zollinger-Ellison syndromeGastrin0.5-2Duodenum (70%); pancreas (25%); other sites (5%)Abdominal pain, gastroesophageal reflux, diarrhea, duodenal ulcers, PUD/GERD
Less common syndromes (additional, rarer syndromes also exist)
VIPoma (Verner-Morrison syndrome, pancreatic cholera, WDHA syndrome)Vasoactive intestinal peptide0.05-0.2Pancreas (90%, adult); other (10%, neural, adrenal, periganglionic)Diarrhea, hypokalemia, dehydration
GlucagonomaGlucagon0.01-0.1Pancreas (100%)Rash, glucose intolerance, weight loss
SomatostatinomaSomatostatinRarePancreas (55%); duodenum/jejunum (44%)Diabetes mellitus, cholelithiasis, diarrhea
ACTHomaACTHRarePancreas (4-16% all ectopic Cushing's)Cushing's syndrome
Pancreatic NET causing carcinoid syndromeSerotoninRarePancreas (less than 1% all carcinoid syndrome)Flushing, diarrhea
PTHrp-oma (hypercalcemia)PTHrp, others unknownRarePancreasSymptoms due to hypercalcemia
Abbreviations: GERD, gastroesophageal reflux disease; PTHrp, parathyroid hormone-related protein; PUD, peptic ulcer disease; WDHA, watery diarrhea, hypokalemia, and achlorhydria. (Adapted from Jensen et al.17)
Pancreatic NETs frequently secrete several substances into the serum, including chromogranin A (CgA), pancreatic polypeptide (PP), pancreastatin, and neuron-specific enolase, without obvious clinical consequence. As such (assuming they are not secreting any additional hormones, as listed in Table 34.1), these tumors are considered NF-pancreatic NETs.18,21-23 NF-pancreatic NETs occur at least twice as frequently as F-pancreatic NETs in most series.

The etiology of pancreatic NETs largely is unknown. Most pancreatic NETs are thought to be sporadic. Of these, approximately 43% harbor DAXX/ATRX mutations, 44% harbor somatic inactivating mutations of MEN1, and 15% contain mutations in genes encoding mTOR pathway components.24 The prognostic significance of these mutations remains to be determined definitively.24,25 A small fraction of pancreatic NETs (less than 10%) arise in the context of a hereditary cancer syndrome, the most common of which is multiple endocrine neoplasia type 1 (MEN1).26 MEN1 is caused by mutations in the MEN1 gene located at chromosome 11q13 region, thus altering transcriptional regulation, genomic stability, cell division, and cell cycle control.27 Affected patients develop hyperplasia or neoplasia of multiple endocrine and nonendocrine tissues, including parathyroid adenomas (95-100%) resulting in hyperparathyroidism, pituitary adenomas (54-65%), adrenal adenomas (27-36%), various NETs (gastric, lung, thymic; 0-10%), thyroid adenomas (up to 10%), various skin tumors (80-95%), central nervous system tumors (up to 8%), and smooth muscle tumors (up to 10%).17,28 Pancreatic NETs develop in 80-100% of MEN1 patients and are nearly always multifocal. Pancreatic NETs in this setting often are small and nonfunctional. Gastrinomas (greater than 80% duodenal) develop in 54% of MEN1 patients, insulinomas in 18%, and glucagonomas, vasoactive intestinal peptide-secreting tumors (VIPomas), growth hormone-releasing factor-secreting tumors (GRFomas), and somatostatinomas in less than 5%.17 Pancreatic NETs also occur in up to 10% of patients with von Recklinghausen's disease (also known as neurofibromatosis type 1 [NF1]), 10-17% of patients with von Hippel-Lindau (VHL) syndrome, and rarely in patients with tuberous sclerosis. The likelihood of an underlying genetic syndrome depends on the type of tumor as well as the patient's personal and family history, which should be recorded for every patient presenting with a pancreatic NET. Multifocal disease is a risk factor, as is the type of hormone produced. MEN1 is present in 20-30% of patients with Zollinger-Ellison syndrome (ZES; usually associated with a duodenal gastrinoma) and 5% of patients with an insulinoma.17 Given the high incidence of parathyroid adenomas in MEN1 patients, assessment of ionized calcium and serum parathyroid hormone (PTH) may be used as a screening tool in appropriate patients, with the caveat that secondary elevation of PTH may occur in the setting of vitamin D deficiency.29,30

