Large Somatostatin-Producing Endocrine

George H Sakorafas, George A Giannopoulos, Aikaterini Parasi, George Konstantoudakis,
Nikolaos Tzanakis, Spiridon Stergiopoulos, George Peros
Fourth Department of Surgery, Athens University Medical School, Attikon University Hospital.
Athens, Greece
ABSTRACT
Context Somatostatin-producing endocrine
tumors of the duodenum are very rare
neoplasms of the gastrointestinal tract. These
tumors may be associated with von
Recklinghausen’s disease.
Case report We present the case of a 49-
year-old female patient with von
Recklinghausen’s disease and an incidentally
diagnosed ampullary neoplasm. The patient
was treated with a classical pancreatico-
duodenectomy. At surgery, a mass was found
in the greater curve of the stomach which was
resected using the classic Whipple procedure.
Histology and immunohistochemistry showed
that the duodenal tumor was an ampullary
somatostatin-producing endocrine carcinoma
while the gastric tumor was a gastrointestinal
stromal tumor (GIST). The postoperative
course was uneventful and the patient is alive,
without tumor recurrence, six years after
surgery.
Conclusion Somatostatin-producing endocrine
tumors of the duodenum are rare tumors,
often associated with von Recklinghausen’s
disease; these neoplasms should be treated
aggressively using radical surgical resection.
Although local resection may be appropriate
for small duodenal somatostatin-producing
tumors, a pancreaticoduodenectomy is usually
required for larger tumors.
INTRODUCTION
Duodenal endocrine tumors comprise 2-3% of
all gastrointestinal endocrine tumors and are
increasing in frequency. These include tumors
producing a variety of peptides (gastrin,
somatostatin, VIP, PP, etc.), non-functioning
endocrine
tumors,
gangliocytic
paragangliomas and poorly differentiated
endocrine carcinomas. Although most of
these tumors are non-functioning,
duodenal/pancreatic endocrine tumors are a
frequent cause of Zollinger-Ellison syndrome
and can cause other clinical hormonal
syndromes (carcinoid, Cushing's, etc.) [1].
Nowadays, the term “somatostatin-producing
endocrine tumors” has replaced earlier terms,
such as somatostatinomas, according to the
recent World Health Organization
Classification of Tumors [2]. These tumors
are very rare neoplasms. Until recently, only
about 170 cases have been reported in the
literature [3]. These unusual neoplasms are
often found in extra-pancreatic locations
(most commonly in the duodenum, about
70%). The first case of a duodenal tumor
exclusively producing somatostatin was
reported by Kaneko et al. in 1979 [4]. Since
that time, we have only been able to find only
109 cases of duodenal somatostatin-producing
endocrine tumors published in the
international literature.

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In this paper, we present the case of a patient
with von Recklinghausen’s disease, an
ampullary somatostatin-producing endocrine
carcinoma and a gastrointestinal stromal
tumor in the gastric antrum (found
incidentally during surgery and treated with a
classic Whipple procedure). The relevant
literature is briefly reviewed.
CASE REPORT
A 49-year-old female patient, with known von
Recklinghausen’s
disease,
underwent
abdominal ultrasonography during the follow-
up for a known uterine leiomyoma.
Ultrasound examination incidentally showed
dilation of the biliary tree. The patient was
asymptomatic and in good general condition.
No weight loss, anorexia, nausea or vomiting
had been reported. Clinical evaluation was
unremarkable, without abnormal findings,
except for the clinical manifestations of von-
Recklinghausen’s disease (multiple skin
pigmentation and subcutaneous tumors). Past
medical history was unremarkable (except for
the von Recklinghausen’s disease and the
known uterine leiomyoma).
A diagnostic work-up revealed biochemical
evidence of biliary obstruction. Abdominal
computed tomography (CT), upper
gastrointestinal endoscopy, and ERCP
showed a duodenal mass at the ampulla of
Vater, causing biliary tree dilatation.
Preoperative endoscopic biopsy was negative
for malignancy. The patient underwent a
classic pancreaticoduodenectomy (Whipple
procedure), with the presumed diagnosis of an
ampullary neoplasm.
Macroscopic evaluation of the resected
specimen showed a large (5 cm in diameter)
polypoid mass at the ampulla of Vater. The
distal part of the common bile duct was
markedly dilated (2 cm in diameter). Of note,
another mass was noted in the resected part of
the stomach (5 cm in diameter, at the greater
curvature) which was adherent to the
omentum (Figure 1). Microscopic evaluation
of the resected specimen showed that the
Figure 1. The surgical specimen is opened. The mass
in the second part of the duodenum is evident,
protruding into the lumen (white arrow). The gastric
mass is also evident (red arrow).
Figure 2. Microscopic evaluation of the resected
specimen. a. Well differentiated endocrine tumor
infiltrating the ampulla of Vater (H&E, x40). b. Tumor
emboli within small veins of the subserosa. (H&E,
x100).

