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Experimental Studies |
-Subunit of Glycoprotein Hormones
Departments of Medicine (F.N., W.D.H., S.L.), Nuclear Medicine (D.K., E.K.), and Clinical Laboratory (C.S., J.L.), University Hospital Dijkzigt, Rotterdam, The Netherlands; and the Laboratory of Experimental Medicine and Endocrinology, University Hospital Gasthuisberg (W.C., R.B.), Leuven, Belgium
Address all correspondence and requests for reprints to: Dr. F. Nobels, Department of Endocrinology, Onze Lieve Vrouw Hospital, 164 Moorselbaan, 9300 Aalst, Belgium.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit of glycoprotein
hormones (-SU) were determined in 211 patients with neuroendocrine
tumors and 180 control subjects with nonendocrine tumors. The
concentrations of CgA, NSE, and -SU were elevated in 50%, 43%, and
24% of patients with neuroendocrine tumors, respectively. Serum CgA
was most frequently increased in subjects with gastrinomas (100%),
pheochromocytomas (89%), carcinoid tumors (80%), nonfunctioning
tumors of the endocrine pancreas (69%), and medullary thyroid
carcinomas (50%). The highest levels were observed in subjects with
carcinoid tumors. NSE was most frequently elevated in patients with
small cell lung carcinoma (74%), and -SU was most frequently
elevated in patients with carcinoid tumors (39%). Most subjects with
elevated -SU levels also had elevated CgA concentrations. A
significant positive relationship was demonstrated between the tumor
load and serum CgA levels (P < 0.01, by
2 test). Elevated concentrations of CgA, NSE, and -SU
were present in, respectively, 7%, 35%, and 15% of control subjects.
Markedly elevated serum levels of CgA, exceeding 300 µg/L, were
observed in only 2% of control patients (n = 3) compared to 40%
of patients with neuroendocrine tumors (n = 76). We conclude that
CgA is the best general neuroendocrine serum marker available. It has
the highest specificity for the detection of neuroendocrine tumors
compared to the other neuroendocrine markers, NSE and -SU. Elevated
levels are strongly correlated with tumor volume; therefore, small
tumors may go undetected. Although its specificity cannot compete with
that of the specific hormonal secretion products of most neuroendocrine
tumors, it can have useful clinical applications in subjects with
neuroendocrine tumors for whom either no marker is available or the
marker is inconvenient for routine clinical use. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit of glycoprotein
hormones (-SU).
We investigated the roles of the serum concentrations of CgA, NSE, and
-SU in a large study group of patients with neuroendocrine tumors,
including tumors with a small volume, and in a control group consisting
of patients with several nonendocrine tumors. The results suggest that
the determination of CgA is useful in selected clinical conditions when
either no known specific peptide markers are available or when the
available markers are inconvenient for routine clinical practice.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum samples were obtained from 211 subjects with the following neuroendocrine neoplasms: carcinoid tumor (n = 62), medullary thyroid carcinoma (n = 26), paraganglioma (n = 25), pheochromocytoma (n = 9), neuroblastoma (n = 3), small cell lung carcinoma (n = 23), insulinoma (n = 21), gastrinoma (n = 9), nonfunctioning pancreatic islet cell tumor (n = 13), Merkel cell tumor (n = 4), clinically nonfunctioning pituitary adenoma (n = 10), and GH-secreting pituitary adenoma (n = 6). All diagnoses were made histologically, except in a few patients with small tumors of the neuroendocrine pancreas. In these cases the following diagnostic criteria were used: paradoxical rise in gastrin levels after stimulation by iv injection of secretin in gastrinoma, and hypoglycemia with inappropriate hypersecretion of insulin and C peptide during a diagnostic fast in insulinoma. All plasma samples were obtained before operation.
Serum samples were also obtained from 180 subjects with a variety of "control" neoplasms of nonendocrine origin, both benign and malignant, including hematological and neurological tumors. This control group consisted of patients with breast carcinoma (n = 64), nonsmall cell lung cancer (n = 24), pancreatic adenocarcinoma (n = 21), adenocarcinoma of unknown origin (n = 12), non-Hodgkin lymphoma (n = 25), Hodgkin lymphoma (n = 13), multiple myeloma (n = 7), meningioma (n = 10), and astrocytoma (n = 4). All of these diagnoses were confirmed by histological examination.
