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Original Studies |
Nuclear Medicine (E.B., M.S.), Clinical Biology (J.M.B., V.L., F.T., E.C.), Medicine (Ph.R., P.R., M.D.), Biostatistics and Epidemiology (J.R.), Pathology (J.-C.S.), Surgery (P.L.), and Interventional Radiology (T.D.), Institut Gustave-Roussy, 94805 Villejuif Cedex, France
Address all correspondence and requests for reprints to: Dr. Eric Baudin, Service de Médecine Nucléaire, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: baudin{at}igr.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit (GP), hCG ß-subunit (free hCGß),
and somatostatin levels. Twenty-four-hour urinary free cortisol (UFC)
and 5-hydroxyindolacetic acid (5-HIAA) determinations were also
performed. Four patients had hyperparathyroidism, none of whom had
pituitary or familial disease. Hyperprolactinemia was compatible with a
pituitary disease in one patient. No acromegalic feature or any
increase in IGF-I was found. Hypergastrinemia, compatible with an
associated pancreatic NET, was found in one patient. Genetic screening
of the MEN1 gene was performed in five of the six patients with two
components of the MEN1 syndrome. A nonsense mutation
(Arg108stop) was identified in the tumor of one patient.
Elevated NSE, 5-HIAA, CT, GP, free hCGß, SMS, and nonsuppressible
UFC were found in 47%, 46%, 14%, 19%, 12%, 3%, and 6% of NET
patients, respectively. Production of CT, GP, and free hCGß was
highly related to the primary site: all but two of these secretions
originated in foregut NET. 5-HIAA secretion was found in 27% of
foregut-derived and 85% of midgut-derived NET.
In conclusion, MEN1 is a rare event in patients presenting with
apparently sporadic NET. It occurred mainly in foregut NET and should
be screened for by serum calcium and PTH-(1–84) measurements. Routine
hormonal measurements should depend on the primary site. NSE, 5-HIAA,
CT, and GP should be routinely measured in foregut-derived NET; only
serum NSE and 5-HIAA measurements are recommended in midgut-derived
NET.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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NET are characterized by their ability to produce multiple endocrine and nonendocrine markers. Considering gastroenteropancreatic (GEP) NET, the spectrum of hormonal secretions in tumors may reflect the normal secretion of the original cell: pancreatic peptides [e.g. insulin, glucagon, somatostatin (SMS), and pancreatic polypeptide] and serotonin are highly conserved markers of pancreatic and digestive tumors, respectively. In addition, a number of other hormonal secretions, generally called ectopic, may be associated with these tumors (2). Finally, serum measurement of general markers such as NSE and chromogranin A may also be of interest during the work-up of NET (3). Hormonal screening in GEP NET is influenced by the clinical presentation, standard biological results, and knowledge of the primary site (4). Even in NET devoid of clinically apparent symptoms or eutopic hormone secretions, the production of hormones may be demonstrated. Hormonal production in GEP NET can reflect secretion by the primary tumor and its metastases or by an associated NET in the context of the multiple endocrine neoplasia type 1 (MEN1) syndrome. MEN1 syndrome, the gene for which has recently been cloned (5, 6, 7), are characterized clinically by the association of parathyroid, pancreatic, and pituitary tumors. The functional characterization of these NET may have multiple consequences; it may help to localize the primary tumor, better define the prognosis, improve the choice of treatment, serve as a marker during the follow-up, and finally, contribute to the understanding of tumor growth patterns. At present, no standard GEP NET biological screening procedure exists because studies measuring a large panel of hormones concomitantly in a large population of GEP NET patients of various origins are lacking.
