Solid Tumors and Tumor-like Lesions of the Pancreas
Moderators: Dr. Ralph H. Hruban and Dr. Günter Klöppel
Section 4 -
Well Differentiated Pancreatic Endocrine Neoplasms and Related Tumors
David S. Klimstra
Memorial Sloan-Kettering Cancer Center
General Features and Classification
PENs account for roughly 2-4% of clinically detected
pancreatic neoplasms. Males and females are equally affected. PENs may arise at any age ,
but most occur between the ages of 30 and 60 yrs; those arising in patients with multiple endocrine
neoplasia 1 (MEN1) syndrome occur at a younger age.
The majority of endocrine neoplasms are in the well differentiated category, in the sense that they
retain the organoid architecture typical of endocrine organs and have a relatively low proliferative rate
(less than 10 mitoses per 10 high power fields). PENs measuring less than 0.5 cm are designated endocrine microadenomas and are regarded to be biologically benign. Most
clinically relevant endocrine neoplasms fall in the category of well differentiated
PENs and are low to intermediate grade malignancies. A small group of primary pancreatic
neoplasms qualify as poorly differentiated endocrine carcinomas due to their
diffuse architecture, high proliferative rate, and abundant necrosis. Finally, there are rare mixed
endocrine neoplasms that contain elements with ductal or acinar differentiation (e.g., mixed ductal endocrine carcinoma, mixed acinar endocrine
The well differentiated PENs are also subclassified based on the presence and type of associated
clinical syndrome due to inappropriate hormone secretion. PENs are designated as insulinoma,
glucagonoma, gastrinoma, etc. if the patient exhibits characteristic clinical findings. PENs without a
clinical syndrome are termed "nonfunctional", although most of these PENs also exhibit some evidence of
hormone production if serum peptide levels are measured or immunohistochemistry is employed to detect
them . A nonfunctional PEN that is documented to produce a specific hormone may be
designated based on the corresponding cell type (e.g., " a cell neoplasm", " b cell neoplasm", etc.), but
they should not be labeled as functional tumors in the absence of the appropriate clinical
syndrome . It should be noted that rare PENs have been described that exhibit expression of
pancreatic polypeptide (PP) by immunohistochemistry, associated with elevations in serum PP
levels . Although these neoplasms have been designated "PPomas", there is no specific
clinical syndrome associated with PP hypersecretion, so PPomas are technically nonfunctional PENs.
However, PP cell PENs are still designated as PPomas and classified with the functional group, largely
for historical reasons. Approximately one third of all PENs are nonfunctional
MEN1 patients with multiple PENs, a greater proportion of the individual tumors are
but most MEN1 patients have at least one PEN that is functional
Insulinomas are the most common functional tumors (45%), followed by gastrinomas (20%),
glucagonomas (13%), VIPomas (10%), and somatostatinomas (5%). PENs producing other unusual syndromes
(Cushing's syndrome, carcinoid syndrome, acromegaly, etc.) occur but are rare.
PENs may be associated with a number of genetic syndromes, most importantly MEN1 and von
Hippel-Lindau (VHL) syndromes
In these cases, the genetic abnormality underlying
the syndrome plays a role in the development of the PENs, which often are multiple
The pathologic features of these PENs are generally similar to those occurring sporadically, although the
PENs in VHL syndrome patients may have clear cell features .
Grossly, PENs are generally circumscribed, solid
masses composed of tan, uniform, fleshy parenchyma. Larger PENs are multinodular, with fibrous septa
dividing the neoplasm. Cystic change is a less common phenomenon , usually in the form of
a single central locule lined by a thin rim of neoplastic cells. Most PENs have an expansile growth
pattern, and small neoplasms may be completely surrounded by a fibrous capsule. It is common to find
invasive growth, however, including extension into the adjacent pancreatic parenchyma or peripancreatic
Histologically, PENs have characteristic features of well differentiated endocrine-type neoplasms at
both the architectural and cytologic levels. Cells usually are arranged in regular nests, ribbons, or
trabecula, and it is common for more than one pattern to be found in different regions of a single
neoplasm. The nuclei are usually round to oval and uniform, although scattered enlarged nuclei are not
uncommon. The chromatin is coarsely granular and clumped, imparting the classic "salt and pepper"
appearance. Nucleoli may be inconspicuous, although some PENs have easily identifiable or even prominent
Although the architectural and cytologic features described above are key to recognizing PENs, there
are many variations in histology that may cause diagnostic dilemmas. The stroma varies considerably in
amount. Some PENs have nearly no collagen within the neoplasm, whereas other examples contain abundant,
hyalinized or amyloid-like stroma. Calcifications may be found, including psammoma bodies
. The quantity and appearance of the cytoplasm also varies. A moderate amount of
amphophilic to basophilic cytoplasm is typical, but PENs with oncocytic cytoplasm
clear cell change have been described . Some PENs have scant cytoplasm, and the resulting
high nucleus-to-cytoplasm ratio may cause confusion with small cell carcinomas or primitive
neuroectodermal tumors. The nuclear morphology also may vary; PENs with marked nuclear pleomorphism have
been reported ("pleomorphic PENs") , and these cases are commonly confused with ductal
adenocarcinomas or other high grade neoplasms. In these instances, the nuclear atypia is not generally
accompanied by an increased proliferative rate and does not appear to have adverse prognostic
The mitotic rate is an important measure of aggressiveness in PENs. Well differentiated PENs are
defined to have less than 10 mitotic figures per 10 high power fields (hpf); neoplasms with 10 or more
mitoses per 10 hpf are considered poorly differentiated (high grade) endocrine carcinomas (see below).
