Advances in Anatomic Pathology:
Pancreatic Endocrine Tumors: An Update
Chetty, Runjan MB, BCH, DPHIL; Asa, Sylvia L MD, PHD
From the Department of Pathology, University Health Network/Toronto Medical Laboratories, University of Toronto, Toronto, Canada.
Reprints: Dr Sylvia Asa, MD, PhD, Department of Pathology, Princess Margaret Hospital, 610 University Avenue, Fourth floor, Suite 302, Toronto, ON M5G 2M9, Canada (e-mail: email@example.com).
The morphology of pancreatic endocrine tumors (PETs) is similar to that of endocrine tumors elsewhere in the body. PETs are usually encountered in adults. They may be clinically functional and associated with various syndromes related to hormone excess. However, it must be remembered that absence of obvious clinical symptoms may not necessarily reflect true lack of clinical function, and subtle clinical manifestations may be missed. Current thinking indicates that PETs arise from totipotential stem cells as well as preexisting endocrine cells. PETs may be hereditary or sporadic. The hereditary forms are associated with multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome, neurofibromatosis, and tuberous sclerosis. In sporadic PETs, the most consistent and recurring chromosomal abnormality is allelic loss of chromosome 11q, which includes the MEN-1 locus. Loss of a sex chromosome has been shown to be associated with metastasis, local invasion, and poor survival.
“All truths are easy to understand once they are discovered; the point is to discover them.” - —Galileo Galilei
Pancreatic endocrine tumors (PET) have been associated with a certain mystique despite their somewhat obvious and easily recognizable clinical and pathologic manifestations. Perhaps it is the syndromic clinical scenario and its infrequency that have intensified fascination among pathologists and clinicians alike and ensured that PETs have come under closer scrutiny of late, especially in terms of molecular pathogenesis.
It has been estimated that the incidence of PETs is 0.4 to 1 per 100,000 people.1–4 Autopsy surveys have shown the incidence to range from 0% to 10% of autopsies depending on the thoroughness of sectioning and sampling of the pancreas.5,6 In a surgical series, PETs were found to account for about 15% of pancreatic neoplasms.7,8
PETs are encountered in adults, and most occur in patients over the age of 30 years.9 Clinically, there are functioning and nonfunctioning PETs depending on whether clinical symptoms caused by hormone/peptide production are present or not. Immunohistochemically detected peptides within a tumor do not necessarily equate to clinically functional tumors. Distinct functional states have been ascribed to PETs depending on the dominant hormone that is produced and the associated clinical symptoms (Table 1). These may be caused by excess of gastrin (Zollinger-Ellison syndrome), insulin, vasoactive intestinal peptide (VIP), glucagon, somatostatin, growth hormone-releasing hormone (GHRH), adrenocorticotropic hormone (ACTH), 5-hydroxytryptamine or serotonin (carcinoid syndrome), parathyroid hormone-related peptide (PTHrP), and calcitonin. Of the functional tumors, some controversy exists as to whether insulin- or gastrin-producing tumors are more common. Some studies suggest that the former account for the majority of PETs (range 46%–85%),9,10 but others are of the opinion that the gastrin-producing tumors are more frequently encountered.11–15 Overall, nonfunctioning tumors are more common than the functional ones.4
The concept of a totipotential stem cell within ductules as a progenitor of both exocrine and endocrine cells is now well established and generally accepted. In addition, it is thought that both exocrine and endocrine pancreatic tissue can be derived from preexisting, differentiated exocrine and endocrine cells. This observation is based on experimental models that demonstrate regeneration of both exocrine and endocrine pancreas from existing cells and regenerating ductules.16 A slightly opposing view has been proposed based on studies in transgenic mice that develop PETs17; in these models it appears that endocrine tumors develop from mature endocrine cells located within preexisting islets of Langerhans. It is therefore likely that there is more than one source of origin for PETs: they arise from totipotential stem cells and from differentiated, mature endocrine cells, and a multistep process of genetic alterations with tumor cell proliferation is mediated by growth factors including insulin-like growth factor-1 (IGF-1).18
The gross and microscopic appearances of PETs are well characterized, and detailed descriptions are available, especially in some of the recently written textbooks.1,2 However, there are a few associated entities that are worth highlighting.
The size and shape of normal islets of Langerhans vary. The most recognizable islet is spherical or round, but more elongated or “arching” islets are also described.1 The size of islets varies from 50 to 150 μm in newborns and from 50 to 250 μm in adults. Thus, islets larger than 250 μm but less than 0.5 mm are regarded as hyperplastic islets. Lesions 0.5 mm in diameter are considered microadenomas.