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ampullary mass was a well-differentiated
endocrine carcinoma, causing an ulceration of
the duodenal mucosa and infiltration of the
ampulla of Vater (Figure 2a). Perineural
infiltration and vascular emboli were also
observed (Figure 2b). Early infiltration of the
pancreatic head by the tumor was also
evident. Three of the eleven resected lymph
nodes were infiltrated by tumor cells.
Immunohistochemistry revealed that the
tumor was neuron-specific enolase (NSE)-
positive, synaptophysin-positive, chromogranin
A (CGA)-positive, and somatostatin-positive
(Figure 3). Based on these findings and
according to the recent WHO classification of
gastroenteropancreatic endocrine tumors, the
neoplasm was characterized as a large
ampullary well-differentiated endocrine
carcinoma composed exclusively of
somatostatin immunoreactive cells (somato-
statin-producing
ampullary
endocrine
carcinoma), with lymph node metastases.
Histology showed that the incidentally found
mass in the greater curvature of the stomach
was a gastrointestinal stromal tumor (5 cm in
diameter), with low mitotic activity (1-4/10
HPF) (Figure 4).
The postoperative course was uneventful. The
patient was discharged on postoperative day
8. During regular follow-up (which has
included periodic abdominal CT and
OctreoScan), no evidence of tumor recurrence
has been observed for the six years following
surgery.
DISCUSSION
Duodenal somatostatin-producing endocrine
tumors are a rare type of neoplasm, belonging
Figure 3. Immunohistochemistry. a. Tumor cells
strongly positive for synaptophysin (x100). b. Diffuse
immunoreactivity for somatostatin (x100).
Figure 4. Histology. a. Gastric mesenchymal tumor
with morphological features of a stromal tumor with
mild atypia and low mitotic activity (H&E, x100). b.
Gastric GIST: diffuse immunopositivity of neoplastic
cells for c-kit protein (x200).

