Neuroendocrine tumors and their association with rare tumors: observation of 4 cases.

Abstract

Neuroendocrine tumors are rare neoplasms, with an incidence of about 1/100,000/year. The association between digestive neuroendocrine tumors and epithelial tumors is known, accounting for about 10% of cases, whilst in a very small number of other cases an association with other low incidence tumors has been observed.
During the past 19 years the Rare Hormonal Tumors Group of the Istituti Ospitalieri in Cremona, Italy has observed 300 patients affected by neuroendocrine tumors. We report here on four cases in which there was an unusual association with other rare neoplasms.
Overall, four of the 300 observed cases (1.3%) showed an unusual association with rare nonepithelial neoplasms: (1) gastric carcinoid and glioblastoma multiforme; (2) Merkel cell tumor and squamous cell carcinoma of the skin; (3) medullary thyroid carcinoma, yolk sac tumor of the testis and gastrointestinal stromal tumor (GIST); (4) gastric carcinoid and gastrointestinal stromal tumor (GIST).
There cases are of interest not only from an epidemiological point of view, but also offer insight into possible geno-phenotypical implications. The c-kit expression, typical of GISTs but observed also in other epithelial and neuroendocrine tumors, not only broadens the possibility to gain insight into the carcinogenesis of these neoplasms, but also opens the field to possible new therapeutic opportunities using multitargeted molecules. The contemporaneous presence of other lesions, such as the Merkel cell tumor and the squamous cell carcinoma of the skin can be interpreted as an answer by the cell to the same mutagenic stimulus. In other cases, where a possible link is not yet found which could explain the synchronism or metachronism of low incidence neoplasms, it remains possible that the associations are entirely coincidental. We await for new instruments which could help us demonstrate the possible relationships between low incidence neoplasms.

Full text

Page 1

Abstract. – Purpose: Neuroendocrine tu-
mors are rare neoplasms, with an incidence of
about 1/100,000/year. The association between
digestive neuroendocrine tumors and epithelial
tumors is known, accounting for about 10% of
cases, whilst in a very small number of other
cases an association with other low incidence
tumors has been observed.
Methods: During the past 19 years the Rare
Hormonal Tumors Group of the Istituti Ospitalieri
in Cremona, Italy has observed 300 patients af-
fected by neuroendocrine tumors. We report
here on four cases in which there was an unusu-
al association with other rare neoplasms.
Results: Overall, four of the 300 observed
cases (1.3%) showed an unusual association
with rare nonepithelial neoplasms: (1) gastric
carcinoid and glioblastoma multiforme; (2)
Merkel cell tumor and squamous cell carcinoma
of the skin; (3) medullary thyroid carcinoma, yolk
sac tumor of the testis and gastrointestinal stro-
mal tumor (GIST); (4) gastric carcinoid and gas-
trointestinal stromal tumor (GIST).
Discussion: There cases are of interest not
only from an epidemiological point of view, but
also offer insight into possible geno-phenotypi-
cal implications. The c-kit expression, typical of
GISTs but observed also in other epithelial and
neuroendocrine tumors, not only broadens the
possibility to gain insight into the carcinogene-
sis of these neoplasms, but also opens the field
to possible new therapeutic opportunities using
multitargeted molecules. The contemporaneous
presence of other lesions, such as the Merkel
cell tumor and the squamous cell carcinoma of
the skin can be interpreted as an answer by the
cell to the same mutagenic stimulus. In other
cases, where a possible link is not yet found
which could explain the synchronism or
metachronism of low incidence neoplasms, it re-
mains possible that the associations are entirely
coincidental. We await for new instruments
which could help us demonstrate the possible
relationships between low incidence neoplasms.
Key Words:
Gastrointestinal stromal tumor, Neuroendocrine tu-
mor, Gastric carcinoid tumor, Merkel cell carcinoma,
European Review for Medical and Pharmacological Sciences
Neuroendocrine tumors and their association
with rare tumors: observation of 4 cases
F . CIRILLO
Department of General Surgery, General Surgery Unit, Rare Hormonal Tumors Group,
AO Istituti Ospitalieri, Cremona (Italy)
Corresponding Author: Fernando Cirillo, MD; e-mail: f.cirillo@neuroendocrini.it
577
Medullary thyroid carcinoma, Squamous cell carcino-
ma, Yolk sac tumor, Glioblastoma multiforme, Syn-
chronous neoplasms, c-kit.
Introduction
Neuroendocrine tumors are rare neoplasms,
having an average clinical incidence of about 1
case per 100,000 of the population per year, with
variations due to the histotype. In most cases these
tumors are characterized by a low level of malig-
nancy and long survival. Exceptions are malignant
forms where the neoplasm metastasizes towards
the regional lymph nodes and commonly towards
the liver (15-20%) and undifferentiated forms with
a high degree of malignancy1.
From a clinical point of view neuroendocrine
tumors can be divided into two different groups:
functional tumors (secreting or symptomatic,
about 20% of cases) and nonfunctional tumors
(not secreting, asymptomatic) according to their
capacity to produce and secrete peptidic sub-
stances that cause non-specific symptoms that
are nevertheless strongly characteristic for this
group of neoplasms.
A complete updated anatomic-pathological re-
vision distinguishes these neoplasms according
to their different degree of malignancy, where the
traditional morphological criteria (histotype and
grading) are now associated with new immuno-
histochemical diagnostic parameters about the
biological activity of the tumor2.
Patients and Methods
The Rare Hormonal Tumors Group at the Isti-
tuti Ospitalieri in Cremona, Italy monitors the in-
cidence of unusual neuroendocrine tumors. Dur-
2010; 14: 577-588