Islet hyperplasia is considered to be an increase in volume density of the endocrine component that is accomplished by an increase in both islet size and islet number. This condition has been encountered in a diverse range of conditions and has even been documented in asymptomatic patients with normal pancreatic function. Some of the discrepancies may be explained by failure to recognize the important differences in islet mass in the various parts of the pancreas; islet mass in the tail is greater than that in the body and head of the organ, and there are regional differences in cell distribution, with more PP cells in the islets of the uncinate process. Conditions that have been associated with islet hyperplasia include α1-antitrypsin deficiency, hyperinsulinism, Zollinger-Ellison syndrome, Verner-Morrison syndrome, maternal diabetes, erythroblastosis fetalis, acquired immunodeficiency syndrome (AIDS), Simpson-Golabi-Behmel syndrome, hereditary tyrosinemia of hepatorenal type, Zellweger cerebrohepatorenal syndrome, leprechaunism, and Beckwith-Weidemann syndrome.19
Microscopy of islet hyperplasia reveals large islets that vary in size and shape and exhibit a degree of coalescence (Fig. 1). Within the islets there is retention of the spatial arrangement and distribution of the 4 main endocrine cell types. Markedly enlarged, sometimes bizarre B cells are sometimes encountered, especially in cases of neonatal nesidioblastosis.
Islet Dysplasia (Nesidiodysplasia)
La Rosa and colleagues highlighted 3 characteristic features of islet dysplasia19:
1. Normal-sized or slightly enlarged islets with cells often arranged in trabeculae.
2. Loss of the normal spatial and quantitative arrangement of the 4 main cell types with altered dominance of 1 cell type.
3. Mild cytologic atypia.
These morphologic features are demonstrated in Figure 2.
Once islet dysplasia attains a size of 0.5 mm, it is called microadenoma.1 Islet dysplasia is most frequently associated with multiple endocrine neoplasia (MEN) type 1.
The definition of nesidioblastosis, in the broadest sense, is the occurrence of endocrine cells often in clusters intimately associated with pancreatic ductules and forming so-called ductuloinsular complexes (Fig. 3). Often associated with this is so-called endocrine cell “maldistribution” or islet hyperplasia with prominent, hypertrophic, bizarre cells resulting in hyperinsulinemic hypoglycemia.20 The term “nesidioblastosis” was coined in 1938 by Laidlaw to describe the phenomenon of islet cells originating from pancreatic duct epithelium.21 The term has embryologic roots in that the same phenomenon or process occurs during embryonic or fetal life. After 10 to 11 weeks of gestation, endocrine cells can be seen budding off pancreatic duct epithelium and then proliferating to form the islets of Langerhans.22 Thus, nesidioblastosis is a reflection of this particular embryologic event, but the term has also been used to describe islet hyperplasia. The frequent coexistence of ductuloinsular complexes and islet hyperplasia and the overlap of conditions in which both have been described (alone or together such as MEN type 1, chronic pancreatitis) lend support to the concept that they are part of the same spectrum of lesions. From a purist’s point of view, nesidioblastosis is the presence of endocrine cells budding off pancreatic ductule epithelium, a condition that is seen in many pancreatic conditions, including chronic pancreatitis with ductular proliferation.
Unusual Histopathologic Appearances
Most PETs conform to the typical neuroendocrine pattern with the well-recognized “zellballen” or packeted arrangement evident. Equally commonly seen is a trabecular pattern. Variations in both cell morphology and pattern have been well described.1 The less commonly encountered morphologic variants include PETs composed of oncocytes (Fig. 4a) and those composed of so-called “rhabdoid” cells (Fig. 4b). Unusual patterns include cases that can sometimes mimic a pancreatic acinar carcinoma by virtue of its microglandular or tubuloacinar pattern (Fig. 5).
These lesions are readily classified by the immunohistochemical localization of common markers of neuroendocrine differentiation. They almost uniformly stain for synaptophysin, a 38-kD molecule that is associated with synaptic vesicles of neurons and neuroendocrine cells. Most contain chromogranins, proteins associated with secretory granules. There are 2 families of chromogranins, A and B; to appropriately classify these lesions one needs to identify both chromogranins. Moreover, chromogranin immunoreactivity is directly related to the number of secretory granules, which may be scarce in some tumors that are poorly differentiated or those that rapidly secrete their hormone product without storing it in significant amounts. Other markers of neuroendocrine differentiation include CD57 (Leu 7), neural cell adhesion molecule (NCAM; CD56), neuron-specific enolase (NSE), and Protein Gene Product 9.5 (PGP 9.5), which stain variable subpopulations of endocrine lesions, and some, such as NCAM and NSE, that stain some nonendocrine tumors as well.