Immunoassays
CgA was measured in serum samples, stored at -20 C, by a polyclonal RIA, using human CgA isolated from pheochromocytomas as tracer and standard, as previously described (6). The within-assay coefficients of variation were 6.5% and 8.6% for mean concentrations of 95 and 1160 ng/mL (n = 18), respectively. The between-assay coefficients of variation were 6.9% and 6.3% for mean concentrations of 90 and 698 ng/mL (n = 38), respectively. The detection sensitivity was 1.6 µg/L. The CgA immunoreactivity remained stable whether the serum samples were immediately frozen or kept at 4 C or at room temperature for 24 h, or whether blood was centrifuged immediately to obtain serum or after 24-h storage at room temperature. The reference value in 568 normal subjects of both sexes, aged 6–50 yr, is 90 ± 24 µg/L (range, 35–176); in 33 normal men older than 50 yr, it is 106 ± 22 µg/L (range, 70–159); in 249 normal postmenopausal women older than 50 yr, it is 110.1 ± 35.5 µg/L (range, 54–220). In men and premenopausal women, 175 µg/L was chosen as the upper cut-off value, and in postmenopausal women, 220 µg/L was used, to avoid overlapping values with normal subjects. This corresponds to slightly more than 3 SD above the mean.
NSE was measured by RIA. The upper cut-off value is 12.5 µg/L.
-Subunit was measured by RIA using antibodies purchased from UCB
(Brussels, Belgium). The upper cut-off values are 1.1 µg/L in men,
2.3 µg/L in premenopausal women, and 4.0 µg/L in postmenopausal
women.
Determination of tumor mass
The number of neuroendocrine tumor localizations was counted using computed tomography scan images and [111In-DTPA-D-Phe1]octreotide scanning (7). The tumor load was considered limited when one or two localizations were found; it was considered extensive when more than three localizations were demonstrated.
Statistical analysis
Results are reported as the mean ± SD. To
compare the different markers, 2 tests and Spearman rank
correlations were used. To study the effect of tumor load on
circulating concentrations of the markers, 2 tests were
used.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-SU, and NSE were
determined in 211 patients with neuroendocrine tumors and compared to
levels in a control group, consisting of 180 patients with nonendocrine
neoplasms. The study and control groups showed comparable age
distributions (53 ± 14 and 54 ± 13 yr, respectively). The
sex distribution showed a higher male/female ratio for the study group
(1.67 vs. 0.68), which can be ascribed to the high number of
patients with breast carcinoma in the control group.
Because renal failure can increase circulating CgA concentrations (4),
we evaluated whether this could cause falsely elevated levels. In the
control group a significant relationship was demonstrated between a
serum creatinine level higher than 133 µmol/L and increased levels of
CgA (P < 0.001, by 2 test). A
creatinine concentration above 133 µmol/L was found in seven patients
in the control group. Elevated serum concentrations of CgA (maximum,
371 µg/L) were present in six of these patients. A creatinine level
above 133 µmol/L was also present in three subjects in the study
group (all with carcinoid tumor). One of these patients had normal and
one had slightly increased CgA concentrations (268 µg/L). The third
patient, with an extensively metastasized carcinoid tumor, had a
creatinine level of 220 µmol/L and very high levels of CgA (188, 160
µg/L). Although these extreme elevations probably cannot be
attributed to the diminished renal function (4), these three study
patients and seven control subjects with creatinine levels above 133
µmol/L were eliminated for further analysis of the data. Slightly
elevated CgA concentrations can also occur in cases of severe liver
dysfunction (4). This was not encountered in any of our study or
control patients.
The results are summarized in Tables 1
and 2 and Fig. 1. The serum concentrations of
CgA were elevated in 103 of 208 patients with neuroendocrine tumors.