To provide guidelines for GEP NET biological screening, we measured a panel of 11 hormonal and nonhormonal markers in a large single center population of patients with apparently sporadic GEP NET, to assess 1) the prevalence of MEN1 syndrome and 2) the prevalence of hormonal secretion and factors influencing their secretion. Furthermore, genetic testing was performed in patients in whom two components of the MEN1 syndrome were diagnosed.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All patients with GEP NET referred to our institution from November 1993 to October 1996 were enrolled consecutively. Their medical history and clinical data were recorded. Patients were considered as suspect of MEN1 when at least two components of the MEN1 syndrome were diagnosed. In these patients, blood or tumor tissues were collected to perform MEN1 gene analysis. The histological diagnosis was confirmed by a panel of pathologists (coordinated by J.-C.S.) and, when possible, the degree of differentiation was analyzed according to the classification of Warren and Gould (8). All tumors disclosed NET morphological features, including regular cells, normochromatic nucleus, and eosiniphilic cytoplasm, arranged in ribbons, nests, or sheets separated by a fine fibrovascular stroma. An immunohistochemical study with NSE, chromogranin A, and synaptophysin antibodies (Dako Corp., Glostsup, Denmark) was performed when the morphological structure precluded an unequivocal diagnosis of NET. NET were classified according to their primary site as foregut-derived (head and neck, respiratory tract, pancreas, stomach, and duodenum), midgut-derived (ileum, appendix, and right colon), and hindgut-derived (left colon and rectum) tumors. Patients with mixed tumors and small cell lung cancer were excluded. Patients were considered as having limited disease when only the primary site or lymph node metastases were known and as having extensive disease when distant metastases were known. This study was performed in accordance with local ethical rules.
Samples
All blood samples were collected at the same time after overnight fasting without any dietary restrictions. When chemotherapy was prescribed, blood samples were collected before treatment. In patients treated with SMS analogs, samples were collected before the morning injection. Measurements were artificially classified as screening for MEN1 or hormonal production.
Screening for MEN1
Total serum calcium, phosphate, and creatinine levels were measured. Ionized calcium (specific electrode; normal, 1.12–1.30 mM/L) was measured when total serum calcium was found to be elevated after adjustment to albuminemia. Serum intact PTH [PTH-(1–84); PTH intact, Diagnostic Products Corp., Los Angeles, CA; normal, 10–70 pg/mL], PRL (ELSA-PROL, CIS-Bio International, Gif-sur-Yvette, France; normal, <20 ng/mL), insulin-like growth factor I (IGF-I; SM-C-RIA-CT, Medgenix Diagnostics, Fleurus, Belgium; normal, 90–270 ng/mL), and gastrin (GASK-PR, CIS-Bio International; normal, 25–100 ng/mL) were measured in the first 89 patients. Thereafter, only serum PTH and calcium measurements were performed.
Blood and/or tumor DNA were extracted using the Qiagen kit (Qiagen, Chatsworth, CA). Published primer sequences flanking exons 2–10 of the MEN1 gene were used for PCR amplification (5, 6). All PCR products were then directly sequenced on a PE/ABI 377A automated sequencer using the ABI Prism Dye Terminator Cycle Sequencing Ready Reaction kit with AmpliTaq DNA polymerase (Perkin-Elmer, Norwalk, CT).
Screening for NET hormonal production
It included measurements of NSE (CISPACK NSE, CIS-Bio International; normal, <12.5 µg/L) and calcitonin (CT) levels
(ELSA-hCT, CIS-Bio International; normal, <10 pg/mL). The
glycoprotein hormone -subunit (GP; normal in men and
premenopausal women: <1 ng/mL; normal in postmenopausal women, <3
ng/mL) and hCG ß-subunit (free hCGß; normal < 0.1 ng/mL) were
measured using specific immunoradiometric assays, as previously
described (9). Twenty-four-hour urinary 5-hydroxyindolacetic acid
excretion was measured by a high performance liquid chromatography
method [5-hydroxyindolacetic acid (5-HIAA) reagent kit, Bio-Rad,
Munich, Germany; normal, <42 µmol/24 h]. NSE, 5-HIAA, CT, and GP
levels were measured in the 130 patients, and free hCGß was measured
in the first 89 patients. SMS (SMS RIA kit, Incstar Corp.;
normal, <10 pg/mL) and 24-h urinary free cortisol (UFC; CORT-CT2,
CIS-Bio International; normal, <50 µg/24 h) were also
measured in the first 64 patients.