In many PENs, mitotic figures are nearly undetectable, a search of 30 to 50 hpf (or more) being required
to find even a single mitotic figure. Some PENs have a higher proliferative rate, and the finding of 2
or more mitoses per 50 hpf places a PEN in a worse prognostic category . Necrosis is also
variably present; most commonly it is accompanied an increase in proliferative rate and signifies a more
Glands may also be found in PENs and may take several forms. In some cases, the neoplastic endocrine
cells form lumina. Although these gland-forming PENs may be mistaken for adenocarcinomas, the cells
lining the lumina retain endocrine differentiation. In other cases, non-neoplastic ductules are
entrapped within PENs
The neoplastic endocrine cells are often closely juxtaposed
to the ductules, but they are cytologically distinct. Finally, true mixed ductal-endocrine carcinomas
occur (see Mixed Endocrine Carcinomas, below).
Once the diagnosis of PENs is suspected based on
the histologic features, there are several methods to confirm the diagnosis. Immunohistochemical
expression of general endocrine markers including chromogranin, synaptophysin, and neural cell adhesion
molecular (CD56) is detectable in essentially all PENs . Synaptophysin expression is
commonly more diffuse, and some PENs may demonstrate only focal staining for chromogranin. Expression of
peptides such as insulin, glucagon, PP, somatostatin, gastrin, or vasoactive intestinal polypeptide is
common, and most functional PENs can be shown to produce the appropriate peptide by immunohistochemistry
. In addition, minor cell populations producing a variety of other peptides are commonly
Nonfunctional PENs also contain a variety of peptide cell types, usually
(but not inevitably) comprising less than 25% of the total cell population.
Many PENs also immunolabel for glycoproteins such as carcinoembryonic antigen (CEA) and
especially those with gland formation. Focal acinar differentiation may
also be present in scattered cells that label for trypsin or chymotrypsin
of PENs expresses CD99, as do normal islet cells. Labeling of PENs with the proliferation marker MIB1
demonstrates a relatively low proliferative rate in keeping with their low mitotic rate. Generally 1-5%
of the nuclei are labeled, but some examples demonstrate labeling of up to 10% of cells .
Fine needle aspiration (FNA) is a sensitive technique
for the preoperative diagnosis of PENs
Aspirates of PENs produce relatively
cellular smears with a clean background. The cells are arranged in clusters and individually. Nuclei
are round to oval and uniform, and the characteristic endocrine chromatin pattern is often present. The
nuclei are eccentrically located, producing a plasmacytoid configuration to the cells. Endocrine
differentiation may be documented by immunohistochemical labeling for chromogranin or synaptophysin to
confirm the diagnosis .
