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Articles |
1
USA hCG Reference Service, Obstetrics and Gynecology, University of New Mexico, Albuquerque, NM 87131.
2
Obstetrics and Gynecology, Yale University, New Haven,
CT 06510.
3
Medical Oncology, Charing Cross Hospital, London W68RF,
United Kingdom.
4
Department of Pathology, Hurley Medical Center, Flint,
MI 48501.
a Address correspondence to this author at: Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Lomas Blvd., Albuquerque, NM 87131. Fax 505-272-6385; e-mail
larry{at}hCGlab.com.
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Abstract |
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Methods: Standards for five irregular forms hCG produced in trophoblastic diseases, serum samples from 59 patients with confirmed trophoblastic diseases, and serum samples from 12 women with previous false-positive hCG results (primarily in the Abbott AxSYM assay) were blindly tested by commercial laboratories in the Beckman Access hCGß, the Abbott AxSYM hCGß, the Chiron ACS:180 hCGß, the Baxter Stratus hCG test, the DPC Immulite hCG test, the Serono MAIAclone hCGß tests, and in the hCGß RIA.
Results: Only the RIA and the DPC appropriately detected the five irregular hCG standards. Only the Beckman, DPC, and Abbott assays gave results similar to the RIA in the patients with confirmed trophoblastic diseases (values within 25% of RIA in 49, 49, and 54 of 59 patients, respectively). For samples that were previously found to produce false-positive hCG results, no false-positive results were detected with the DPC and Chiron tests (5 samples, median <2 IU/L), but up to one-third of samples were false positive (>10 IU/L) in the Beckman (1 of 5), Serono (2 of 9), and Baxter assays (1 of 5), and the hCGß RIA (3 of 9; median for all assays, <5 IU/L). These samples, which produced false-positive results earlier in the Abbott AxSYM assay, continued to produce high values upon reassessment (median, 81 IU/L).
Conclusions: Of six frequently used hCG immunometric assays, only the DPC detected the five irregular forms of ßhCG, agreed with the RIA, and avoided false-positive results in the samples tested. This assay, and similarly designed assays not tested here, seem appropriate for hCG testing in the diagnosis and management of trophoblastic diseases.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß subunits, joined noncovalently. Approximately 30% of
the molecular weight of hCG comprises carbohydrate side chains: four
N-linked oligosaccharide and four O-linked oligosaccharides. The hCG
and ß subunits are heterogeneous in both peptide and
oligosaccharide side chain structures (1)(2).
Ordinary hCG (-ß dimer with no cleavages, monoantennary or
biantennary N-linked oligosaccharides, and trisaccharide and
tetrasaccharide O-linked oligosaccharides) is the principal form of hCG
in serum during normal pregnancy. Ordinary hCG is accompanied by small
and varying amounts of nicked hCG (cleaved on the ß subunit, between
residues 47 and 48), hyperglycosylated hCG (hCG with an abundance of
larger or triantennary N-linked oligosaccharides and hexasaccharide
O-linked oligosaccharides), nicked and hyperglycosylated hCG, free ß
subunit, nicked free ß subunit, free subunit, and large free
subunit ( subunit with triantennary N-linked oligosaccharides)
(1)(2). Commercial hCG (or hCGß) assays all
detect ordinary hCG, and to various extents detect nicked hCG,
hyperglycosylated hCG, nicked and hyperglycosylated hCG, and nicked and
nonnicked free ß subunit. None of the commercial hCG (or hCGß)
methods detect either form of free subunit (2).
With the preponderance of ordinary hCG in normal pregnancy serum, the
ability of the assay to fully detect nicked hCG, hyperglycosylated hCG,
nicked and hyperglycosylated hCG, and nicked and nonnicked free ß
subunit may make only a small difference to the immunoassay results and
to the utility of the assay for pregnancy testing
(1)(3)(4). Trophoblastic diseases include complete and partial hydatidiform mole, postmolar tumor, gestational choriocarcinoma, testicular choriocarcinoma, and placental site trophoblastic disease. These are also major sources of hCG. Precise hCG determinations are crucial in patients with trophoblastic diseases to assess the mass of tumor, the successful treatment of malignancy, or recurrence or persistence of disease (3)(4)(5). In trophoblastic diseases, hyperglycosylated hCG, nicked hCG, hyperglycosylated and nicked hCG, or nicked or nonnicked free ß subunit may be the principal source of immunoreactivity in serum (2)(3)(4)(5)(6)(7). Additional hCG variants are found in patients with trophoblastic diseases. These include nicked hCG missing the ß subunit C-terminal peptide, residues 92–145, and alternatively nicked hCG (cleaved at ß43–44 or ß44–45) (1). The inability of commercial hCG tests to fully detect these hCG variants has led to failure to detect persistent or recurrent trophoblastic diseases, requiring urgent chemotherapy or other surgery (4)(8)(9).