They were more frequently increased (in 50% of the subjects) than the
concentrations of NSE and -SU (in 43% and 24% of the subjects,
respectively). The highest elevations of CgA were observed in subjects
with carcinoid tumors (up to a maximum of 52,340 µg/L). Very high
levels (>1,000 µg/L) were also seen in subjects with nonfunctioning
pancreatic islet cell tumor, medullary thyroid carcinoma,
pheochromocytoma, paraganglioma, small cell lung carcinoma, gastrinoma,
and Merkel cell tumor. The levels were most frequently elevated in
subjects with gastrinoma (100%), pheochromocytoma (89%), and
carcinoid tumor (80%). In subjects with pituitary adenoma (13%),
insulinoma (10%), and paraganglioma (8%), elevated CgA levels were
only rarely present (Tables 1 and 2 and Fig. 1).
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The levels of -SU were most frequently elevated in patients with
carcinoid tumors (39%). Very high levels (up to a maximum of 353
µg/L) were found in these patients. -SU concentrations higher than
10 µg/L were found in 7 of 59 subjects with carcinoid tumors (12%),
whereas they were never encountered in subjects with other
neuroendocrine neoplasms.
Elevated levels of CgA, -SU, and NSE were present in respectively 9
(69%), 4 (31%), and 3 (23%) of 13 patients with nonfunctioning
pancreatic islet cell tumors (Table 3). In 7 (54%) of
these 13 patients, CgA levels were markedly elevated (>300
µg/L).
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-SU, and NSE were present in, respectively,
7%, 15%, and 35% of control subjects with nonendocrine
neoplasms.
When these control subjects were used as reference population, the
sensitivities of CgA, NSE, and -SU for the diagnosis of peripheral
neuroendocrine tumors (pituitary adenomas excluded) were, respectively,
53%, 46%, and 26%, with specificities of 93%, 65%, and 85%. We
applied, however, a rather high upper cut-off value for CgA,
corresponding to slightly more than 3 SD above the mean, to
avoid overlapping values with normal subjects. Usually 2 SD
above the mean is used as the upper cut-off level, increasing the risk
of overlap. When we reanalyzed our data using 2 SD as the
upper cut-off level, the sensitivity hardly improved to 58% with a
specificity of 90%. When using 300 µg/L as the upper cut-off
concentration for CgA, elevated levels were found in only 3 of 173
patients (2%) with nonneuroendocrine control tumors compared to 76 of
192 patients (40%) with peripheral neuroendocrine tumors (sensitivity,
40%; specificity, 98%). Thus, finding an excessively elevated level
of CgA firmly suggests the presence of a neuroendocrine tumor.
Relationships among the general neuroendocrine markers CgA, NSE,
and -SU
In subjects with peripheral neuroendocrine tumors (pituitary
adenomas excluded), a statistically significant relationship was
demonstrated between the presence and absence of elevated serum levels
of CgA and -SU (P < 0.001, by 2
test), but not between CgA and NSE or between -SU and NSE (Table 4). A weak, but significant, relationship was present
between the presence and absence of elevated serum concentrations of
CgA and -SU (P = 0.05, by 2 test) in
subjects with carcinoid tumors, who frequently had elevated -SU
levels. In patients with small cell lung carcinoma, who frequently had
elevated NSE levels, no significant relationship could be shown between
CgA and NSE concentrations.
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Measurements of 24-h urinary 5-hydroxyindole acetic acid (5-HIAA)
excretions were available in 46 of 59 patients with carcinoid tumors.
Increased levels (>40 µmol/24 h) were present in 31 patients (67%).
Elevated serum concentrations of CgA were demonstrated in 30 of these
31 subjects (97%; P < 0.01, by 2
test). A significant correlation was also present between the absolute
values of serum CgA and 24-h urinary 5-HIAA excretion (Spearman rank
correlation test; r = 0.65; P < 0.01). No
significant relationships were demonstrated between -SU and NSE
concentrations, on the one hand, and urinary 5-HIAA excretions, on the
other hand (P > 0.05, by 2 tests).