The staging of pancreatic NETs depends on the size and extent of the primary tumor (including whether there is lymph node involvement and /or distant metastasis). Importantly, the American Joint Committee on Cancer (AJCC) TNM classification system for pancreatic NETs was first introduced in the AJCC Cancer Staging Manual, 7th Edition and was based on the staging algorithm for exocrine pancreatic carcinomas. Recognizing that exocrine and neuroendocrine tumors of the pancreas are distinct entities in terms of underlying tumor biology and prognosis, other staging classification systems have been proposed.12,13,31-33 The 7th Edition AJCC staging system is significantly associated with survival, but its value is limited by the inability to discriminate between the intermediate stages (i.e., Stages II and III are prognostically indistinguishable).12 Furthermore, some of the parameters necessary for staging (e.g., presence of extrapancreatic extension) are difficult to assess pathologically because of the expansile growth pattern common in pancreatic NETs. The system developed by ENETS in 2006 incorporates a narrower T definition. It has proven prognostic value and appears to provide superior distinction among stages (I, II, III, and IV) compared with the AJCC/Union for International Cancer Control (UICC)/WHO 2010 system.12 Therefore, the AJCC Cancer Staging Manual, 8th Edition staging system has been modified to be consistent with the ENETS system.

Importantly, even the current ENETS staging system is imperfect; patients with Stage IIIB (any T N1 M0) disease fare better than those with Stage IIIA (T4 N0 M0) disease, and clear discrimination between stages has not been evident in all validation studies.12,13 There are several potential reasons for this, including the generally favorable survival outcomes of patients with nonmetastatic disease, which limits the ability to distinguish prognostic groups, especially in the absence of very long-term follow-up. In addition, inconsistent lymph node sampling may underlie the conflicting findings of the prognostic importance of lymph node involvement.34 Further refinement of the ENETS staging system is likely, although inadequate data exist for modifications at present.12,33

Surgical resection remains the only potentially curative treatment for well-differentiated (G1/G2) pancreatic NETs. The natural history of these tumors is poorly understood because of their relative rarity, but accepted prognostic factors include patient age, distant metastases, tumor grade, and tumor differentiation.12 Recent studies suggest that lymph node involvement also may be an important prognostic factor.35,36 For accurate staging, routine lymph node sampling is critical for most patients with pancreatic NETs undergoing surgery.

Well-differentiated insulinomas rarely metastasize and have a particularly good prognosis (greater than 90% have a benign clinical course); the prognosis of other functional tumors appears to match that of nonfunctional tumors in most series, although this is not consistent in all studies.12 The type of surgery performed depends on the tumor stage, location, and functional status, and ranges from enucleation to pancreaticoduodenectomy.37 Because insulinomas typically are small and pursue a benign clinical course, enucleation of tumors located away from the main pancreatic duct usually is curative. For insulinomas close to the main pancreatic duct, a pancreatectomy, such as distal pancreatectomy for left-sided lesions or pancreaticoduodenectomy for right-sided lesions, may be required. Insulinomas located in the pancreatic neck region may be treated with a central pancreatectomy. Because most insulinomas are very indolent, a lymphadenectomy typically is not necessary, and spleen preservation may be considered.

In contrast, most NF-pancreatic NETs and other F-pancreatic NETs (i.e., not insulinomas) are capable of malignant behavior. The optimal treatment of incidentally identified small NF-pancreatic NETs less than 1.5 cm is unclear. Recent analyses suggest that surveillance, rather than surgery, is appropriate in many cases. A careful analysis of the potential risks and benefits of pancreatic resection is required, particularly in asymptomatic elderly patients with significant comorbidities.4,38