Page 2

F . Cirillo
cystectomy for biliary lithiasis, and histological
examination confirmed a surrenalic myelolipoma
and chronic cholecystitis. The post-operation
blood chemistry continued to show high values
for chromogranin A and gastrin (188 ng/ml and
1798 pg/ml, respectively), while control of arteri-
al blood pressure was improved. Digestive en-
doscopy revealed a polypoid formation of about
1 cm in diameter at the antral-corpus boundary,
with non-significant histological examination.
We suspected the presence of an underestimated
gastric carcinoid and the patient began treatment
with the somatostatin analog, octreotide LAR, 20
mg every 28 days, in combination with lansopra-
zole, 30 mg twice daily. Six months later the
chromogranin A and gastrin values were still
high and for this reason the octreotide LAR
dosage was raised to 30 mg every 28 days and
lansoprazole was replaced by omeprazole at a
dosage of 40 mg twice daily. A subsequent di-
gestive endoscopy confirmed the presence of a
simple hyperplasia of endocrine cells on the gas-
tric fundum. Two months later the patient report
disturbances in her speech and signs of ideomo-
tor apraxia; for this reason cerebral CT and nu-
clear magnetic resonance (NMR) were per-
formed, showing the presence of a large irregular
solid lesion, supratentorial, on the left parietal
occipital region, compatible with a glioblastoma
multiforme (Figure 1). The patient underwent an
open biopsy of the cerebral lesion, and histologi-
cal results indicated a grade IV glioblastoma
with weak and focal immunophenotypical ex-
pression of glial fibrillary acidic protein, no ex-
pression of p53 and a cell proliferation index
(ki67 clone MIB1) equal to 10%. The patient
commenced radiation treatment (30 Gy) associat-
ed with temozolomide, 75 mg/m2/day. Unfortu-
nately, death occurred 4 months later due to pro-
gression of the cerebral disease.
Case 2
Case 2 was a female patient aged 80 who had a
raised and eroded pinkish lesion on the back of her
right foot. The size of the lesion on presentation
was 1.7 × 1.5 cm and had been increasing in the
previous few months. The lesion was surgically re-
moved under local anesthetic. Histological exami-
nation showed an ulcerated Merkel cell tumor infil-
trating the reticular dermis up to the boundary with
the hypodermis, associated with a squamous carci-
noma at the early stages of infiltration, scarcely dif-
ferentiated. There was no evidence of angioinvasiv-
ity. Immunohistochemical results were as follows:
ing the last 19 years, as of the 31st of December
2008, our Group has observed 300 neuroen-
docrine tumors, 220 of which were gastroen-
teropancreatic, 27 bronchial, 26 Merkel cell tu-
mors, 9 carcinomas with neuroendocrine differ-
entiation, 8 pheochromocytomas, 7 medullary
thyroid carcinomas, and 3 neuroendocrine carci-
nomas of the prostate. In 10% of cases we ob-
served a rare association of a digestive neuroen-
docrine neoplasm with epithelial neoplasms3, and
even less frequently [4 patients (1.3% of cases)]
an association with nonepithelial neoplasms. In
the latter category, the 4 cases involved: (1) type
1 gastric carcinoma and glioblastoma multiforme
of the encephalon; (2) Merkel cell tumor and
squamous cell carcinoma of the skin; (3)
medullary thyroid carcinoma, gastrointestinal
stromal tumor (GIST) and mixed germinal tumor
of the testis; (4) gastric carcinoid and GIST.
Due to the infrequent and uncommon associa-
tion, we believe it to be important to highlight
the series described hereafter.
Results
Case 1
Case 1 was a female patient aged 65 who had
type 1 diabetes and arterial hypertension treated
with β-blockers. The patient had experienced ab-
dominal colic pains for several months that were
associated with sporadic episodes of biliary vom-
it. Abdominal computed tomography (CT) was
performed, showing a surrenalic lesion to the
right (10.7 × 7.7 × 8.3 cm), and its radiological
appearance suggested a myelo-fibrolipoma.
Amongst the blood chemistry tests, chromo-
granin A showed a value of 212 ng/ml (radioim-
munoassay method), gastrin 1540 pg/ml, beta-
human chorionic gonadotropin 1.57 ng/ml, calci-
tonin 20 pg/ml, and neuron-specific enolase
(NSE) 19 ng/ml. Thyroid-stimulating hormone,
parathormone, thyreoglobulin and thyroxine
were all within the normal range. The urinary 24-
hour values of vanillylmandelic acid and of 5-hy-
droxyindoleacetic acid were also within the nor-
mal range. The patient denied experiencing
flushing, chronic diarrhea or dyspeptic symptoms
that could indicate a neuroendocrine pathology,
in particular a functional pheochromocytoma as-
sociated with the known hypertension or even
multiple endocrine neoplasia (MEN). The patient
underwent a right surrenalectomy and a chole-
578