Determinations of serum calcitonin and carcinoembryonic antigen (CEA)
concentrations were available in, respectively, 20 and 21 of 26
subjects with medullary thyroid carcinoma. Calcitonin was elevated
(>0.14 µg/L) in 18 of 20 patients (90%), and CEA (>10 µg/L) was
elevated in 18 of 21 patients (86%). Elevated CEA levels were present
in the 2 patients with normal calcitonin levels. In 1 of these 2
subjects, slightly elevated concentrations of CgA (192 µg/L) and
-SU (1.5 µg/L) were found. CgA, -SU, and NSE levels were not
increased in the 3 patients with normal CEA levels. Significant
correlations were demonstrated between serum CgA, on the one hand, and
calcitonin (by Spearman rank correlation test: r = 0.79;
P < 0.01) and CEA (r = 0.84; P <
0.01), on the other hand, as well as between NSE, on the one hand, and
calcitonin (r = 0.71; P < 0.01) and CEA (r =
0.82; P < 0.01), on the other hand. -SU showed a
correlation with calcitonin (r = 0.63; P < 0.01),
but no significant correlation with CEA (r = 0.33;
P > 0.05).
Determinations of 24-h urinary excretions of vanilmandelic acid (VMA) were only available in five of nine patients with pheochromocytoma. The highest levels of CgA were found in the patients with the highest urinary VMA excretion, although the small number of cases did not permit statistical evaluation.
Relationship with tumor load
Using computed tomography scan images and octreotide scintigrams,
information on tumor volume could be obtained in subjects with the
following neuroendocrine neoplasms: 60 carcinoid tumors, 26 medullary
thyroid carcinomas, 25 paragangliomas, 11 small cell lung carcinomas, 9
gastrinomas, and 12 nonfunctioning pancreatic islet cell tumors. Tumor
load was considered to be limited when 1 or 2 localizations were found
and was considered extensive when more than 3 localizations were
demonstrated. A highly significant positive relationship was
demonstrated between the tumor load and serum CgA levels
(P < 0.01, by 2 test). Such a
relationship could not be shown for -SU or NSE. In the individual
neuroendocrine neoplasms, the relationship between tumor load and CgA
levels was only significant in subjects with carcinoid tumors. Because
they represent the largest subgroup, statistical significance is more
easily reached. Gastrinomas form an exception to the rule that small
neuroendocrine tumors have low CgA levels; elevated CgA levels were
detected in all patients with gastrinomas, although they all presented
with limited neoplastic disease.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-SU as
serum markers of neuroendocrine neoplasia in general. Serum
concentrations were measured in a large group of patients with several
neuroendocrine tumors and compared with those in a large control group
with a variety of nonendocrine tumors. The highest concentrations of CgA, with values up to 250 times the upper limit of normal, were observed in subjects with carcinoid tumors, medullary thyroid carcinomas, pheochromocytomas, and some tumors of the endocrine pancreas. This confirms the results of previous smaller studies (2, 4, 5). Elevated levels were also frequently encountered in subjects with peripheral (nonpituitary) neuroendocrine tumors without detectable hormonal secretion. These so-called chromograninomas were first described by Sobol and co-workers (3). Serum concentrations of CgA are only rarely increased, however, in cases of clinically nonfunctioning pituitary adenomas. This is probably due to the small volume of these adenomas (6).
We demonstrated a significant positive relation between the serum levels of CgA and the tumor mass of the neuroendocrine neoplasms. This confirms our earlier findings in Cushing’s syndrome caused by ectopic ACTH production by extrapituitary neuroendocrine tumors (8) and the findings by O’Connor and Deftos (2) and Hsiao and co-workers (9) in pheochromocytomas. The serum concentrations of CgA are only rarely slightly elevated in subjects with small neuroendocrine tumors, such as insulinomas, paragangliomas, or pituitary adenomas (6, 8, 10). These tumors are usually detected at an early stage of oncological evolution, because they rapidly induce symptoms due to active hormonal secretion or compression of important surrounding tissues. The presence of CgA or its messenger ribonucleic acid can nearly always be demonstrated in the cells of these tumors by immunohistochemistry or in situ hybridization (6, 11, 12). Nevertheless, it must be assumed that the small amount of CgA released by these neoplasms usually fails to elevate the serum concentration above the physiological background level. Increased CgA concentrations were detected, however, in all of our patients with gastrinoma, although they all had a very limited tumor burden. It is well known that chronic elevation of gastrin levels provokes hyperplasia of the neuroendocrine cells of the stomach (13). As these cells are able to secrete CgA, they might be responsible for the elevated CgA concentrations. Stabile and co-workers demonstrated that the CgA concentrations can be normalized by gastrectomy alone, without resection of the gastrin-producing tumor (and thus without correction of the elevated gastrin levels) (14).