Serum PTH-related protein (PTHrp immunoradiometric assay kit, Incstar Corp., Stillwater, MN; normal, <1.5 pM/L) was measured in two patients with increased ionized calcemia, low PTH-(1–84) levels, and normal bone scintigraphy. Seven patients with elevated basal CT levels had a pentagastrin stimulation test (0.5 µg/kg peptavlon with CT measurements at 0, 2, and 5 min). Elevated hormonal levels, below twice the upper limit of the normal range, were confirmed by a second measurement. As hypothyroidism and renal insufficiency are known to increase the level of most hormones, all patients had serum TSH (Immulite Third generation TSH, Diagnostic Products Corp., Los Angeles, CA; normal, 0.4–4 µIU/mL) and serum creatinine measurements. No case of hypothyroidism was diagnosed during the study, and patients with renal insufficiency were excluded.
Statistical analysis
The four main secretions individualized in this study (NSE,
5-HIAA, CT, and GP), analyzed as elevated or normal, were
successively compared to patient (age, sex), tumor (embryological
origin, differentiation, disease extent), and treatment characteristics
in the whole group of patients, then in foregut-derived NET patients,
considering the main influence of embryological origin. Fisher’s exact
test was used to compare proportions. When there were more than two
means, means were compared using either Wilcoxon or Kruskal-Wallis
nonparametric tests.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical characteristics of the 130 consecutive patients (67
males and 63 females; mean age ± SD, 55 ± 12
yr; range, 20–76 yr) enrolled in this study are reported in Table 1
. NET arose in the foregut, midgut, and
hindgut in 74, 33, and 3 patients, respectively, and the primary site
was unknown in 20 cases. Of the 38 patients with pancreatic NET, 9 had
clinical symptoms related to hormonal hypersecretions, including
gastrinomas (4), insulinomas (2), somatostatinomas (2), and vasoactive
intestinal polypeptide-secreting carcinoma (1). Among the 108
tumors in which differentiation could be investigated, 78 were well
differentiated, and 30 were poorly differentiated. At the time of the
study, 116 patients had distant metastases, and 14 had a primary tumor
without distant metastases, which was isolated in 2 and associated with
lymph node involvement in the other 12. Ninety-one (70%) patients had
already undergone 1 (39 patients) or multiple (52 patients) treatment
modalities: surgery (64 patients), chemotherapy (64 patients), SMS
analog therapy (18 patients), interferon (5 patients), and external
radiotherapy (5 patients). The mean follow-up since diagnosis was
49 ± 50 months (range, 3–306 months). These characteristics were
not significantly different between patients with foregut or midgut
tumors, except for histological differentiation; poorly differentiated
NET were found in 40% and 7% of foregut and midgut tumors,
respectively (P = 0.001). Ninety-one patients were
still alive at the end of the study. No familial history of
MEN1-related NET was found in any of these patients.
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Two patients (one lung and one pancreatic NET) had undergone
surgery for a single parathyroid adenoma before the diagnosis of NET as
reported in Table 2. In one of these two
patients, who had lung NET, hyperparathyroidism recurred 4 yr later;
two parathyroid adenomas and one hyperplastic gland were then found at
surgery.
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Eighty-nine patients were screened for PRL, gastrin, and IGF-I. Hyperprolactinemia was found in six patients, was slightly elevated in five (<36 ng/mL), and was considered drug induced. In the other patient, who had an ileum NET, PRL attained 498 ng/mL, and magnetic resonance imaging suggested cystic prolactinoma. An elevated gastrin level was found in two patients (147 and 407 ng/mL, respectively). One of these two patients had a pancreatic tumor, whereas the other had a lung NET associated with a pancreatic mass. Gastric fibroscopy was normal as was the octreoscan in both subjects. In the first patient, with a previous history of chronic autoimmune thyroiditis, hypergastrinemia was attributed to chronic atrophic gastritis, and in the other patient, an associated gastrinoma was hypothesized because the gastrin level rose to 2800 ng/L before death. No clinical features indicative of acromegaly or elevated IGF-I levels were found.
Therefore, two associated NET were diagnosed in six patients who were
then considered as suspect for MEN1. In five of them (see Table 2
),
blood and/or tumor tissues were available for MEN1 genetic screening,
which did not reveal any mutation in four patients. In one patient,
with lung NET and involvement of multiple parathyroid glands, a
nonsense (Arg108stop) mutation was detected in the tumor
sample.