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to the group of gastrointestinal endocrine
tumors. Gastrointestinal endocrine tumors are
increasingly being recognized in clinical
practice. These tumors may be either
functioning or non-functioning, depending on
their hormonal activity. Functioning and non-
functioning gastrointestinal endocrine tumors
are identical as regards development and
histology but differ in their clinical course and
outcome [5]. Non-functioning gastrointestinal
endocrine tumors occur with the same
frequency as hormonally active ones and they
too therefore deserve consideration [5, 6].
Although somatostatin-producing gastro-
intestinal endocrine tumors may be of
pancreatic origin, extrapancreatic (most
commonly duodenal) somatostatin-producing
gastrointestinal endocrine tumors are very
common. The classic somatostatinoma
syndrome (steatorrhea, cholelithiasis, and
diabetes mellitus-like symptoms) is often
observed
in
somatostatin-producing
pancreatic endocrine tumors; in contrast, the
somatostatinoma syndrome is a rare clinical
manifestation in duodenal somatostatin-
producing endocrine tumors (less than 10%)
[3, 7]. Duodenal somatostatin-producing
endocrine tumors tend to produce only local
symptoms or are completely asymptomatic [5,
6, 8]. In symptomatic patients, jaundice
induced by a periampullary tumor is the most
common symptom reported [8, 9, 10]. The
severity of these symptoms is directly related
to the size and the location of the tumor and
to the presence of metastases. Most
symptomatic
duodenal
somatostatin-
producing endocrine tumors are located at the
ampulla of Vater and are usually more than 1
cm in diameter. The association of duodenal
somatostatin-producing endocrine tumors
with somatostatinoma syndrome is more
probable in large tumors with metastatic
disease; however, the presence of a large
tumor or massive metastases does not
guarantee
symptoms
of
excessive
somatostatin production [10, 11, 12, 13, 14].
Multiple neurofibromatosis or von
Recklinghausen’s disease was first described
in 1882 by von Recklinghausen [15]. It is a
relatively common autosomal hereditary
dominant disorder with a variable expression
having a frequency of 1 out of 3,000-4,000
live births and a high rate of new mutations.
Von
Recklinghausen’s
disease
is
characterized by multiple skin pigmentation
(‘café au lait’ spots) and the formation of
multiple nerve-sheath tumors. Neuro-
fibromata originate from Schwann cells and
may occur in any location, although they are
found predominantly in the skin and
subcutaneous tissue. The association between
von Recklinghausen’s disease and tumors of
neurogenic and neuroendocrine origin, such
as meningiomas, gliomas, and pheochromo-
cytomas is well known. Its association with
duodenal neuroendocrine tumors, particularly
somatostatin-producing endocrine tumors,
though uncommon, has become more widely
recognized as a distinct neuroendocrine
syndrome during the two last decades [5, 16].
Up to the time of writing (November 2006),
by reviewing the international literature, we
found that duodenal somatostatin-producing
endocrine tumors were associated with von
Recklinghausen’s disease in 30 of 109
patients (27.5%). Duodenal somatostatin-
producing endocrine tumors associated with
von Recklinghausen’s disease tend to be
located in the periampullary area, thereby
causing biliary obstruction which is clinically
manifested as painless obstructive jaundice
(as occurred in our patient). Patients with von
Recklinghausen’s disease have a tendency to
develop periampullary tumors, most
commonly somatostatin-producing endocrine
neoplasms [17]. The prevalence of
pheochromocytomas is also high (about 1%)
in patients with von Recklinghausen’s disease
as compared to the general population [18].
The incidence of pheochromocytomas is even
higher (about 15%) in patients with duodenal
somatostatin-producing endocrine tumors
associated with von Recklinghausen’s disease
[5]. This association (von Recklinghausen’s
disease, duodenal somatostatin-producing
endocrine tumors, pheochromocytoma)
suggests an inherited endocrinopathy and
represents a particular form of multiple
endocrine neoplasia syndrome [3, 18]. Our
patient also had a gastric GIST, incidentally

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found in the gastric antrum during surgery
using a classic Whipple procedure which was
confirmed after histological examination of
the resected specimen. The association of
duodenal somatostatin-producing endocrine
tumor with von Recklinghausen’s disease and
GIST is extremely rare. We found four papers
in the international literature describing this
association [19, 20, 21, 22]. We also found
only a reported case of duodenal
somatostatin-producing endocrine tumor
associated with an appendiceal carcinoid
tumor. Table 1 summarizes the differences
between duodenal somatostatin-producing
endocrine tumors associated with von
Recklinghausen’s disease and duodenal
somatostatin-producing endocrine tumors not
associated with von Recklinghausen’s
disease. In Table 2, the differences between
pancreatic and duodenal somatostatin-
producing endocrine tumors are presented.
In patients with clinical manifestations of
somatostatinoma syndrome, diagnosis is
established by demonstrating elevated
somatostatin levels and the presence of a
duodenal tumor [3]. As noted above,
however, duodenal somatostatin-producing
endocrine tumors are most often manifested
by local symptoms. Diagnostic evaluation
usually includes abdominal ultrasonography
and abdominal computed tomography; as
expected, a periampullary mass is commonly
associated with dilatation of the biliary tree.
However, radiological techniques often fail to
detect small duodenal somatostatin-producing
endocrine tumors [23]. Hypervascular lesions
in the arterial phase, imaged on CT, are often
characteristic of neuroendocrine tumors [23];
however, the different types of neuron-
endocrine tumors have similar radiological
features. Somatostatin-receptor scintigraphy
can be used to locate the primary tumor (if
occult) and to stage the disease [24]. The
sensitivity of this method is impaired when
the tumor is small and when there are not
many surface receptors, as in less-
differentiated tumors.
The presence of the duodenal tumor is
confirmed by upper gastrointestinal
endoscopy. However, preoperative histological
documentation of the diagnosis is not always
possible. As a consequence, these patients are
operated on with the presumed diagnosis of a
periampullary tumor. Surgical resection is the
Table 1. Comparison between duodenal somatostatin-producing tumors in patients with or without von
Recklinghausen’s disease (modified, from [5, 17])a.
Patients with von
Recklinghausen’s disease
Patients without von
Recklinghausen’s disease
Somatostatinoma syndrome
Rare
Rare
Mean tumor size
2.6 cm
2.4 cm
Psammoma bodies
65%
59%
Additional hormonal production (multihormonal)
Less frequent (16%)
More frequent (43%)
The statistical significance of these reports is limited, due to the small number of patients
Table 2. Differences between duodenal and pancreatic somatostatinomas.
Duodenal
Pancreatic
Somatostatinoma syndrome
Rare (<10%)
Frequent (about 70%)
Local symptoms (most commonly, biliary obstruction)
Common
Rare
Psammoma bodies
Frequent (about 60%)
Not observed
Association with von Recklinghausen’s disease
Frequent
Not observed
Hepatic/lymph node metastasesa
Less frequent (about 35%) More frequent (about 72%)
Tumor size
Larger
Smaller
This may be due to an earlier diagnosis of the duodenal as compared to the pancreatic somatostatinomas