Most larger NF-NETs or localized pancreatic NETs with an elevated proliferative index have a higher risk of invasion and metastases; thus, resection with a lymphadenectomy should be strongly considered for these neoplasms. Even small pancreatic NETs may be associated with significant lymph node and /or liver metastases.39 Several factors influence the choice of surgical procedure, including primary tumor size, Ki-67 labeling index, mitotic index, location, and medical comorbidities. For left-sided lesions, a distal pancreatectomy and , if necessary, an en bloc splenectomy should be done to ensure adequate lymphadenectomy. A pancreaticoduodenectomy (Whipple procedure) should be considered for right-sided lesions. Rarely, a total pancreatectomy with en bloc splenectomy is required for large lesions that occupy much of the pancreas, but given the high morbidity of such a procedure, a thorough evaluation should be performed first to rule out metastatic disease. A central pancreatectomy with regional lymphadenectomy might be considered for lesions located in the pancreatic neck. If enucleation is considered for these neoplasms, a regional lymphadenectomy may be done to ensure adequate lymph node sampling for staging. Removal of a pancreatic primary tumor in the setting of resectable liver metastases may be considered, particularly if a pancreaticoduodenectomy is not required. Although complete resection and /or palliative debulking surgeries (i.e., primary tumor and liver metastases) are not necessarily curative, data from nonrand omized studies suggest they may be associated with improved hormone-mediated symptoms and improved survival in carefully selected patients.40,41

Several treatment options exist for patients with advanced, unresectable pancreatic NETs. Somatostatin analogs have cytostatic activity and may be used to treat hormone-mediated symptoms.42-44 Chemotherapy has been used with some success, although the optimal regimen remains unclear.45-47 Two targeted therapies are approved for this indication: everolimus (an inhibitor of mTOR signaling) and sunitinib (an oral inhibitor of vascular endothelial growth factor signaling) both delay progression of progressive panNETs.48,49 The use of liver-directed therapy or other treatments depends on several factors, including the tumor's growth rate, extent of disease, and whether the tumor is functional. See published guidelines for additional information regarding the workup and treatment of panNETs.17,37,50

Anatomy ⬆ ⬇

Primary Site(s)

The pancreas is a long, coarsely lobulated gland that lies transversely across the posterior abdomen and extends from the duodenum to the splenic hilum. The organ is divided into a head with a small uncinate process, a neck, a body, and a tail. These are contiguous regions without sharp anatomic distinctions. The pancreas neck lies anterior to the superior mesenteric vessels. The anterior aspect of the body of the pancreas is covered by peritoneum and is in direct contact with the posterior wall of the stomach; posteriorly, the pancreas extends within the retroperitoneal soft tissue to the inferior vena cava, superior mesenteric vein, splenic vein, and left adrenal and kidney.

Pancreatic NETs are distributed throughout the pancreas.1,11,12 Tumors of the head of the pancreas are those arising to the right of the superior mesenteric-portal vein confluence (Figure 34.1). The uncinate process is the part of the pancreatic head that extends behind the superior mesenteric vessels. The neck overlies the superior mesenteric vessels. Tumors of the body of the pancreas are defined as those arising to the left of the neck. Laterally to the left side, the body becomes the tail of the pancreas without any clear junction point.

34.1 Anatomy of the pancreas.

Regional Lymph Nodes

The stand ard regional lymph node basins and soft tissues resected for tumors located in the head and neck of the pancreas include lymph nodes along the common bile duct, common hepatic artery, portal vein, posterior and anterior pancreatoduodenal arcades, and the superior mesenteric vein and right lateral wall of the superior mesenteric artery (Figure 34.2). For cancers located in the body and tail, regional lymph node basins include lymph nodes along the common hepatic artery, celiac axis, splenic artery, and splenic hilum (Figure 34.2). Involvement of peripancreatic lymph nodes is considered regional disease and classified as N1.

34.2 Regional lymph nodes of the pancreas (anterior view).

Metastatic Sites

Distant spread is common on presentation and most commonly involves the liver. Metastases to other sites, such as lung, bones, and peritoneum, also may occur. Involvement of the para-aortic or other distant lymph nodes (i.e., retroperitoneal, retrocrural, and mesenteric lymph nodes) is considered M1 disease (see Figure 34.2 for regional lymph nodes). Seeding of the peritoneum (even if limited to the lesser sac region) is considered M1.

Classification Rules ⬆ ⬇

Clinical Classification

Guidelines have been established for the workup of patients with pancreatic NETs.37,50,51 In general, patients should be evaluated by multiphasic computed tomography (CT) or magnetic resonance (MR) imaging to assess 1) the proximity of the primary pancreatic NET to major vessels and 2) the clinical T, N, and M staging of the lesion before any surgical or medical therapy is considered. In addition, biochemical assessment, somatostatin receptor scintigraphy (SRS), and endoscopic ultrasonography (EUS) should be performed as appropriate. For localized tumors, a biopsy is not necessarily required before surgical resection. However, if a biopsy (e.g., endoscopic biopsy, percutaneous core needle biopsy, fine-needle aspiration) is performed, the results should be incorporated when assessing clinical stage.