Screening for NET hormonal production
The results of the biological markers used for screening for NET
are presented in Table 3 and Fig. 1. Increased levels of NSE were found in
61 of the 130 patients (47%); in 32 of 74 (43%), 14 of 33 (42%), 2
of 3 (66%), and 13 of 20 (65%) cases of foregut, midgut, hindgut, and
NET of an unknown primary site, respectively. NSE levels were above 20
µg/L in 42 patients and above 100 µg/L only in patients with
foregut-derived NET. However, mean NSE levels in foregut and midgut NET
did not differ.
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The CT level was elevated in 18 of the 130 patients (14%) and was above 20 pg/mL in 13. Fifteen of them had a foregut-derived NET, including 3 head and neck, 7 lung and 5 pancreatic tumors, in only 1 ileal tumor, and 2 NET of unknown primary site. Thyroid ultrasonography performed in all patients demonstrated thyroid nodules more than 1 cm in diameter in 4 of them and enlarged neck lymph nodes in 2. A pentagastrin test, performed in 7 patients, showed no significant response in 5, including the 2 patients with enlarged neck lymph nodes, and found a 2-fold increase in the CT level in 2 patients with lung NET whose thyroid gland was normal at ultrasonography.
GP levels were elevated in 25 of the 130 patients (19%) and were
above 3 ng/mL in 23. Elevated GP levels were found in 21 patients
with foregut-derived primary NET, including 1 mediastinal, 10 lung and
10 pancreatic tumors, in only 1 patient with a rectal NET, and in 3
patients with a primary NET of an unknown origin. None of the patients
with an elevated GP level had pituitary disease, as shown by
biological screening and, in 11 of them, by CT scan.
Free hCGß levels were elevated in 11 of 89 patients (12%). Elevated
free hCGß levels were found in 10 patients with foregut-derived NET,
including 1 mediastinal, 3 lung, and 6 pancreatic NET and in 1 patient
with NET of an unknown primary site. Five patients had elevated levels
of both free hCGß and GP (4 pancreatic and 1 NET of unknown
primary site), but none had elevated hCG levels.
Elevated SMS levels were found in 2 of 64 patients (3%) without a known pancreatic tumor. Both patients had lung tumors, and SMS levels were above 50 pg/mL. Four other patients, 1 lung, 2 pancreatic, and 1 mediastinal NET, respectively, had a slight increase in the SMS level (<36 pg/mL). Three of these patients had diabetes, and 1 had hypoglycemia related to an insulinoma. These 4 patients were not considered as having tumor-induced SMS secretion.
Elevated 24-h excretion of UFC was found in 4 of 64 patients (6%; range, 58–337 µg/24 h), including 1 patient with clinical Cushing’s syndrome. None of these patients received corticosteroid treatment. These 4 patients had foregut-derived NET, including 1 head and neck, 1 lung, and 2 pancreatic tumors. In 2 of these patients with basal 24-h excretion of UFC below 200 µg/24 h, a standard dexamethasone suppression test (2 mg/day during 2 days) showed incomplete suppression of UFC, and a CRH test was abnormal in only 1 patient, but immunohistochemistry with ACTH antibodies was positive on tumor tissue in the other patient.
Multiple hormonal secretions and relationships with clinical and tumoral characteristics
Among the 130 patients screened, at least 1 of these markers was elevated in 108 patients (83%), only 1 was elevated in 58 patients (45%), and at least 2 were elevated in 50 patients (38%). In 22 (17%) patients all markers were normal. In the subgroup of 64 patients in whom all markers were measured, isolated or combined secretions were, respectively, found in 30 (47%) and 25 (39%) patients, and all measurements were normal in only 9 subjects (14%). At the end of hormonal screening, 20 of 74 (27%) and 2 of 33 (6%) of foregut and midgut NET were negative for all markers screened.