Several centers have claimed that the competitive polyclonal
anti-hCGß RIA is the only type of assay that detects all of these
variants equally and is the only test appropriate for monitoring
trophoblastic diseases
(4)(7)(10)(11). For this
reason, the hCGß RIA has been proclaimed the "gold standard" for
hCG testing in trophoblastic disease applications
(4)(7). A hCGß RIA should not be mistaken for
a hCG, hCG, or hCGß C-terminal peptide RIA, which may be much less
broad in specificity. Other laboratories have found that newer
immunometric assays and automated immunometric assays may also be
appropriate for trophoblastic disease management or may even offer an
improvement for this application (6)(12)(13)(14)(15).
Our objective was to thoroughly examine the appropriateness of
different hCG (or hCGß) assays for monitoring patients with
trophoblastic diseases. We examined the ability of six of the most
commonly used automated immunometric assays to detect hCG and its
variants in trophoblastic disease cases and to avoid unduly low or
false-negative immunoassay values. Results were compared with a
commercial laboratory’s competitive hCGß RIA, the gold
standard.
A recent article identified 12 patients falsely treated for presumed choriocarcinoma because of false-positive hCG results (16)(17). Other reports have also identified patients erroneously diagnosed with choriocarcinoma because of false-positive hCG results (9)(18)(19). False-positive hCG results have also been identified in three patients after evacuation of complete hydatidiform mole (Cole LA and Butler SA, unpublished data). This can lead to false diagnosis of a postmolar tumor. A recent report from the Trophoblastic Disease Center in London noted that a significant proportion of choriocarcinoma cases are presumed solely on the basis of persistently increased hCG results (20). Most cases of postmolar tumor are assumed on the basis of increased hCG results after evacuation of a complete hydatidiform mole. Our objective was to also examine the accuracy of hCG (or hCGß) assays for diagnosing patients with choriocarcinoma or postmolar tumor. Samples that had been found to produce false-positive results previously (16)(17)(19) were examined using the same six automated immunometric hCG (or hCGß) tests and the hCGß RIA.
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Materials and Methods |
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In addition to these 59 serum samples, five standards were prepared from pure hCG preparations. These were pure hyperglycosylated hCG, pure nicked hCG, pure asialo hCG (hCG missing sialic acid residues on N- and O-linked oligosaccharides), pure hCG minus the C-terminal peptide, and nonnicked free ß subunit. These were purified and prepared from pregnancy, complete hydatidiform mole, or choriocarcinoma urine samples, as described previously (1). Peptide and oligosaccharide structures had been determined to fully characterize the preparations (1).
Additional serum samples were collected from 12 women erroneously diagnosed as having choriocarcinoma or gestational trophoblastic disease because of false-positive hCG results (16)(17). In all 12 cases, the false-positive results were seemingly attributable to the presence of heterophilic antibodies in blood (Cole LA and Shahabi S, unpublished data). All 12 women were shown to lack measurable concentrations (>2 IU/L) of true hCG or its breakdown products (16)(17). The 12 serum samples were those sequentially accrued by the hCG Reference Service and were not selected in any way. Ten of the 12 patients were falsely monitored by their physicians, using the Abbott AxSYM hCGß test, 1 patient was monitored using both the Abbott AxSYM and IMx hCGß tests, and 1 was monitored using the Bayer Immuno-1 hCGß assay.
On the basis of the hCG results supplied by Charing Cross Hospital and
patient treatment centers, the 59 confirmed trophoblastic disease serum
samples were each diluted with normal male serum (Sigma) to
200 IU/L (samples with hCG <200 IU/L were not diluted). The five
hCG structure standards were calibrated by amino acid analysis. Results
were converted to IU/L hCG, or molar equivalents of hCG based on the
molecular weights of hCG and its ß subunit (21), using the
formula established by the World Health Organization for the
preparation of the First International Reference Preparation and the
Third International Standard for immunoassays (1 µg of pure hCG
= 9.3 IU) (22). Standards were diluted in normal male serum
to a concentration of 200 IU/L or the molar equivalent (0.57 pmol/L
hCG).