By definition, patients with F-pancreatic NETs present with hormone-mediated symptoms consistent with a characteristic syndrome.17,37 As such, the diagnosis of F-pancreatic NETs requires demonstration of a significantly elevated hormone combined with clinical signs or symptoms of oversecretion (e.g., ulcers in the setting of gastrinoma, hypoglycemia in the setting of insulinoma).37 Specifically, for insulinomas, assessment of plasma insulin, proinsulin, and C-peptide is needed at the time of glucose determinations, usually during a 72-hour supervised fast.17 For ZES, fasting serum gastrin (FSG) should be assessed, unstimulated or during a secretin provocation test.18 The diagnosis of ZES requires demonstration of an inappropriate elevation of gastrin in the presence of hyperchlorhydria or an acidic pH (less than 2). FSG alone is not diagnostic, because hypergastrinemia may be caused by hypochlorhydria/achlorhydria (chronic atrophic fundic [autoimmune] gastritis, often associated with pernicious anemia) and is a common consequence of proton pump inhibitor (PPI) use. Ideally, PPIs should be stopped in order to make the diagnosis of gastrinoma, but this may be difficult in patients with severe gastroesophageal reflux disease/gastrinoma and necessitates switching to an H2 blocker (ideally in the context of a specialty unit with experience in diagnosing ZES). Furthermore, other disorders cause hypergastrinemia with hyperchlorhydria (e.g., Helicobacter pylori infection, gastric outlet obstruction, renal failure, antral G-cell syndromes, G-cell hyperplasia, short bowel syndrome, retained antrum). FSG level alone cannot distinguish ZES from achlorhydric states including PPI use.

For VIPomas, the plasma vasoactive intestinal peptide level must be determined. For glucagonoma, measurement of plasma glucagon levels is appropriate. For GRFomas, plasma growth hormone and growth hormone-releasing factor levels should be measured. For Cushing's syndrome, urinary cortisol, plasma ACTH, and appropriate ACTH suppression studies should be performed. For pancreatic NET-associated hypercalcemia, measurement of both serum PTH and PTHrP levels is indicated, and for a pancreatic NET associated with carcinoid syndrome, urinary or plasma 5-hydroxyindoleacetic acid (5-HIAA) should be measured.18,52 Assessment for hormones associated with rarer syndromes should be performed as clinically indicated.19

In contrast, unless incidentally discovered during a workup for an unrelated problem, NF-pancreatic NETs typically present with symptoms due to the tumor itself, including abdominal pain (40-60%), weight loss, or jaundice.18,23 53 Although NF-pancreatic NETs do not secrete peptides causing a clinical syndrome, they characteristically secrete several other peptides, such as CgA, PP, neuron-specific enolase, and /or pancreastatin (a subunit of chromogranin), which may be helpful for the diagnosis and monitoring of affected patients.18,23 At this time, there is insufficient evidence regarding the impact of any individual tumor marker on clinical decision making to recommend a particular assay.

Imaging

Information necessary for the clinical staging of pancreatic NETs may be obtained from physical examination; cross-sectional radiographic imaging studies, including triphasic (noncontrast, arterial, and venous) contrast-enhanced CT or MR imaging; and SRS.5 (Refer to established guidelines for details.)37 The detection rate of pancreatic primary tumors is in the range of 75-79% with cross-sectional imaging, and the sensitivity for detection of liver metastases is up to 80% with contrast-enhanced, multiphasic CT or MR imaging.5,54 SRS with indium-111 pentetreotide imaging (Octreoscan; Mallinckrodt Pharmaceuticals, Dublin, Ireland ) has a sensitivity of up to 90% for pancreatic NETs, depending on tumor size and type (e.g., 20-60% sensitivity for detecting insulinomas).54 Stand ard fluorodeoxyglucose positron emission tomography (PET) with fluorine-18 glucose has limited value in the evaluation of well-differentiated pancreatic NETs. EUS also provides useful information for detection of small and /or multifocal pancreatic NETs and is the procedure of choice for performing fine-needle aspiration biopsy of the pancreas. Studies suggest detection rates of 90-100% for pancreatic lesions and 45-60% for tumors arising in the duodenum.55

Unlike its exocrine counterpart (pancreatic ductal adenocarcinoma), tumor involvement of the celiac axis or superior mesenteric artery is rare in pancreatic NETs. The stand ard radiographic assessment of resectability includes evaluation for distant metastases (e.g., peritoneal, liver, bone); the patency of the superior mesenteric vein and portal vein, as well as the relationship of these vessels and their tributaries to the tumor; and the relationship of the tumor to the superior mesenteric artery, celiac axis, and hepatic artery.