No significant statistical relationship was found between NSE and the
clinical parameters analyzed. 5-HIAA secretion was correlated with the
embryological origin (P < 0.0001) and histological
differentiation (P = 0.01); 5-HIAA secretion was found
in 1) 85% of midgut-derived NET compared to 27% of foregut-derived
NET, and 2) 56% of well differentiated compared to 30% of poorly
differentiated NET. However, when foregut-derived NET were considered
alone, 5-HIAA secretion was found in a similar proportion of patients
with either well or poorly differentiated NET. CT secretion was
correlated with sex (P = 0.0006) and embryological
origin (P = 0.04). CT secretion was found in: 1) 23%
of male compared to 3% of female patients, and 2) all CT secretions
but one arose in foregut-derived NET. GP secretion was correlated
with sex (P = 0.008) and embryological origin
(P = 0.0004). GP secretion was found in 1) 28% of
male compared to 9% of female patients, and 2) all GP secretions
but one arose in foregut-derived NET. Furthermore, all patients with
GP secretions had metastatic disease. When taking into account only
foregut-derived NET, GP secretion and disease extent were
significantly correlated (P = 0.05). A trend toward a
positive statistical significance between a previous therapy, including
SMS analog therapy, and positive hormonal secretions, particularly
5-HIAA, was found. Indeed, patients with hormonal secretions may be
diagnosed and hence treated earlier.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Apart from patients with gastrinoma, prospective data on the incidence of MEN1 in patients presenting with apparently sporadic GEP NET are lacking. Previous retrospective studies suggest a 4–7% prevalence of GEP NET, mainly of foregut origin (10, 11, 12). After the biological screening, six patients were found to have associated NET compatible with a MEN1 syndrome, including three patients with atypical NET association, as two cardinal tumors of the syndrome were not present. The responsible MEN1 gene has recently been isolated, and its germline mutations, scattered along the gene sequence, have been identified in most familial MEN1 (5, 6, 7). Direct sequencing of the MEN1 gene was performed in five of six patients with two components of MEN1 syndrome and did not show any mutation in four patients. Only one tumor nonsense mutation, at codon 108, was found in a patient with a history of multiple parathyroid tumors, highly suggestive of a MEN1 syndrome. As no familial NET history was known in this patient, it may correspond to a sporadic MEN1 syndrome. This observation suggests a low prevalence of MEN1 syndrome in patients presenting with apparently sporadic GEP NET (<1%). Serum calcium and PTH-(1–84) measurements appear to be sufficient for MEN1 screening, and they should be performed especially in patients with foregut NET. Even if the genetic screening was not performed in the entire population, the high penetrance of MEN1 by age 50 yr (12), the characteristics of our population, and the results of the biological screening suggest that the prevalence of MEN1 in the other patients is extremely low.
Five markers were increased in more than 10% of patients. NSE and
5-HIAA levels were elevated in almost half the patients, and CT, GP,
and free hCGß were elevated in 12–19% of the patients. Only 17% of
the patients had no increase in any marker level, and a single hormone
secretion was found in the majority of patients. These results were
only slightly modified when all the markers studied were taken into
account, because many tumors gave rise to multiple secretions. The
biological behavior of NET was highly dependent on the primary tumor
site. All peptidic and glycoproteic hormone secretions originated in
foregut-derived NET, except in two patients. 5-HIAA secretion was more
frequently observed in midgut-derived NET. These biological results
confirmed the relevance of using the classification based on
embryological origin, as first suggested by Williams and Sandler (13),
to define the biological behavior of NET. These results are consistent
with immunohistochemical findings that revealed that normal foregut
neuroendocrine cells and NET often exhibit multihormonal production
with many peptide-producing cells (14). In contrast, normal midgut
neuroendocrine cells and NET contain a limited variety of endocrine
cells that mainly produce serotonin and tachykinins (15). Despite the
diversity of secretion typical of foregut-derived NET, a greater
percentage (27%) of these patients, compared to midgut-derived NET
patients (6%), remained negative for hormonal screening. Our results
may help both to define which hormones should be screened when the
primary is known and to search for the primary site when a metastasis
is the first known event. NSE, 5-HIAA, CT, and GP ought to be
routinely measured in foregut-derived NET patients, and only NSE and
5-HIAA should be measured in those with midgut-derived NET.
Interestingly, no relationship was found between histological
differentiation and the four main secretions studied. Nevertheless, an
impact of histological differentiation on other hormonal secretions
should not be ruled out.