The trophoblastic disease patient samples, the 5 standards, and 4 of the 12 false-positive serum samples (only 4 samples were available at the time of initial coding), a total of 68 samples, were mixed, coded, and sent to independent commercial laboratories for blind testing. The remaining eight false-positive samples were tested by commercial laboratories at later times, when samples became available.
Samples were tested by four commercial laboratories. The Chemistry
Laboratory in the Department of Pathology at Hurley Medical Center
(Flint, MI) blindly tested coded samples in the Beckman Access hCGß
(total hCG), the Abbott AxSYM hCGß (total hCG), the Chiron ACS:180
hCGß (total hCG), and the Baxter Stratus hCG test (intact hCG). This
was carried out by Dr. Harland Verrill as part of a collaboration,
without charge. Two of the samples were tested by the Abbott AxSYM
hCGß assay at Quest Diagnostics (Teterboro, NJ). The Endocrinology
Laboratory at Yale-New Haven Hospital (New Haven, CT) blindly tested
the coded samples in the Serono MAIAclone hCGß (total hCG)
and in their tumor marker hCG test, a goat polyclonal anti-hCGß
competitive RIA (total hCG test; 3-day assay using rabbit polyclonal
anti-ß antisera and 125I-hCG tracer, bound
material precipitated with goat anti-rabbit 
-globulin). A standard
immunoassay fee was paid for this service. Finally, the DPC Immulite
hCG test (total hCG) was run blindly at the laboratories of Diagnostic
Products Corp. (Los Angeles, CA) without charge. This is an independent
research study. The authors received no funds from, and have neither
personal interest in nor conscious bias for or against any of the
described manufacturers.
Results were decoded and entered into a Microsoft Excel spreadsheet. The six automated immunometric assay hCG/hCGß assay values were compared with the hCGß RIA results, and we tabulated the number of samples in which results were >25% below or >25% above the RIA result. Because individual hCG values usually are logarithmically distributed (23)(24), the median results are presented.
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Results |
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The six examined assays varied in their recognition of purified (200
IU/L) hCG variants (Table 1
). The Serono MAIAclone hCGß assay ineffectively recognized
free ß subunit (3.8% recovery), hyperglycosylated hCG (3.9%), and
nicked hCG (27%). The Baxter Stratus hCG test did not detect free
ß-subunit standard (<1% recovery). The Chiron ACS:180 hCGß test
underdetected free ß-subunit standard (70%). Three tests, the
Beckman Access, Abbott AxSYM, and Chiron ACS:180, did not detect the
hCG minus C-terminal peptide (<1% recovery). The commercial hCGß
RIA (the gold standard) and the DPC Immulite hCG automated immunometric
assay were the only tests with apparent recoveries of at least 75% for
all five hCG-related molecule standards.
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We examined the detection of hCG and related molecules in serum samples
from patients with complete hydatidiform mole. Samples from 30 patients
were collected before and up to 2 week after evacuation of a complete
hydatidiform mole (Table 2
). Additional samples were collected from 21 patients at 2–6
weeks after evacuation of hydatidiform mole (Table 3
), and from 8 women with choriocarcinoma (Table 4
). Results from the six automated immunometric assays were
compared with those from the commercial laboratory’s hCGß RIA. For
the purposes of this study, errors were considered as results deviating
from the RIA value by >25%. The fewest errors were found with the
Abbott AxSYM hCGß test (5 errors in 59 patients total;
8.5%) and with the DPC Immulite hCG and Beckman Access hCG (10 errors
total; 17%). More errors were found with the Serono
MAIAclone (14 errors total; 24%) and with the Chiron ACS:180 hCGß
(16 errors total; 27%). The most errors were noted with the Baxter
Stratus hCG (22 errors total; 37%).
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Most of the errors were noted in samples taken 2–6 weeks after
evacuation of hydatidiform mole (Table 3
) and with choriocarcinoma
serum samples (Table 4
). These errors were particularly evident with
the Chiron ACS:180 hCGß test (errors in 5 of 21 mole and 5 of 8
choriocarcinoma cases), the Serono MAIAclone assay (errors in 7 of 21
mole and 6 of 8 choriocarcinoma cases), and the Baxter Stratus hCG
assay (errors in 15 of 21 mole and 5 of 8 choriocarcinoma cases).