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treatment of choice for duodenal
somatostatin-producing endocrine tumors.
Local resection may be appropriate for small
duodenal somatostatin-producing endocrine
tumors. To achieve radical resection, larger
tumors
should
be
treated
by
pancreaticoduodenectomy. During pancreatico-
duodenectomy, excision of localized
metastatic disease could be achieved at the
same time. Complete tumor resection or even
debulking - when there is extensive metastatic
disease (for example, massive liver
metastases) - is of benefit for the patient [25]
and can achieve long-term palliation or even
cure [10].
A definitive diagnosis is established by
histology and confirmed by immuno-
histochemistry. Immunohistochemistry is of
particular importance when the tumor is not
associated with the somatostatinoma
syndrome (which is very common in
duodenal somatostatin-producing endocrine
tumors). The presence of psammoma bodies
is a distinguishing feature of duodenal
somatostatin-producing endocrine tumors. For
unclear reasons, psammoma bodies are not
observed in pancreatic somatostatin-
producing endocrine tumors [12]. The
surgical pathologist should be aware of this
characteristic of duodenal somatostatin-
producing endocrine tumors to avoid a
potentially serious misdiagnosis [26].
The overall postoperative 5-year survival rate
is 75% (ranging 40-60% in patients with
metastases and 100% in patients without
metastases) [3, 27]. Predictors of an
unfavorable prognosis include size greater
than 3 cm, poor cytological differentiation,
regional and/or portal metastases and
incomplete surgical resection [28]. Currently,
there are no clinical trials demonstrating
significant improvement in survival with the
use of adjuvant therapy. The administration of
somatostatin analogues inhibit somatostatin
receptor activation and may alleviate
symptoms in symptomatic patients [3].
Somatostatin-receptor scintigraphy is very
useful for the follow-up of patients following
surgical resection in order to detect
incomplete tumor removal or distant
metastases [24].
In conclusion, duodenal somatostatin-
producing endocrine tumors are rare
neoplasms, often associated with von
Recklinghausen’s disease. The clinician
should be aware of this association and should
include duodenal somatostatin-producing
endocrine tumors in the differential diagnosis
when he/she faces a patient with known von
Recklinghausen’s disease presenting with
painless obstructive jaundice or a mass in the
duodenum.
Received May 16
th
, 2008 - Accepted June
30
th
, 2008
Keywords Duodenal Neoplasms; Duodenum;
Gastrointestinal Stromal Tumors; Neoplasms;
Neuroendocrine Tumors; Somatostatin-
Secreting Cells; Somatostatinoma
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
George H Sakorafas
Arkadias 19-21
GR-115 26 Athens
Greece
 
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