The structure-function correlations of these lesions are best defined by their immunoreactivity for specific peptide hormones. Those associated with clinical symptoms and predictive of biologic behavior are the most important to evaluate and are listed in Table 1. In most laboratories the panel of antisera available for characterization of hormone production is limited; however, at a minimum, these lesions should be examined for production of the eutopic hormones insulin, glucagon, somatostatin, and pancreatic polypeptide as well as for the important common ectopic substances gastrin and VIP.
Functional PETs have been named for the peptide that is released. Insulinomas, gastrinomas, glucagonomas, and somatostatinomas have all become popular appellations for PETs elaborating the corresponding peptides or hormones. However, as pointed out by Wick and Graeme-Cook,4 this occurrence is not specific, and several neuroendocrine tumors such as paragangliomas and neuroblastomas are also capable of producing some of the aforementioned hormones. It is recommended that the morphologic and functional status should be recorded, and a more appropriate diagnosis is: “primary pancreatic (neuro)endocrine tumor/neoplasm producing somatostatin,” or “somatostatin-producing pancreatic (neuro)endocrine tumor/neoplasm.” It is worth reiterating that immunohistochemically detected peptides do not imply that the patient has clinical symptoms, nor does this finding imply that the tumor is functional. If clinically nonfunctional, these tumors may be designated as “nonfunctioning pancreatic (neuro)endocrine tumor/neoplasm composed mainly of somatostatin-producing cells.” However, it must be recognized that absence of recognized clinical features may not necessarily reflect true lack of clinical function, and subtle clinical manifestations may be missed. Most patients are not evaluated biochemically for the full spectrum of peptide products of PETs. Should no dominant hormone be detected immunohistochemically, the tumor is a simply “primary pancreatic (neuro)endocrine tumor/neoplasm, with insulin-, glucagon-, VIP-, and somatostatin-producing cells present.” The above nomenclature is allied to the classification of PETs, which will also convey the biologic behavior of the tumor in question.
Several classification systems have been suggested, both morphologic and functional. The World Health Organization (WHO) classification factors in both histopathologic and functional parameters23 (see Table 2). Wick has proposed an all-embracing classification of neuroendocrine tumors, irrespective of site.24 Whatever classification system is applied, it is clear that tumor size, lymphovascular invasion, nuclear atypia, mitotic rate, extension through the tumor capsule, lymph node spread, and distant metastases are features that impact on tumor behavior. It has also been demonstrated that hormone production detected by immunohistochemistry and not necessarily clinically functional also influences behavior. Hormone production may be subdivided into production of hormones that are intrinsic to the pancreas (insulin, pancreatic polypeptide, somatostatin, and glucagon) and hormones that are identified as enteric in origin (vasoactive intestinal peptide and gastrin).4 Tumors producing the former behave better than those that produce the latter. Insulin-producing tumors have a low risk of behaving aggressively, whereas those producing pancreatic polypeptide, somatostatin, and glucagon have a worse prognosis. In addition, tumors producing inappropriate hormones such as ACTH, calcitonin, or GHRH are also associated with aggressive behavior.
Table 3 summarizes some of the criteria used to assess for malignancy.