Page 3

Figure 1. A, B, Nuclear magnetic resonance encephalon: oval lesion with irregular edges, 45 mm in diameter in the left pari-
etal-temporal area. Significant peripheric edematous and central necrotic component.
A
B
Neuroendocrine tumors and their association with rare tumors: observation of 4 cases
579
and carcinoembryonic antigen (CEA) (9.9 ng/ml)
were noted and the disease restaged (CT and
NMR total body,18F-DOPA positron emission to-
mography [PET]-CT,68Ga-DOTATOC PET-CT).
Evidence was found of a relapse of the disease
on the neck and liver that was confirmed by his-
tological examination. The patient has begun ra-
diometabolic treatment with targeted molecules.
Case 4
Case 4 was a male patient aged 79 years who
required emergency hospitalization due to a di-
gestive hemorrhage of gastric origin, as con-
firmed by endoscopy. The hemorrhage could not
be controlled despite multiple transfusions, ne-
cessitating a total gastrectomy. Macroscopic ex-
amination of the specimen removed showed a le-
sion 1 cm in diameter near the pylorus, under the
gastric mucosa, whilst a whitish nodule about 0.5
cm in diameter and with a wood-hard consisten-
cy was found along the greater curvature, about 8
cm from the esophageal boundary. Histological
examination of the pyloric lesion indicated a well
differentiated neuroendocrine tumor with a low
level of malignancy, with a proliferation index
ki67 (clone MIB 1) equal to 2%.The overall clin-
ical picture of the second lesion indicated instead
a low-risk GIST, with positivity for CD 117 and
CD 34, and a cell proliferation index equal to
1%. After a long rehabilitation period the patient
was discharged under watchful care.
chromogranin +; NSE +; synaptophysin +; ki67
(clone MIB 1) equal to 80% (Figure 2). Six months
after the removal there are no signs of any local or
remote relapse of the disease.
Case 3
Case 3 was a male patient aged 25 who had
undergone total thyroidectomy for medullary
thyroid carcinoma (Figures 3 and 4). At that time
there was no germinal mutation in the RET gene,
the pentagastrin test was negative and the patient
received no ancillary treatment. Nine years later
the patient approached his doctor due to a tume-
faction of about 5 cm in diameter on the right
testis (Figure 5), with subsequent orchiectomy.
Histological results showed a mixed germinal
neoplasm comprising 20% embryonal carcinoma
and 80% yolk sac tumor, with evidence of
Schiller Duval bodies and strong positivity on
immunohistochemical analysis for alpha-fetopro-
tein, and metastatic involvement of the lymph
nodes. The patient subsequently received ancil-
lary PEB chemotherapy (cisplatin, etoposide,
bleomycin) with the conventional pattern, for 3
cycles. During follow-up, tomography revealed a
hypodense lesion about 3.5 cm in diameter on
the lesser curvature (Figure 6) that was found on
subsequent resection and histological examina-
tion to be a gastric GIST with low grade malig-
nancy. Seventeen years after the thyroidectomy,
high values of plasmatic calcitonin (992 pg/ml)

Page 4

580
F . Cirillo
Figure 2. Merkel cell tumor and squamous cell carcinoma of the skin. Clockwise, from top to bottom: Merkel cell tumor in
close proximity with squamous cell carcinoma of the skin (Haematoxylin-Eosin 2 ×), same frame with greater magnification
(40 ×), evident expression for synaptophysin (20 ×) and for CAM 5.2 (10 ×) for the neuroendocrine portion.
Figure 3. A, B, Echography of the thyroid showing enlarged dimensions to the right due to the presence of a solid formation
with isoechogen echostructure, about 37 mm in diameter.
A
B

Page 5

Discussion
Neuroendocrine tumors are rare and represent
a group of neoplasms that is rather heteroge-
neous, characterized by an extremely variable
and unpredictable evolution. Recently an in-
crease in the incidence of these tumors has been
observed, from 1.09 to 5.25/100,000/year in the
period 1973-20044. This increased incidence has
been accompanied by an increase in survival,
suggesting that neuroendocrine tumors have a
greater prevalence than previously reported4. In
70% of the cases, neuroendocrine tumors are
well differentiated, and are characterized by long
581
Neuroendocrine tumors and their association with rare tumors: observation of 4 cases
Figure 4. Scintigraphy of the thyroid with99mTc showing enlarged right lobe, presenting a void of uptake of the marker at the
lower-middle third, corresponding to a formation which can be locally felt by touch.
Figure 5. A, B, Echography of the right testis showing a lesion of 5 cm in diameter, almost entirely overturning the right testis.
A
B