Molecular Genetic Features
Recent cytogenetic and molecular studies have
identified many chromosomal alterations in PENs. Interestingly, activation of oncogenes does not appear
to play a major role in the development of these tumors. In PENs arising in patients with MEN1 or VHL
syndromes, the genetic defect responsible for the syndrome is involved in the pathogenesis of the
. PENs arising in MEN1 patients show a germ line mutation
in the menin gene on chromosome 11q13 coupled with a somatic (acquired) loss
of the normal copy of this gene. Studies on sporadic PENs have also detected relatively common losses at
11q13 or elsewhere on the short arm of chromosome 11 (70%), but specific menin gene mutations are only present in approximately 20% of the neoplasms,
suggesting involvement of another tumor suppressor gene
The VHL gene is usually
normal in sporadic PENs . Most of the genes targeted in the development of ductal
adenocarcinomas of the pancreas are not targeted in PENs
In particular, KRAS, p53, p16, and
SMAD4 are not mutated in most PENs, although the p16 gene is inactivated via hypermethylation of the promotor in 40% of cases
Some of the genetic alterations in PENs are more commonly detected in larger or higher stage
neoplasms, suggesting that there is continuing genetic progression in PENs that parallels clinical
progression. Fewer gains and losses of genetic material are seen in smaller PENs (less than 2 cm)
. In fact, some data suggest that smaller PENs may represent poly- or oligoclonal
proliferations from which more aggressive monoclonal neoplasms may arise .
Natural History and Prognostic Considerations
The natural history of
PENs is highly variable. Small neoplasms without adverse prognostic features (see below) are readily
curable by surgical resection. Many insulinomas fall into this category, since they generally measure
less than 2 cm when detected. Most other functional and all nonfunctional PENs are usually larger at
diagnosis, and the outcome is much less favorable . Approximately 50-70% of these
neoplasms will recur or metastasize
, and up to 30% of patients already have
metastatic disease at first presentation. The five year survival after surgical resection for
nonfunctioning PENs is 65%, but the ten year survival is only 45% .
Despite the high rate of metastasis, relatively long survival is typical. Because the disease
progresses slowly, many patients live for several years or even over a decade following the appearance of
metastases. Unfortunately, metastatic PENs are relatively resistant to chemotherapy, and cure is
unlikely after metastases develop.
One of the most controversial aspects of PENs is the predicting their clinical behavior. For many
years, attempts were made to separate PENs into benign and malignant categories; recently, a borderline
malignant potential category was proposed as well . Because some PENs that demonstrate
malignant behavior have deceptively bland histologic features, it was felt that few pathologic parameters
accurately stratify PENs, and only the finding of locally invasive growth, large vessel invasion, or
distant metastases could be considered absolute criteria of malignancy. Even with these criteria,
however, some "malignant" PENs do not recur after resection and some "benign" PENs lacking these features
ultimately prove lethal. Several different grading schemes have been proposed for PENs. Based in part
on the Capella classification of endocrine neoplasms, the most recent WHO classification 
separates PENs into two general groups: "well-differentiated endocrine
tumors" and "well-differentiated endocrine carcinomas". In this classification, well-differentiated
endocrine tumors are confined to the pancreas (or have only local extension into peripancreatic tissues)
whereas well-differentiated endocrine carcinomas have either gross local invasion or metastases. Within
the well-differentiated endocrine tumor category, those PENs that measure less than 2 cm in diameter,
have less than 2 mitoses per 10 hpf (or have a Ki67 labeling index less than 2%), and demonstrate no
perineural or vascular invasion are predicted to have "benign behavior"; those that either are greater
than 2 cm in diameter, have 2-10 mitoses per 10 hpf (or have a Ki67 index greater than 2%), or have
perineural or vascular invasion are considered to have "uncertain behavior". In this scheme, no group of
PENs other than microadenomas is designated as a benign neoplasm; the subcategories are intended to
provide an indication of the likely clinical behavior based on relatively well characterized prognostic
factors. An alternative system uses the mitotic rate and presence of necrosis to separate low grade PENs
from an intermediate grade category . Under that proposal, cases demonstrating two or
more mitoses per 50 hpf or the presence of necrosis are considered intermediate grade, whereas those
lacking these features are considered low grade. Both of these systems accurately stratify the outcome
of patients after resection, although there is something of a philosophical difference between the two
Other studies have focused on defining additional prognostic factors for resected PENs. As expected
from the grading parameters mentioned above, general features of prognostic significance in PENs include
tumor size, mitotic rate, presence of necrosis, extrapancreatic invasion, and vascular invasion, in
addition to the presence of nodal or distant metastases
. Peptide production
detected in the serum or by immunohistochemistry is not a prognostic factor for nonfunctional PENs
Nuclear pleomorphism is also not a useful predictor ; however, some
studies have demonstrated a correlation between overall nuclear grade and prognosis .
Other factors reportedly predictive of more aggressive behavior include loss of progesterone receptor
aneuploidy , increased Ki67 or PCNA labeling index
loss of heterozygosity (LOH) of chromosome 17p13 , LOH of chromosome 22q
increased fractional allelic loss , upregulated CD44 isoform expression
and immunohistochemical expression of cytokeratin 19 .
