Special Feature: The Phantom hCG Phenomenon
Special Feature: The Phantom hCG Phenomenon
By David M. Gershenson, MD
The issue of the false-positive human Chorionic Gonadotropin (hCG), or the so-called "phantom hCG," has received increasing media and scientific attention and scrutiny over the past several months. The Society of Gynecologic Oncologists and the Diagnostics Division of Abbott Laboratories have recently issued alerts for physicians regarding the pitfalls of this phenomenon.
There is really nothing new about the phenomenon of a falsely positive hCG result. For several years, we have known about the fact that high levels of serum luteinizing hormone (LH) in menopausal patients may cross-react with hCG radioimmunoassays, giving a falsely abnormal value of hCG in the range of 5-10 mIU/mL. In such instances, oral contraceptives could be used to suppress the LH and thus eliminate concern about such a slightly elevated hCG. However, media coverage of recent multimillion dollar lawsuits has heightened our awareness of this most recent twist on the subject.
Laurence Cole, a PhD at Yale at the time, was really the scientist responsible for highlighting and describing in detail the phenomenon of phantom hCG in 1998.1 Prior to this time, Dr. Cole and others had published scattered case reports on the subject. In his 1998 report, Dr. Cole described 3 cases in which phantom hCG occurred. In the first, a 26-year-old woman was diagnosed with gestational trophoblastic disease following a dilatation and currettage (D&C) for a miscarriage. She had low levels of hCG in the range of 49-89 IU/L. Imaging studies were negative. She subsequently received chemotherapy and underwent hysterectomy for persistent elevations of hCG. Later, the diagnosis of phantom hCG was made, and therapy was discontinued. In the second case, a 28-year-old woman with a serum hCG of 69 IU/L and no fetal sac on sonogram underwent D&C and laparoscopy for a suspected ectopic pregnancy. No ectopic pregnancy was identified, and subsequent studies confirmed phantom hCG. In the third case, a 24-year-old woman with a serum hCG of 117 IU/L, diaphragmatic pain, and nausea, was diagnosed as having an early miscarriage. Because of persistence of abnormal hCG levels in the range of 45-135 IU/L over a 4-month period, the diagnosis of gestational trophoblastic disease was made. Imaging studies were negative, and the patient underwent D&C and subsequent chemotherapy. Studies later confirmed the diagnosis of phantom hCG.
Until the recent news stories of a malpractice suit based on misdiagnosis and unnecessary treatment of a woman with phantom hCG emerged, however, even gynecologic oncologists and obstetrician-gynecologists paid little attention to Dr. Cole’s warning. Based on the recent flurry of headlines and alerts, we now better understand the phenomenon of phantom hCG. Phantom hCG appears to be a substance in blood that interferes with the hCG immunoassay. These interfering substances may represent heterophilic antibodies, human antimouse antibodies (HAMA), or other human antibodies to rabbit, goat, or sheep immunoglobulin, nonspecific protein binding, or hCG-like substances. Because the antibodies are large glycoproteins, they are not excreted in urine in any significant quantities. Therefore, if the phantom hCG phenomenon is suspected, it may be diagnosed by the absence of urinary hCG. In addition, a repeated hCG test using a different immunoassay platform usually reveals a normal hCG value. Dr. Cole also pointed out that serial dilutions of samples that contain interfering substances rather than true hCG give nonlinear results.
More recent reports in the literature include those of 12 patients who were incorrectly diagnosed with gestational trophoblastic disease because of phantom hCG (5 suffered surgical loss of reproductive potential, and 6 received unnecessary chemotherapy),2 and another of 2 patients diagnosed with phantom hCG (one of whom received unnecessary chemotherapy and the other of whom was correctly diagnosed without unnecessary treatment).3 This latter article was accompanied by a nice editorial authored by Charles B. Hammond, President-Elect of the American College of Obstetricians and Gynecologists.4
Phantom hCG is clearly a diagnosis that must be suspected before it can be made. As obstetrician-gynecologists or gynecologic oncologists, we are particularly vulnerable to falling prey to this diagnostic error since we are the physicians who generally treat pregnancy-related conditions, such as ectopic pregnancy and gestational trophoblastic disease. Furthermore, the initial diagnosis of such conditions may lead to surgical or chemotherapeutic treatment without a histopathologic diagnosis. Therefore, one should consider the diagnosis of phantom hCG in any patient who has hCG elevations in the lower range and a working diagnosis of ectopic pregnancy or gestational trophoblastic disease. In suspected cases of phantom hCG, it would behoove the attending physician to consider performing both a urinary hCG assay and another type of serum hCG assay in a reference laboratory prior to initiating therapy, thereby avoiding a potentially disastrous situation for the patient and the risk of liability for the physician.
References
1. Cole LA. Gynecol Oncol. 1998;71:325-329.
2. Rotmensch S, Cole LA. Lancet. 2000;355:712-715.
3. Olsen TG, et al. Obstet Gynecol. 2001;98:843-845.
4. Hammond CB. Obstet Gynecol. 2001:98;719-720.
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