We also examined serum from 12 patients with a history of
false-positive hCG results (Table 5
). These were tested in the commercial RIA and in the six
automated immunometric assays. Insufficient serum was available to test
all samples in each of the seven assays. We considered false-positive
results >10 IU/L for diagnosis of trophoblastic disease (or
pregnancy). Concentrations up to 10 IU/L hCG can be produced by the
pituitary and other sources
(3)(10)(12). None of the samples
tested exceeded 10 IU/L in the DPC Immulite hCG or the Chiron ACS:180
hCGß test (0 of 6 and 0 of 5 samples, respectively). Less than
one-third of the samples tested exceeded 10 IU/L in the Baxter Status
hCG, Beckman Access hCGß, and Serono MAIAclone hCGß assays, or in
the commercial hCGß RIA (1 of 5, 1 of 5, 2 of 9, and 3 of 9 samples,
respectively). Because most of these samples were known to produce
false-positive results in the Abbott AxSYM assay, we expected and found
false-positive results in the Abbott AxSYM hCGß test (10 of 10
samples).
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To evaluate the extent of false positivity, we calculated the median concentrations. The median result was <2 IU/L in four of the assays and <5 IU/L in two other assays. In the Abbott AxSYM hCGß test, however, the median was 81 IU/L.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Textbooks on obstetrics and gynecology emphasize the essentiality of hCG testing in patients with trophoblastic diseases. This is a mandated application, although it is not approved by the FDA and has not been formally tested by hCG assay manufacturers. hCG is the vital test in the identification of choriocarcinoma, differentiating this cancer from others. It acts as a perfect tumor marker (100% sensitivity) for managing the treatment for choriocarcinoma and for detecting recurrences of disease (18)(25). Although hCG testing is not essential in the diagnosis of hydatidiform mole, it is essential for demonstrating the complete removal of molar tissue and for the rapid identification of postmolar tumor or persistent trophoblastic disease (26). Problems have been reported in the use of hCG immunoassays for both detecting (false-positive results) and monitoring the progress of (false-negative or unduly low results) trophoblastic diseases (2)(3)(4)(5)(6)(7)(8)(10). In this study, we examined the performance of the competitive hCGß RIA (the gold standard hCG test for trophoblastic diseases) and six of the most commonly used automated immunometric assays in diagnosing and monitoring hydatidiform mole and choriocarcinoma.
Hyperglycosylated hCG, nicked hCG, hCG minus C-terminal peptide, asialo hCG, and free ß subunit are either unique to trophoblastic diseases or more abundant in trophoblastic disease samples (1)(2)(3)(4)(5)(6)(7). Only the hCGß RIA and the DPC test effectively detected all of the hCG breakdown products or glycosylation variants. Not surprisingly, three tests, the Beckman, Abbott, and Chiron assays, did not detect hCG minus C-terminal peptide. The C-terminal peptide is a commonly used hCG epitope because it is unique to the ß subunit of hCG and is not present on luteinizing hormone. Other ß-subunit core epitopes can be targeted to effectively differentiate hCG and luteinizing hormone (2).
Considering the assay specificities, we examined serum from 59 patients with confirmed trophoblastic diseases. Results were compared with the hCGß RIA. Three tests (the Abbott, the DPC, and the Beckman) performed well, with few important differences in results compared with the hCGß RIA. For three of the six tests (the Serono, Chiron, and Baxter tests), however, 24%, 27%, and 37% of results compared poorly with the hCGß RIA. Errors were most evident with these three assays in serum samples from women 2–6 weeks after evacuation of hydatidiform mole and in samples from patients being monitored for choriocarcinoma (34%, 45%, and 69% errors, respectively). These are clinical situations in which accurate hCG measurements are needed. We infer that theses three assays, and other similar assays not tested in this study, should probably be avoided in the management of trophoblastic disease. These three assays (Serono, Chiron, and Baxter) have minimal or less than normal detection of free ß subunit. This is the likely cause of the poor performance in samples from patients with trophoblastic diseases. Clearly, equimolar detection of hCG and free ß subunit is important in the management of trophoblastic diseases (2)(3)(4)(5)(6)(7). The Serono test also poorly detected nicked hCG and hyperglycosylated hCG, which are also important in the management of trophoblastic diseases (1)(2)(4).
In four individual cases (patients with total hCG concentrations of 14,
124, 162, and 3 456 000 IU/L; see Tables 3
and 4
), unduly low results
were found with three other assays (Beckman, Abbott, and Chiron). These
three methods did not detect hCG minus C-terminal peptide. Detection of
this hCG degradation product may also be important in the management of
patients with trophoblastic diseases.