The pathologic differential diagnosis for PENs
includes acinar cell carcinoma, pancreatoblastoma, solid-pseudopapillary neoplasm, and ductal
adenocarcinoma. Acinar cell carcinoma and pancreatoblastoma exhibit acinar differentiation and
demonstrate well-formed acinar structures and granular, eosinophilic cytoplasm
Pancreatoblastomas also have distinctive squamoid nests and a hypercellular stromal component. Both
acinar cell carcinoma and pancreatoblastoma consistently produce pancreatic exocrine enzymes and can be
distinguished from PENs by immunohistochemical labeling for trypsin and chymotrypsin, which are usually
diffusely expressed. However, both acinar cell carcinoma and pancreatoblastoma may also contain a minor
component of endocrine cells, so focal labeling for chromogranin and synaptophysin may be found.
Solid-pseudopapillary neoplasms have many histologic similarities with PENs but can be distinguished by
the presence of pseudopapillae, nuclear grooves, aggregates of foamy tumor cells and histocytes, and
collections of large hyaline globules . By immunohistochemistry, solid-pseudopapillary
neoplasms do express CD56 and often also synaptophysin, but they are never positive for chromogranin.
The hyaline globules of solid-pseudopapillary tumors stain for alpha-1-antitrypsin, and there is
consistent positivity for CD10 and nuclear accumulation of b -catenin. Solid-pseudopapillary neoplasms
express vimentin but are negative or only focally positive for keratin. Pancreatic ductal
adenocarcinomas generally are not difficult to distinguish from PENs, with the exception of PENs that
exhibit gland formation. Even in such PENs, the glands are found within larger nests of cells, in
contrast to the individual infiltrating glands of ductal adenocarcinomas, and intracellular mucin is not
present. Ductal adenocarcinomas usually also have a higher mitotic rate and more significant nuclear
High Grade Endocrine Carcinoma
High grade endocrine carcinomas are
extremely rare in the pancreas. These neoplasms are related to small cell carcinomas
, and metastasis from sites such as the lung have to be excluded before an example can be
accepted as primary in the pancreas. Most patients are older adults. The neoplasms are often large and
metastatic at diagnosis, so resected examples are few. Histologically, high grade endocrine carcinomas
may be composed of either small or large cells. The neoplastic cells grow in diffuse sheets and have a
markedly infiltrative growth pattern. There is often little nesting or other architectural patterns.
The principle feature that separates this group from well differentiated PENs is the proliferative rate.
More than 10 mitoses per 10 hpf should be found, and often the rate is 50 or more. In addition, there is
abundant necrosis. A diagnosis of small cell carcinoma may be rendered for a high grade endocrine
carcinoma when there are predominantly cells with minimal cytoplasm and fusiform nuclei with a granular
chromatin pattern and inconspicuous nucleoli. In other high grade endocrine carcinomas the cells are
larger, with moderate amounts of cytoplasm, the nuclei are round, and nucleoli are prominent. These
large cell endocrine carcinomas must be distinguished from poorly differentiated carcinomas lacking
endocrine differentiation, so immunohistochemical staining for chromogranin or synaptophysin must be
performed to confirm the diagnosis. High grade endocrine carcinomas of the pancreas are highly
aggressive neoplasms, with a natural history equal to or more virulent than that of ductal
Mixed Endocrine Carcinomas
Minor endocrine elements are relatively
common in predominantly exocrine pancreatic neoplasms. Thus, it should not be surprising that rare
neoplasms exist in which both endocrine and exocrine components are significantly represented. These
"mixed" neoplasms have been arbitrarily defined to contain more than 25% of each component, and
endocrine, acinar, and ductal lines of differentiation may all be represented. Reported mixed neoplasms
that contain an endocrine component include mixed ductal-endocrine carcinoma, mixed acinar-endocrine
carcinoma, and mixed acinar-endocrine-ductal carcinoma
In most reported examples,
the exocrine elements predominate. The different cell types are usually intimately intermixed, and
immunohistochemical labeling is often necessary to detect the various lines of differentiation. It
should be noted that ductal differentiation in the form of lumen formation or expression of glycoproteins
such as Ca19.9 is common in conventional PENs  and does not constitute sufficient evidence
for a diagnosis of mixed ductal-endocrine carcinoma. Rather, a separate distinct gland-forming component
with intracellular mucin production should be found combined with the endocrine elements. Most reported
mixed pancreatic neoplasms have demonstrated aggressive clinical behavior, paralleling that of the more
aggressive exocrine component.
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