In our hands, CgA had a smaller sensitivity for the detection of neuroendocrine neoplasms than reported in previous studies (2, 4, 5). However, the technical characteristics of our RIA for CgA are very similar to those of the other assays used in frequently cited publications (4, 15). A small neuroendocrine tumor mass was present in a rather large percentage of our patients, in contrast to the hitherto published series, in which almost all tumors were extensively metastasized (2, 4, 5). This can probably be explained by the fact that patients tend to be transferred earlier in their oncological evolution, after the development of [111In-DTPA-D-Phe1]octreotide scanning for the visualization of neuroendocrine tumors in our hospital. Many patients with biochemical proof of a neuroendocrine tumor were transferred for somatostatin receptor scintigraphy after conventional radiography failed to elucidate the location of the tumor. The inclusion of a number of patients with these smaller tumors decreased the overall sensitivity of serum CgA in our series.
The specificity of elevated levels of CgA in the diagnosis of neuroendocrine tumors was also lower in our study than in previous ones (2, 4, 5). O’Connor and co-workers (2, 4) and Erikkson and co-workers (5) reported specificities of 100%. By contrast, we used a much larger control group, consisting of patients with a greater variety of nonendocrine tumors. After excluding patients with decreased renal function, elevated serum concentrations of CgA were demonstrated in 12 of 173 nonendocrine neoplasms (7%). The serum levels in these control patients were usually only slightly elevated. They exceeded 300 µg/L in only 3 of 173 patients (2%) compared to 76 of 208 patients (37%) with neuroendocrine tumors. Thus, finding an excessively elevated level of CgA firmly suggests the presence of a neuroendocrine tumor.
It is well established that many nonendocrine tissues contain neuroendocrine cells, belonging to the amino-precursor-uptake-decarboxylation system. A substantial body of data has accumulated in the literature during recent years, revealing that these cells are also present in most tumors of nonendocrine origin (16, 17, 18, 19, 20). They are either diffusely scattered throughout the tumor or multifocally located in small nests. In malignant tumors these neuroendocrine cells even participate in the neoplastic growth, as they show nuclear abberations and are present in locally invasive or metastatic tumor tissue. The number of tumors harboring these neuroendocrine cells or the percentage of neuroendocrine cells in a tumor depend on the tumor type, the number of neuroendocrine markers used, and the detection technique (histochemistry for argyrophilia, immunohistochemistry, or detection of messenger ribonucleic acid of neuroendocrine markers). These cells probably secrete CgA, as it is present in their dense core secretory granules. There are only scarce data available in the literature concerning serum levels of CgA in subjects with nonendocrine tumors. Elevated levels were reported in patients with carcinomas of the prostate gland (21, 22) and in cases of nonsmall cell lung cancer (23). Whether proliferation of neuroendocrine cells also occurs in hematological neoplasms is not known. One study reported the presence of scarcely distributed CgA-positive cells in the normal spleen, lymph nodes, and thymus (24).
As a general neuroendocrine marker, CgA cannot differentiate between different subtypes of neuroendocrine neoplasms. Most tumors of neuroendocrine origin release typical secretion products that can be used as specific serum markers. These markers usually provide a higher sensitivity and specificity than CgA, as illustrated by our data comparing calcitonin and CEA with CgA in subjects with medullary thyroid carcinoma. In these situations the usefulness of CgA is limited, because it does not provide additional information. By contrast, CgA can have interesting clinical applications in so-called nonfunctioning neuroendocrine tumors that are either not able to secrete hormonal products or release products that cannot be detected by current techniques. It can also be useful in neuroendocrine tumors in which other diagnostic procedures have their limitations (e.g. fluctuating levels of serum catecholamines in pheochromocytoma) or are inconvenient (e.g. 24-h urine collections for 5-HIAA determination in carcinoid tumors). Our data illustrate the value of CgA in these conditions: increased levels were found in 69% of nonpituitary, hormone-negative neuroendocrine tumors, 89% of pheochromocytomas, and 80% of carcinoid tumors. Very high concentrations were frequently encountered in these patients.