NET imaging using PET with gallium-68 (68Ga)-labeled somatostatin analogs appears promising (same-day results, potential for increased sensitivity, broader affinity profile, better spatial resolution, easier quantification of tracer uptake).56, 57,58 Studies to assess the value of 68Ga-labeled somatostatin analog-based PET/CT and PET/MR imaging relative to stand ard somatostatin scintigraphy are ongoing. This technology represents an emerging imaging tool for NETs in the United States; a kit for the preparation of 68Ga-dotatate injection for PET imaging recently received U.S. Food and Drug Administration approval.59

Pathological Classification

Pathological staging is based on surgical resection specimens. The most sensitive pathological staging is obtained by examining surgically resected primary tumor(s), lymph nodes, and distant metastases according to an established minimum pathology dataset.10,60-62

Partial resection (pancreaticoduodenectomy or distal pancreatectomy) or complete resection of the pancreas, including the tumor and associated regional lymph nodes, provides the optimal information for pathological staging. In pancreaticoduodenectomy specimens, the bile duct, pancreatic duct, and superior mesenteric artery margins should be evaluated grossly and microscopically. The superior mesenteric artery margin also has been termed the retroperitoneal, vascular, or uncinate margin. In total pancreatectomy specimens, the bile duct and retroperitoneal margins should be assessed. Duodenal (with pylorus-preserving pancreaticoduodenectomy) and gastric (with stand ard pancreaticoduodenectomy) margins rarely are involved, but their status should be included in the surgical pathology report. Reporting of margins may be facilitated by ensuring documentation of the pertinent margins: 1) common bile (hepatic) duct, 2) pancreatic neck, 3) superior mesenteric artery, 4) other soft tissue margins (i.e., posterior pancreatic, duodenum, and stomach).

A rich lymphatic network surrounds the pancreas, and accurate tumor staging requires analysis of all lymph nodes removed. Optimal histologic examination of a pancreaticoduodenectomy specimen should include analysis of a minimum of 12 lymph nodes. However, the number of lymph nodes removed depends on the type of surgery performed and may not be feasible in the setting of a distal pancreatectomy without en bloc splenectomy. Therefore, spleen preservation should not be done when there is a high chance of malignancy (i.e., for any pancreatic NET other than a small insulinoma). Furthermore, lymph nodes typically are not sampled in the setting of an enucleation procedure. The number of lymph nodes examined should be specified in the pathology report. Anatomic division of regional lymph nodes is not necessary; however, separately submitted lymph nodes should be reported as labeled by the surgeon. Finally, an N category (N1 or N0) should be assigned as long as at least one lymph node has been assessed, even if the optimal number of lymph nodes have not been examined. Nx should be applied only if no lymph nodes were assessed (e.g., if enucleation was performed). Positive peritoneal cytology is considered M1.

The pathological diagnosis of pancreatic NETs may be established by histologic evaluation alone if classic morphologic features are present. However, the morphology of pancreatic NETs is highly variable, and alternative diagnoses, such as acinar cell carcinoma (or mixed acinar NEC), solid pseudopapillary neoplasm, or ductal adenocarcinoma, may be considered in many cases. Immunolabeling for the general neuroendocrine markers chromogranin and synaptophysin is helpful to support the diagnosis of pancreatic NETs, provided other markers are performed to exclude the alternative diagnoses, some of which share expression of chromogranin or synaptophysin with pancreatic NETs.

Immunohistochemistry for hormones is optional and does not have prognostic significance. Positive immunostaining for a hormone does not necessarily indicate the presence of a hormonal syndrome.

For pancreatic NETs, the r prefix is used for recurrent tumor status (rTNM) following a disease-free interval after treatment.