HEREDITARY FORMS OF PET
Multiple Endocrine Neoplasia (MEN) Syndrome, Type 1
This is an autosomal dominant condition, and affected individuals show 94% penetrance with manifestation of associated pathology by the age of 50 years.25 There are germline mutations of the MEN-1 tumor suppressor gene located on chromosome 11q13 and consequent loss of a 610-amino-acid nuclear protein, menin, which suppresses cell proliferation.26 Hereditary PETs occur in more than 60% of patients with MEN-1.27,28 Patients usually manifest primary hyperparathyroidism before pancreatic lesions.29 MEN-1 involvement of the pancreas is in the form of multiple, small, nonfunctioning benign PETs, often microadenomas, associated with foci of nesidioblastosis. If a functional tumor occurs, 50% will be gastrin-producing and 20% insulin-producing tumors. It is worth remembering that in MEN-1, duodenal gastrin-producing tumors are more common than those arising in the pancreas. In contrast to sporadic PETs, those associated with MEN-1 tend to present at an earlier age, have a higher rate of postoperative recurrence, and are a common cause of death in these patients.28
von Hippel-Lindau Disease
von Hippel-Lindau (VHL) disease is an autosomal dominant condition caused by deletions or mutations in a tumor suppressor gene located on chromosome 3p25.5.29 The disease profile is typified by retinal and central nervous system hemangioblastomas, cysts in the kidney, epididymis (papillary cystadenoma), and liver, hemangiomas of the adrenal, liver, and lung, renal cell carcinoma, pheochromocytoma, and endolymphatic sac tumors. Pancreatic pathology in VHL is usually in the form of benign cysts and microcystic or serous adenomas, which occur in 35%–70% of VHL patients.30–33 Pancreatic endocrine tumors, on the other hand, are less common and encountered in only 2%–12% of patients.32–35
Endocrine tumors of the pancreas in VHL are uncommon, also occur in young patients, occur anywhere in the pancreas, are said to be functionally inactive (immunohistochemistry does demonstrate focal positivity for pancreatic polypeptide, somatostatin, glucagon, and/or insulin in 30%–40% of cases), multiple (up to 5), and not associated with either microadenomas (endocrine cell foci less than 0.5 cm in diameter) or nesidioblastosis.32 However, we have observed a case of VHL in which these latter findings were present.36 VHL-associated PETs tend to be arranged in trabeculae, glandular configurations, and solid foci. Characteristically, up to 60% of the tumors contain clear cells or multivacuolated lipid-rich cells in varying proportions.
Rare cases of somatostatin-producing PETs have been encountered in neurofibromatosis. These tumors are far more common in the duodenum or periampullary region in patients with neurofibromatosis. The VHL gene has been found to contain inactivating somatic mutations in neurofibromatosis-associated PETs.10
Rare PETs have been reported in patients with tuberous sclerosis37,38; it is not clear if there is a causal or a casual association.
MOLECULAR PATHOGENESIS OF PETS
Although much is known about the morphology and immunohistochemical aspects of PETs, very little is known about the cellular and molecular mechanisms that are at play in the pathogenesis of these lesions. For the sake of simplicity, the molecular events in PETs can be divided into the hereditary (syndromic) and sporadic forms.
The majority of MEN-1 families have heterozygous germline mutations scattered throughout the MEN-1 protein-coding region.19 Numerous unique mutations have been described, but the majority (about 70%) involve truncation mutations resulting from frame shift (deletions, insertions, deletion/insertion, or splice site defects) and nonsense mutations.39,40 No correlation has, thus far, been shown between specific genetic aberrations in MEN-1 and clinical features in these patients. MEN-1-associated PETs display a wide variety of molecular abnormalities including chromosomal loss, chromosomal loss with duplication, mitotic recombination, or a point mutation of the second wild-type allele.19 The molecular aberrations in MEN-1 lead to loss of the growth-suppressive effects of the tumor suppressive protein menin. Menin may play a role in DNA repair or synthesis, and it may also interact with a host of transcription factors.19 Hessman and colleagues undertook a genome-wide scan of PETs arising in the clinical context of MEN-1 and showed multiple allelic deletions involving chromosomes 6, 8, 10, 11, 18, and 21.41 Interestingly, they also found inter- and intratumoral genetic heterogeneity or variation, suggesting that there is chromosomal instability in these tumors.41
As mentioned earlier, PETs are not commonly encountered in VHL. However, unlike MEN-1, a distinct genotype-phenotype correlation exists in VHL, especially with regard to the development of pheochromocytomas.29 Missense mutations are found more frequently in patients with pheochromocytoma (so-called type 2), whereas those without (type 1) have large deletions or premature truncation mutations.29 Lubensky et al performed a histopathologic and molecular genetic analysis of 30 PETs from 14 VHL patients.31 They showed loss of heterozygosity of one VHL allele in informative cases.31 VHL protein has several functions including regulation of ubiquitination of the hypoxia-inducible factor HIF1α, resulting in up-regulation of angiogenic substances as well as a role in the cell cycle at the G0/G1 checkpoint.19 It is thought that loss of these tumor-suppressive effects of VHL protein is responsible for tumorigenesis.