NSE is the neuron-specific isomer of the glycolytic enzyme 2-phospho-D-glycerate hydrolase or enolase (25). It is a widely used immunohistochemical and serum marker for neuroendocrine tissues and is especially known as a marker for small cell lung carcinoma (26). Our data confirm the frequent elevation of its serum concentrations in patients with several neuroendocrine tumors (27, 28, 29). The highest levels were encountered in small cell lung carcinoma and in the rare cases of Merkel cell tumors. Serum concentrations of NSE are more often elevated than those of CgA in subjects with these tumors and in those with insulinomas, paragangliomas, and neuroblastomas. The specificity of serum NSE for the diagnosis of neuroendocrine tumors is, however, much lower than that of serum CgA. Increased NSE levels were demonstrated in 61 of 173 subjects with nonneuroendocrine neoplasms (35%) compared to 89 of 192 with peripheral (nonpituitary) neuroendocrine tumors (46%). Unlike CgA, the specificity of NSE can hardly be improved by increasing the upper cut-off value. Therefore, NSE cannot be considered a good diagnostic marker for neuroendocrine tumors, but can be very useful as a follow-up marker, especially for small cell lung carcinoma and Merkel cell tumors.
The -SU of the glycoprotein hormones is a well known marker of
pituitary adenomas of gonadotroph origin (6). Recent studies suggest
that determination of the serum concentrations of -SU might also be
of value in patients with peripheral neuroendocrine neoplasms (30, 31, 32).
Our data confirm the presence of elevated serum levels in several
subjects with these neoplasms. Again, as with CgA and NSE, the marker
lacks specificity. Serum levels were elevated in 26 of 173 subjects
with nonneuroendocrine neoplasms (15%) compared to 47 of 192 with
peripheral neuroendocrine tumors (24%). Increasing the cut-off level
again failed to improve the specificity. Very high levels were
frequently detected in patients with carcinoid tumors; 7 of 59 subjects
with carcinoid tumors (12%) had levels higher than 10 µg/L. Such
high levels were only encountered once in the control group, in a
patient with breast carcinoma. Thus, the finding of very high serum
concentrations of -SU suggests the presence of a carcinoid tumor
when tumors of germ cell or trophoblastic origin are excluded. The
clinical usefulness of -SU as a marker for neuroendocrine tumors is
limited, however, because most subjects with elevated levels also have
elevated CgA concentrations.
In conclusion, CgA is the best general neuroendocrine serum marker available. It had the highest specificity for the detection of neuroendocrine tumors of the three tested markers. Unfortunately, it is not a very sensitive marker; its serum concentrations seem to rise relatively late in the evolution of the tumor. Although its specificity cannot compete with that of the specific hormonal secretion products of most neuroendocrine tumors, it can have useful clinical applications in subjects with neuroendocrine tumors for which either no marker is available (so-called nonfunctioning neuroendocrine tumors) or the marker is inconvenient for daily clinical use (e.g. 24-h urinary 5-HIAA excretions and plasma catecholamines).
Received September 18, 1996.
Revised April 23, 1997.
Accepted May 2, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunits and
chromogranin A and their response to TRH in clinically nonfunctioning,
-subunit secreting and gonadotroph pituitary adenomas. J Clin
Endocrinol Metab. 77:784–789.[Abstract]
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T. Borglum Jensen, L. Hilsted, and J. F. Rehfeld Library of Sequence-specific Radioimmunoassays for Human Chromogranin A Clin. Chem., April 1, 1999; 45(4): 549 - 560. [Abstract] [Full Text] [PDF]
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E. Baudin, J.-M. Bidart, P. Rougier, V. Lazar, P. Ruffié, J. Ropers, M. Ducreux, F. Troalen, J.-C. Sabourin, E. Comoy, et al. Screening for Multiple Endocrine Neoplasia Type 1 and Hormonal Production in Apparently Sporadic Neuroendocrine Tumors J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 69 - 75. [Abstract] [Full Text]
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