Prognostic Factors ⬆ ⬇

Prognostic Factors Required for Stage Grouping

Beyond the factors used to assign T, N, or M categories, no additional prognostic factors are required for stage grouping.

Additional Factors Recommended for Clinical Care

Mitotic Count

Tumor grade is determined by mitotic count and Ki-67 labeling index and correlates with progression-free survival, overall survival, and lymph node status in pancreatic NETs.12,63,64 Mitotic count should be assessed as the number of mitoses per 10 high-power fields (HPF): HPF = 2 mm2, at least 50 fields (at 40× magnification) evaluated.

Mitotic count, # of mitoses per 10 HPF (specify:)

  • less than 2
  • 2 to 20
  • greater than 20
  • Not performed
AJCC Level of Evidence: I
Ki-67 Labeling Index

Tumor grade is determined by mitotic count and Ki-67 labeling index and correlates with progression-free survival, overall survival, and lymph node status in pancreatic NETs. The proliferation index as measured by Ki-67 also correlates with these outcome measures in pancreatic NETs.12,38,63,64 The Ki-67 index typically is measured using the MIB1 antibody, by counting the number of immunolabeled tumor cells per 500 to 2,000 cells in areas of highest nuclear labeling; the Ki-67 index is expressed as a percentage.

  • Ki-67 labeling index (specify:)
    • less than 3%
    • 3% to 20%
    • greater than 20%
  • Other (specify)
  • Not performed
AJCC Level of Evidence: I
Associated Genetic Syndrome

Gastroenteropancreatic NETs sometimes arise in the setting of an inherited cancer syndrome characterized by a germline mutation. Tumors arising in the setting of an inherited cancer syndrome may be multiple and appear to be associated with a better prognosis than sporadic tumors, at least in the setting of MEN1.12

This factor should be recorded as follows:

  • Familial syndrome
    • Multiple endocrine neoplasia type 1 (alteration in MEN1)
    • Von Hippel-Lindau disease (mutation in VHL gene)
    • Neurofibromatosis type 1 (mutation inNf1)
    • Tuberous sclerosis complex (mutation in TSC1or TSC2)
    • Mahvash disease (pancreatic NET caused by inactivating glucagon receptor mutation)65
    • Other syndrome
  • Sporadic tumor
  • Unknown/unable to assess
AJCC Level of Evidence: II
Chromogranin A (CgA)

CgA is a 49-kDa acidic polypeptide present in the secretory granules of all neuroendocrine cells. CgA is a general NET marker, and plasma or serum CgA may be used as a marker in patients with either F- or NF-pancreatic NETs.18,66-68 CgA has prognostic significance, with higher levels indicating a worse prognosis.69 Furthermore, changes over time may be useful in assessing for recurrence after surgery or response to therapy in patients with metastatic disease.66,67,70,71

Despite the potential merits of monitoring CgA levels, the clinical utility of CgA is limited by the fact that it is falsely elevated in the setting of PPI use, chronic atrophic gastritis, renal failure, severe hypertension, and other conditions.8 Moreover, levels may fluctuate based on time of collection and fasting versus nonfasting states. Also, the upper limit of normal (ULN) varies widely depending on the assay used and whether plasma or serum is assessed; thus, both the assay and type of sample should be considered when comparing CgA values over time.72 As a result, routine measurement of CgA is not a consensus National Comprehensive Cancer Network (NCCN) recommendation. Multiple Clinical Laboratory Improvement Amendments (CLIA)-licensed and College of American Pathology (CAP)-accredited reference laboratories in the United States can measure CgA levels.

AJCC Level of Evidence: II
Functionality

Tumors with hormone expression noted on immunohistochemistry but not associated with a clinically relevant syndrome or signs should be recorded as nonfunctional. Similarly, tumors associated with elevated blood levels of hormones that are not associated with clinical symptoms also should be recorded as nonfunctional. Insulinomas typically have a low risk of metastasis and thus carry a good prognosis; the outcome of other F-pancreatic NETs appears to be similar to that of nonfunctional tumors in most studies.12,13 Importantly, the clinical manifestations and morbidity of F-pancreatic NETs may differ, and in some cases, mortality may relate to the hormonal syndrome rather than to the extent of the neoplasm.

