Chapter 56

Neoplasms of the Endocrine Pancreas

Harish Lavu, Jonathan R. Brody, and Charles J. Yeo

Key Points

1 Pancreatic endocrine neoplasms (PENs) originate from multipotential stem cells in pancreatic

ductules. Therefore, use of the older terms islet cell tumor and islet cell carcinoma is now discouraged,

in favor of the terms pancreatic endocrine neoplasms or pancreatic endocrine tumors.

2 PENs have traditionally been classified according to the size and the mitotic rate of the tumor into

one of three categories: pancreatic endocrine microadenomas, well-differentiated PENs, and poorly

differentiated or high-grade endocrine carcinomas.

3 The most recent World Health Organization classification uses the combination of a proliferative

index (Ki-67) and mitotic rate to grade PENs while incorporating traditional TNM staging taking into

account tumor size, peripancreatic invasion, and metastatic spread to lymph nodes/distant locations,

which result in the classification of carcinoma.

4 The best initial imaging technique for a PEN is a high-quality multidetector computed tomography

(CT) scan.

5 Endoscopic ultrasonography is particularly useful in localizing tumors in patients with gastrinoma

and insulinoma.

6 Insulinomas may present with either neuroglycopenic symptoms (confusion, seizure, obtundation,

and coma) or hypoglycemic-induced symptoms (palpitations, diaphoresis, and tachycardia).

7 Ninety percent of insulinomas are solitary, 90% are sporadic, and 90% are benign with their location

evenly distributed throughout the pancreas.

8 Seventy-five percent of gastrinomas are sporadic (25% are associated with multiple endocrine

neoplasia type 1 syndrome), and all should be considered to be of malignant potential.

9 Most gastrinomas are located in the gastrinoma triangle and may be intrapancreatic, within the wall

of the duodenum, or in a peripancreatic lymph node, and in most cases local resection (enucleation)

may be adequate therapy.

10 Glucagonomas usually present with a characteristic severe dermatitis (termed necrolytic migratory

erythema) and are typically large and bulky and often with metastatic disease.

1 Pancreatic endocrine neoplasms (PENs) are rare tumors that account for 3% of pancreatic neoplasms

and 7% of all neuroendocrine tumors.1 Their incidence has increased nearly fivefold over the past 30

years, corresponding to the dramatic rise in the use of cross-sectional imaging in modern medicine. This

has led to an increase in the rate of incidental diagnoses in asymptomatic patients.2 First described by

Nicholls in 1902 as a tumor arising from pancreatic islet cells, these “islet cell adenomas” were long

thought to arise from the islets of Langerhans.3 Recent investigations have revealed that PENs more

likely originate from multipotential stem cells in pancreatic ductules.4,5 This non–islet cell origin has

been further demonstrated in tumors arising in patients with multiple endocrine neoplasia type1.6

Therefore, use of the older terms islet cell tumor and islet cell carcinoma is now discouraged, in favor of

the terms pancreatic endocrine neoplasms or pancreatic endocrine tumors.7,8

2 Traditionally, PENs were classified according to their size and the mitotic rate of the tumor. This

system placed PENs into one of three categories: pancreatic endocrine microadenomas, welldifferentiated PENs, and poorly differentiated or high-grade endocrine carcinomas. PENs are also

differentiated by the presence (i.e., functional tumors) or absence (i.e., nonfunctional tumors) of a

syndrome due to hormone production, with nonfunctional PENs (91%) being much more common than

functional tumors (9%).9,10 The production of certain hormones by the functional tumors and their

resulting symptoms lead to well-described clinical syndromes, which are detailed later in this chapter.

PENs less than 0.5 cm in diameter are classified as pancreatic endocrine microadenomas.

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Oncologically, they are considered to be benign lesions. Their prevalence is estimated to be as high as

10% of the population in autopsy series.11,12 Most pancreatic endocrine microadenomas are noted as

incidental findings in pancreata resected for other indications and, by definition, produce no neoplastic

syndromes (i.e., are nonfunctional). Functional PENs less than 0.5 cm are classified with welldifferentiated PENs.

PENs measuring greater than 0.5 cm in diameter and having a low mitotic rate of less than 10 mitoses

per 10 high-power fields are referred to as well-differentiated PENs. This group comprises the large

majority of clinically relevant PENs. They are uncommon, with an estimated incidence of approximately

1 out of 100,000 people.13,14 Although rare in children, cases have been described at all ages, and the

peak incidence occurs between the ages of 40 and 60 years.7 Overall distribution is equal between men

and women with some differences in ratio among different functional types.

3 The classification of PENs has in the past been controversial, with no single dominant staging

system in existence.15 Multiple varying staging schemes (including those by the European

Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC))16,17

have been put forward, attempting to establish prognostic characteristics such as size, mitotic count,

presence of necrosis, extrapancreatic invasion, vascular and perineural invasion, nuclear polymorphisms,

and nodal involvement.18–21 The most recent World Health Organization (WHO) classification attempts

to standardize PEN grading by using a proliferation-based system together with classical histopathologic

diagnostic criteria. This new classification takes into account the increasing importance of the

proliferative index Ki-67 as a prognostic marker for PENs. In this schema, PENs are graded into one of

three categories based upon their Ki-67 proliferation index and mitotic rate. These include two

categories of well-differentiated endocrine tumors and a third category of poorly differentiated

endocrine carcinomas. In this system, the well-differentiated tumors include those which are grade 1

(Ki-67 <3%, <2 mitoses per 10 hpf) and grade 2 (Ki-67 3% to 20%, 2 to 20 mitoses per 10 hpf).