A wide range of chromosomal alterations has been observed in PETs. The most consistent and recurring chromosomal abnormality is allelic loss of chromosome 11q, which includes the MEN-1 locus.42 This particular abnormality occurs frequently in conjunction with loss of chromosome 6 in neurofibromatosis-associated PETs.43,44 Genome-wide studies, using several techniques including comparative genomic hybridization and genome-wide allelotyping, have yielded the following genetic aberrations: (1) losses on chromosomes 3p, 3q, 6q, 6p, 10q, 11q, 11p, 16p, 20q, 21q, 22q, Xq, and Y, ranging from 25% to 50% of PETs; and (2) gains on chromosomes 5q, 7q, 7p, 9q, 12q, 17p, and 20q, ranging from 25% to 35% of PETs.4,43,44
Noteworthy is the observation that PETs harboring losses of 3p, 6p, and 6q and gains of 14q and Xq are associated with advanced tumor stage, suggesting these chromosomal abnormalities are important in tumor progression.4,43,44
Chromosomal deletions occur most frequently on chromosomes 3, 6, and 11.43,44
PETs from women show frequent loss of chromosome X, and men show loss of chromosome Y and rarely of X.4 In addition, loss of a sex chromosome was associated with metastasis, local invasion, and poor survival.4
Somatic mutations of the MEN-1 gene have been found in approximately 30% of sporadic or nonfamilial PETs.45–47 In terms of the different types of PET, there is variation in the frequency of mutations of MEN-1. MEN-1 mutations are found in 55% of gastrin-producing and 50% of VIP-producing PETs but in only 7% of tumors that produce insulin.4,46–50 Primary sporadic gastrin-producing PETs more frequently exhibit mutations in exon 2 of the MEN-1 gene than seen in similar tumors occurring in the duodenum.19 In addition, PETs less than 1 cm in size are less likely to harbor exon 2 mutations of MEN-1.19 These mutations, associated with the frequent loss of 11q as detailed above, explain biallelic inactivation of the tumor suppressive effects of menin.
A study to ascertain the frequency of allelic loss in the 3p region encompassing the VHL gene was undertaken in 43 sporadic PETs.51 Allelic loss was identified in 33% of cases, but the smallest common region of allelic loss was not at the VHL locus but more centromeric, at 3p25.51 Furthermore, those PETs harboring 3p allelic loss were associated with metastatic disease, whereas those with an intact 3p region were more likely to be benign. These authors concluded that the VHL gene is not involved in the development of sporadic PETs but rather some other novel gene close by.52 Moore and colleagues, who found only 1 of 39 sporadic PETs to show a somatic mutation of the VHL gene, confirmed this conclusion.42 As mentioned earlier, some neurofibromatosis-associated PETs contain inactivating mutations of the VHL gene.
Most studies on K-ras in sporadic PETs indicate that mutations in this gene are infrequent.52–56 K-ras mutations, if present, are most commonly seen in insulin-producing PETs.53–55
Somewhat disparate results have been shown with regard to p16 (located on chromosome 9p21) abnormalities in sporadic PETs. Muscarella et al reported that inactivating alterations of p16 were present in 91.7% of the cases that they analyzed.57 However, others found only 1 case of 41 to have a p16 aberration,58 and in another study only 17% of insulin-producing PETs contained a p16 alteration.59 The general consensus is that p16 plays an insignificant role in sporadic PET tumorigenesis.4
This tumor suppressor gene located on chromosome 10q23 was regarded as a possible candidate in PET tumorigenesis because of the frequent chromosomal loss of 10q.4 With this in mind Perren and colleagues analyzed 33 sporadic PETs.60 Loss of heterozygosity for PTEN was found in 53% of malignant PETs but not in any of the benign tumors.60 On further investigation, only 1 tumor was found to contain a mutated PTEN gene. These authors postulated that mutations of the gene are uncommon, but impaired cellular localization of the protein may contribute to tumorigenesis.60
Although the morphologic features and classification of PETs have remained relatively unchanged, significant strides have been made in the molecular investigation of these lesions. Although a diverse array of molecular aberrations have been uncovered, patterns are emerging that suggest that some sporadic PETs may be underpinned by similar gene abnormalities, such as MEN-1 gene abnormalities in nonfunctional PETs as opposed to those that produce insulin. The fact that endocrine cells are characterized by the synthesis and expression of cell type-specific polypeptides has been used for diagnostic purposes. The challenge is to evolve therapeutic strategies based on these molecular advances. The application of a single, unified classification system and nomenclature is important so that consensus is achieved and proper management instituted.
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