Functionality should be characterized as follows:

  • Functional
    • Insulinoma
    • Gasrinoma (ZES)
    • Glucagonoma
    • VIPoma (Verner-Morrison syndrome)
    • Somatostatinoma
    • ACTHoma
    • PanNET causing carcinoid syndrom (5-HIAA, serotonin excess)
    • PanNET causing hypercalcemia (PTHrp or other)
    • Other
  • Nonfunctional
  • Unknown/unable to assess
AJCC Level of Evidence: III

Pancreastatin

Pancreastatin is a posttranslational product of CgA whose blood level inversely correlates with prognosis.67,73 Levels also correlate with the number of liver metastases and may be useful in monitoring for recurrence after surgery or for response to therapy.67,73 Perioperative pancreastatin level is an independent predictor of outcome in resected small bowel NETs and pancreatic NETs.74 Additional studies are needed to validate these findings. Compared with CgA, pancreastatin may have better specificity in diagnosing NETs because it is not affected by PPI use or atrophic gastritis.8,9,75 There are at least three large CLIA-certified and CAP-accredited reference laboratories that routinely measure pancreastatin.

AJCC Level of Evidence: III

Risk Assessment ⬆ ⬇

Risk Assesment Models

The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use.76 Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Recommendations ⬆ ⬇

Histologic grade (G1, G2 vs. G3)

TNM Definitions ⬆ ⬇

Definition of Primary Tumor (T)

T CategoryT Criteria
TXTumor cannot be assessed
T1Tumor limited to the pancreas, less than 2 cm
T2Tumor limited to the pancreas, 2-4 cm
T3Tumor limited to the pancreas, greater than 4 cm; or tumor invading the duodenum or common bile duct
T4Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland ) or the wall of large vessels (celiac axis or the superior mesenteric artery)

Limited to the pancreas means there is no invasion of adjacent organs (stomach, spleen, colon, adrenal gland ) or the wall of large vessels (celiac axis or the superior mesenteric artery). Extension of tumor into peripancreatic adipose tissue is NOT a basis for staging.

Multiple tumors should be designated as such (the largest tumor should be used to assign T category): If the number of tumors is known, use T(#); e.g., pT3(4) N0 M0. If the number of tumors is unavailable or too numerous, use the m suffix, T(m); e.g., pT3(m) N0 M0.

Definition of Regional Lymph Node (N)

N CategoryN Criteria
NXRegional lymph nodes cannot be assessed
N0No regional lymph node involvement
N1Regional lymph node involvement

Definition of Distant Metastasis (M)

M CategoryM Criteria
M0No distant metastasis
M1Distant metastases
M1aMetastasis confined to liver
M1bMetastases in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
M1cBoth hepatic and extrahepatic metastases

Stage Prognostic ⬆ ⬇

!!Calculator!!

AJCC PROGNOSTIC STAGE GROUPS

When T is…and N is…and M is…Then the stage group is…
T1N0M0I
T2N0M0II
T3N0M0II
T4N0M0III
Any TN1M0III
Any TAny NM1IV

Registry Data ⬆ ⬇

Registry Data Collection Variables

  1. Size of tumor (value, unknown)
  2. Presence of invasion into adjacent organs/structures (Y/N)
    1. If yes, which ones (pick all that apply):
      1. Stomach (Y/N)
      2. Duodenum (Y/N)
      3. Spleen (Y/N)
      4. Colon (Y/N)
      5. Other:
    2. If yes, were multiple adjacent organs involved (Y/N)
  3. Presence of necrosis
  4. Number of tumors (multicentric disease at primary site)
  5. Lymph node status (including number of lymph nodes assessed and number of positive nodes)
  6. Grade (based on Ki-67 and /or mitotic count; G1, G2, G3, unknown)
  7. Mitotic count (value, unknown)
  8. Ki-67 Labeling Index (value, unknown)
  9. Perineural invasion (Y/N)
  10. Lymphovascular invasion (Y/N)
  11. Margin status (+/-)
  12. Functional status (Y/N, type of syndrome)
  13. Genetic syndrome (Y/N, type of syndrome)
  14. Location in pancreas (head, tail, body, junction body/tail, junction body/head, unknown)
  15. Type of surgery (enucleation; distal pancreatectomy with splenectomy; distal pancratectomy without splenectomy; central pancreatectomy;; pancreaticoduodenectomy (Whipple procedure); unknown; other)
  16. Preoperative CgA level (absolute value with ULN; unknown)
  17. Preoperative pancreastatin level (absolute value with ULN; unknown)
  18. Age of patient

Histopathologic type ⬆ ⬇

This staging system applies to well-differentiated NETs arising in the pancreas.