The practical interest of serum NSE measurement has been shown in patients with small cell lung cancer (16), but remains debatable in patients with other NET. According to previous results (3, 17), NSE is a poorly specific and sensitive marker of NET, as it is elevated in only 47% of the patients. Chromogranin A has been put forward as a more sensitive and specific general NET marker (3). The sensitivity of these general markers is higher than that of other secretions in foregut-derived NET. Biogenic amines are well known secretions characterizing NET, and 5-HIAA is the most sensitive marker of the carcinoid syndrome (18). Peptides such as neurotensin, neuropeptide K, neurokinin A, and substance P are produced by GEP NET mainly of midgut origin (18, 19, 20), but both their sensitivity and specificity are debatable, and assays are not routinely available. Elevated 5-HIAA was found in 46% of our overall population, and was predominantly produced by midgut-derived tumors in the same range as that previously reported (18, 19, 20, 21).
CT, GP, and free hCGß secretions have previously been demonstrated
in GEP NET (3, 21, 22, 23, 24, 25, 26). In our study, these silent markers were found
to be secreted in 12–19% of patients. We previously reported that CT
secretion is a specific marker not only of MTC, but also of other NET
(26). A 14% incidence of CT secretion was found and was associated
with foregut-derived NET in all cases but one. The increase in
pentagastrin-stimulated CT, used to differentiate GEP NET from
medullary thyroid carcinoma, did not exceed 2-fold the basal level.
Isolated secretion of GP should also be regarded as specific of NET.
Indeed, less than 3% of patients with non-NET malignant tumors
exhibited GP secretion exceeding 3 ng/mL (24). In the present study,
GP secretion was found in 19% of NET patients with levels exceeding
3 ng/mL in 92% of these cases, which is definitively higher than those
observed in pituitary adenomas and other tumors (24, 27). Furthermore,
GP secretions were exclusively observed in foregut-derived NET in
contrast to previous studies reporting GP secretion in
midgut-derived NET (21, 25). Our results, however, are consistent with
a previous immunochemistry study that detected GP in 21–55% of
foregut-derived NET, but not in any ileal NET (28). All patients with
GP secretions had metastatic disease. The interest of GP as a
prognostic marker of malignancy should be evaluated in prospective
studies. GP secretion was associated with free hCGß in 20% of
cases. Interestingly, none of these patients produced dimeric hCG. In
contrast with GP secretion, an increase in free hCGß levels has
been reported to be associated with various neoplastic diseases and
hence should not be considered as specific for NET (24). Recent results
suggest that free hCGß may be a marker of aggressive neoplastic
disease (29). Finally, increases in UFC, SMS, or PTH-related
peptide levels were rare events, and no paraneoplastic
acromegaly was observed. Secretions of ACTH, GHRH, and PTH-related
peptide have been associated with various histological types of
tumor (30). Screening for these markers should depend on clinical
presentation.
Our study shows that MEN1 is a rare event in patients with apparently
sporadic NET. Ionized calcium and PTH-(1–84) measurements are
sufficient diagnostic tools when searching for MEN1 and should be
routinely performed in patients with foregut NET. Routine hormonal
screening is dependent on the primary site. We suggest that NSE,
5-HIAA, CT, and GP should be screened for in foregut-derived NET,
and NSE and 5-HIAA should be screened for in patients with
midgut-derived NET. The prognostic value of these secretions as well as
their interest in the follow-up of NET await assessment in future
studies.
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Acknowledgments |
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Footnotes |
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Received June 4, 1998.
Revised September 23, 1998.
Accepted October 20, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit of glycoprotein
hormones. J Clin Endocrinol Metab. 82:2622–2628., and hCGß as measured by specific monoclonal
immunoradiometric assay. Endocrinology. 120:549–558.[Abstract]
-Subunit and human chorionic gonadotropin-ß immunoreactivity in
patients with malignant endocrine gastroenteropancreatic tumours. Eur
J Clin Invest. 24:131–136.[Medline]
-subunit hyperecretion in patients with pituitary
tumors: clinically nonfunctionning and somatotroph adenomas. J
Clin Endocrinol Metab. 70:859–864.[Abstract]
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