Patients can be diagnosed with choriocarcinoma solely from a persistent positive hCG result, in the absence of an imaged tumor or a pregnancy (16)(18). In most cases, chemotherapy or surgery is initiated solely because of persistent positive hCG results (16). False-positive hCG results can occur in the hCG assay, and patients have been erroneously diagnosed and treated for choriocarcinoma. The hCG Reference Service has now identified 20 such false choriocarcinoma cases; 14 needlessly received surgery or chemotherapy [Ref. (16) and Cole LA, unpublished data]. False-positive results have also been observed in three patients after evacuation of hydatidiform mole (Cole LA and Butler SA, unpublished data). False-positive hCG results typically come from heterophilic antibodies present in human serum (9)(16)(18)(27). We used such sera from the initial 12 patients identified with false-positive hCG results at the hCG Reference Service (16)(17) to further evaluate the hCGß RIA and the six automated immunometric tests.
The DPC and Chiron assays produced no false-positive results (<10 IU/L). Up to one-third of samples gave false-positive results with the hCGß RIA, and the Beckman, Baxter, and Serono assays. It is important to note that 11 of the 12 sera were from patients who had been tested earlier using the Abbott AxSYM test. In fact, 19 of the 20 patients identified to date by the hCG Reference Service with false-positive hCG had been monitored by their physicians using the Abbott AxSYM test [Ref. (16) and Cole LA, unpublished data]. It is no surprise that 10 of 10 samples evaluated here were falsely positive in this assay. The median false-positive hCG result was 81 IU/L in the Abbott test, and <5 IU/L in all other tests. Such (lower) false-positive results found in the other assays are less likely to meet the threshold for the assumed diagnosis of choriocarcinoma and for therapy (16). The finding of multiple serum samples positive in the Abbott test and serum samples producing lower or negative results in other assays suggests a potential problem with this test.
We have examined the specificity of hCG immunoassays for detecting variant forms of hCG present in trophoblastic diseases, compared the utility of automated hCG immunometric assays with the hCGß RIA in the management of trophoblastic diseases, and have examined the potential of hCG assays to give false-positive results. Only the DPC gave consistently acceptable results in all three categories. The DPC test is a chemiluminescence test, using a capture antibody and a tracer antibody directed toward different regions of the core of hCG ß subunit. Several other commercial tests use similar antibody arrangements (2). These assays might be similarly utilized in the management of trophoblastic diseases. The DPC and similarly designed tests may be as useful as hCGß RIA in the management of trophoblastic diseases. One must consider the negative aspects of an hCGß RIA, including its complexity, the extensive pipetting, its relative imprecision, and its time-consuming procedures.
The DPC test and the hCGß RIA both appropriately recognized all of the common hCG metabolic products associated with trophoblastic diseases, but the DPC test yielded results that differed from the hCGß RIA data in 10 of 59 patients with trophoblast disease. In 7 of these 10 cases, the DPC result was close to the mean result for the 7 assays evaluated (within 25%; data not shown), but not close to the hCG RIA data. Thus, the error may lie with the RIA result rather than with the DPC values. The DPC and other similarly designed tests might today be the tests of choice for diagnosing and monitoring trophoblastic diseases and for other applications requiring careful detection of true-positive hCG and recognition of both intact hCG and hCG metabolic products.
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Acknowledgments |
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References |
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- and ß-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma. Endocrine 1997;7:15-32.[Web of Science][Medline]
[Order article via Infotrieve]
and ß subunits of human chorionic gonadotrophin for immunoassay. J Endocrinol 1980;84:295-310.The following articles in journals at HighWire Press have cited this article:
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  B. E.P.B. Ballieux, N. I. Weijl, H. Gelderblom, J. van Pelt, and S. Osanto False-Positive Serum Human Chorionic Gonadotropin (hCG) in a Male Patient with a Malignant Germ Cell Tumor of the Testis: A Case Report and Review of the Literature Oncologist, November 1, 2008; 13(11): 1149 - 1154. [Abstract] [Full Text] [PDF]
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C. M. Preissner, L. A. Dodge, D. J. O'Kane, R. J. Singh, and S. K.G. Grebe Prevalence of Heterophilic Antibody Interference in Eight Automated Tumor Marker Immunoassays Clin. Chem., January 1, 2005; 51(1): 208 - 210. [Full Text] [PDF]
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