Histologic grade ⬆ ⬇

HISTOLOGIC GRADE (G)

Grading of pancreatic NETs is required for prognostic stratification and should be performed on all resection specimens and on biopsy specimens containing sufficient tumor tissue to allow accurate measurement of proliferation (50 HPF for mitotic counting and 500 cells to determine the Ki-67 index). If multiple disease sites are sampled (e.g., a primary tumor as well as a metastasis), the grade of each site should be recorded separately. If multiple foci are sampled within a single anatomic site (e.g., multiple liver metastases), the highest grade may be recorded. The grading scheme described here is currently endorsed by ENETS/WHO for gastrointestinal and pancreatic neuroendocrine neoplasms.

GG Definition
GXGrade cannot be assessed
G1Mitotic count (per 10 HPF) less than 2 and Ki-67 index (%) less than 3
G2Mitotic count (per 10 HPF) equal to 2-20 or Ki-67 index (%) equal to 3-20
G3Mitotic count (per 10 HPF) greater than 20 or Ki-67 index (%) greater than 20

10 HPF = 2 mm2; at least 50 HPF (at 40× magnification) must be evaluated in areas of highest mitotic density in order to match WHO 2010 criteria.

MIB1 antibody; % of 500-2,000 tumor cells in areas of highest nuclear labeling.

The Ki-67 index is based on the region with the highest labeling rate (“hot spot”), determined by examining the Ki-67 stain at low magnification. In the event of discordance between the grade indicated by the mitotic count and that suggested by the Ki-67 index, the higher grade should be assigned. Nuclear pleomorphism is not a useful feature for grading neuroendocrine neoplasms. Although necrosis has been regarded as a prognostic factor in some studies, its presence is not incorporated into the grading scheme.

Well-differentiated NETs are subdivided into G1 and G2 tumors based on proliferative and mitotic index. G1 and G2 refer to well-differentiated NETs displaying diffuse and intense expression of two general immunohistochemical neuroendocrine markers (i.e., CgA and synaptophysin). G3 usually indicates a poorly differentiated NEC, which should be staged using the system for pancreatic carcinomas (Chapter 28). High-grade (G3) tumors typically are characterized by a high mitotic count/Ki-67 index, nuclear pleomorphism, and extensive necrosis. Immunohistochemical expression of CgA and /or synaptophysin may be weak.

In some cases, pancreatic neuroendocrine neoplasms with well-differentiated histologic features have a Ki-67 index (or, more rarely, a mitotic count) within the G3 range.14,77-80 Although these neoplasms currently are considered high grade in the WHO grading scheme, emerging data suggest that they are not as aggressive as poorly differentiated NECs with undifferentiated, small cell, or large cell morphology, and their response to therapy is more in line with that of other well-differentiated pancreatic NETs.77 Progression of a well-differentiated pancreatic NET from G1 or G2 to G3 also has been documented. It has been proposed that these well-differentiated neuroendocrine neoplasms be classified as well-differentiated NETs, G3. As such, they should be staged using the parameters of pancreatic NETs, rather than those of pancreatic carcinomas.

Survival ⬆ ⬇

Four years of data (diagnosis years 2010-2013) from the National Cancer Data Base were used to assess survival. Maximum follow-up time for these patients was 3 years. Selection criteria included primary site codes C25.0, C25.1, C25.2, C25.4, C25.7, C25.8, and C25.9; grade 1 and grade 2; histology codes 8150, 8151, 8152, 8153, 8155, 8156, 8158, 8240, 8249, and 8246; ages 18 and older; and only primary or first of multiple primaries.

In this study, 1,174 pancreatic NETs were identified and recategorized according to the 8th Edition (ENETS) staging system as indicated: Stage 1, n =262; Stage IIA, n = 221; Stage IIB, n = 191; Stage IIIA, n = 32; Stage IIIB, n = 346; and Stage IV, n = 122). Product limit survival curves (Kaplan-Meier) and 95% confidence intervals adjusted for age were produced; however, there were not enough cases or follow-up to assess survival accurately. Therefore, survival tables and charts are not included.

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