Whereas, grade 3 (Ki-67 >20%, >20 mitoses per 10 hpf) tumors are considered poorly differentiated

carcinomas.22,23 By convention, the tumor is assigned the higher grade if the Ki-67 index and mitotic

rate differ. Any local invasion beyond the pancreas or metastatic spread to lymph nodes or distant

locations results in the classification of carcinoma (Table 56-1).

Table 56-1 WHO 2010 Classification of Well-Differentiated Pancreatic Endocrine

Tumors

Well-differentiated PENs can also be classified as functional or nonfunctional based on the presence or

absence of an associated clinically recognizable syndrome (Table 56-2). These syndromes are the result

of the secretion of biologically active hormones by the tumors and are confirmed by measurable

elevations of the hormones in the blood. The most common functional PENs include insulinomas,

gastrinomas, vasoactive intestinal polypeptide-omas (VIPomas), glucagonomas, and somatostatinomas.

The incidence of these lesions ranges from 1 per 1 million for insulinomas to 1 per 40 million for

somatostatinomas.24 Even less common PENs secreting calcitonin,25,26 parathyroid hormone–related

protein,27 growth hormone–releasing factor, and adrenocorticotropic hormone28 have been reported.

Nonfunctional PENs are classified as such due to their lack of an associated clinical syndrome. Some of

the tumors in this group do secrete elevated amounts of hormones, including chromogranin A, which

can be detected in either the serum or in surgical specimens using immunohistochemistry.29 These

secreted hormones either produce no clinical syndromes, as is seen with tumors that secrete pancreatic

polypeptide,30 or secrete hormones in subclinical amounts or inactive forms. Traditionally, functional

PENs were reported to comprise the majority of PENs. As methods of detecting these lesions and

patterns of presentation have evolved, due primarily to the widespread use of high-quality cross1426

sectional imaging, nonfunctional PENs now comprise the vast majority of surgically resected cases.18,31

The least common group of PENs is the poorly differentiated or high-grade endocrine carcinomas.

These are aggressive tumors characterized by their high mitotic count and proliferation index (>20

mitotic figures per 10 high-powered fields, Ki-67 >20%).23,32 These tumors primarily occur in adults

and have a male predominance. Some have been reported to be functional, producing varied clinical

syndromes (commonly gastrinoma, VIPoma, glucagonoma, and, less frequently, insulinoma). Prognosis

is often poor, with the clinical course varying from a rapid decline to a more indolent, prolonged

survival.

Table 56-2 Classification of Functional Pancreatic Endocrine Tumors

MOLECULAR GENETICS

The majority of PENs are sporadic. Some of them, however, occur as part of inherited familial

syndromes such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel–Lindau (VHL) syndrome,

neurofibromatosis (NF-1), and tuberous sclerosis (TSC) (see section below on genetic syndromes) (Table

56-3). Recent advances in high throughput DNA sequencing techniques have provided new insights into

the genesis of PENs and possible reasons why certain tumors behave more aggressively than others as

well as why tumors may respond more favorable to specific therapies (i.e., a more personalized

approach to therapy of PENs).

Whole-Exome Sequencing of PENs

Specifically, in a 2011 landmark paper, Jiao et al. sequenced ∼18,000 coding genes of 10 clinically

well-characterized PENs.33 Technically, this work dovetailed eloquently and aligned with the group’s

previous work of sequencing and analyzing multiple pancreatic ductal adenocarcinoma genomes.34

Importantly, the investigators microdissected the samples in an effort to achieve a high purity and

quality of DNA from neoplastic tissue. In the PENs cancer genomes compared to pancreatic ductal

adenocarcinoma genomes a number of differences were discovered including >50% fewer mutations in

PENs compared to pancreatic adenocarcinoma genomes; and commonly mutated genes such KRAS were

not mutated in PENs (Table 56-4).35 These genetic data support the notion that the chromosomal

instability (CIN) and tumorigenesis process between these two pathologically distant pancreatic

neoplasms are initiated by unique molecular and/or environmental events. The study went on to

validate the common findings in the 10 PENs (labeled a discovery set) with an additional 58 PENs.

Validating previous work and also underscoring the importance of the disruption in the chromatinremodeling pathway in PENS, a majority of PENs harbored a tumor-specific inactivating mutation in

MEN-1. Additional genes functionally important in a chromatin-remodeling complex, DAXX (deathdomain–associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked), were

frequently mutated in PENs as well. Correlating the clinical outcomes of these tumors, the study

demonstrated that patients in this cohort with MEN-1, DAXX, and ATRX mutated tumors had unique

outcomes compared to the other PENs. More recent work published in 2014, correlated DAXX and ATRX

mutations, activation of alternative lengthening of telomeres, and global chromosomal alterations with

pathologic features and outcome data.36 Interestingly, this study identified that PENs harboring DAXX

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