Persistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease

doi:10.1067/mob.2003.271

American Journal of Obstetrics and Gynecology

Volume 188, Issue 5, May 2003, Pages 1254-1259

https://doi.org/10.1067/mob.2003.271 Get rights and content

Abstract

Objective: This study was undertaken to evaluate the significance of persistent low-level human chorionic gonadotropin (hCG) titers (usually <50 IU/L) in the absence of clinical evidence of pregnancy or gestational trophoblastic disease. Study Design: The USA hCG Reference Service consulted on 114 cases with persistent low levels of hCG; 51 had false-positive hCG results. The remaining 63 cases had real hCG results and are presented here. Results: Antecedent gestational events included hydatidiform mole (27), pregnancy (35), and gestational trophoblastic neoplasm (1). Forty of the 63 (64%) cases received therapy, including chemotherapy (38), hysterectomy (2), or both (10). Despite treatment, in all cases, low hCG titers persisted. After 1 to 4.5 years of low titers, four women had a sudden rapid increase in hCG levels, and malignant disease was confirmed or clearly suggested (gestational trophoblastic neoplasm [3] and placental site trophoblastic tumor [1]). Invasive trophoblast antigen (ITA) is a marker of invasive cytotrophoblast cells. ITA was measured in 38 of the cases with persistent low hCG, in all cases ITA accounted for less than 25% of the hCG concentration. It was also determined in the 4 cases indicated with malignant disease, accounting for more than 80% of the hCG. Conclusion: The presence of persistent low-level hCG titers defines a subset of women with preinvasive or quiescent gestational trophoblastic disease. ITA effectively detected the presence or absence of invasive cells in these cases. The recommended management of the quiescent disease is close surveillance without therapy until malignant disease detected. (Am J Obstet Gynecol 2003;188:1254-9.)

Section snippets

Methods

The USA hCG Reference Service is a College of American Pathologist monitored (No. 7176750-01) and Department of Health and Human Services CLIA certified (No. 32D0972561) reference facility. The service considers brief patient histories and the results of multiple tests on supplied parallel serum and urine samples. Samples are initially tested by using the automated DPC Immulite hCG test, the DPC Immulite free hCGβ test, Abbott AxSym total hCG test, and other commercial hCG tests as needed.

Serum

Results

Table I outlines the clinical histories provided for the 63 patients with persistent low-level hCG determinations.

Figure. Use of ITA as tumor marker. Percentage of ITA in 38 patients with persistent low levels of hCG as described in Table I (1). Also shown are percentages of ITA in 4 patients rereferred to USA hCG Reference Service, all of whom initially had persistent low levels of hCG. All were either shown or clinically suspected of having malignant gestational trophoblastic disease when

Comment

In this study, the clinical presentation and follow-up of 63 women with low hCG titers that persisted for 6 months to 6 years are discussed. In all cases, the diagnosis of persistent gestational trophoblastic disease was rendered, although no tumor could be identified by CT or magnetic resonance imaging. Most cases (64%) received single or multiagent chemotherapy, surgery, or a combination. Despite therapy, measurable circulating hCG persisted. In all 38 cases evaluated by the ITA assay, no or

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Cited by (56)

High-risk gestational choriocarcinoma with an unusual presentation and the treatment course of refractory or quiescent/minimally invasive disease
2018, Gynecologic Oncology Reports
Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6 months after uterine evacuation?
2016, Gynecologic Oncology
To compare the outcomes of Brazilian patients with molar pregnancy who continue human chorionic gonadotropin (hCG) surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6 months after uterine evacuation.
Retrospective chart review of 12,526 patients with hydatidiform mole treated at one of nine Brazilian reference centers from January 1990 to May 2016.
At 6 months from uterine evacuation, 96 (0.8%) patients had hCG levels raised but falling. In 15/96 (15.6%) patients, chemotherapy was initiated immediately per FIGO 2000 criteria, while 81/96 (84.4%) patients were managed expectantly. Among the latter, 65/81 (80.2%) achieved spontaneous remission and 16 (19.8%) developed postmolar gestational trophoblastic neoplasia (GTN). Patients who received chemotherapy following expectant management required more time for remission (11 versus 8 months; p = 0.001), had a greater interval between uterine evacuation and initiating chemotherapy (8 versus 6 months; p < 0.001), and presented with a median WHO/FIGO risk score higher than women treated according to FIGO 2000 criteria (4 versus 2, p = 0.04), but there were no significant differences in the need for multiagent treatment regimens (1/15 versus 3/16 patients, p = 0.60). None of the women relapsed, and no deaths occurred in either group.
In order to avoid unnecessary exposure of women to chemotherapy, we no longer follow the FIGO 2000 recommendation to treat all patients with molar pregnancy and hCG raised but falling at 6 months after evacuation. Instead, we pursue close hormonal and radiological surveillance as the best strategy for these patients.
False Positive HCG Assays
2010, Human Chorionic Gonadotropin (hCG)
False positive hCG tests are an old problem regarding quantitative serum hCG assays. Throughout their history, both immunometric and radioimmunoassays have used animal antibodies to bind hCG. Humans produce heterophilic antibodies against human immunoglobulins that can cross-react with animal immunoglobulins. Humans also produce antibodies against the animal antibodies used in vaccinations and other therapies, such as human anti-mouse antibodies (HAMA). Most modern assays use mouse monoclonal antibodies and goat polyclonal antibodies. The presence of HAMA, human anti-animal antibodies (HAAA), and heterophilic antibodies in blood samples can interfere with assays and cause false positive results. Hormones like hydrocortisone, luteinizing hormone (LH), estradiol, and progesterone are always present in serum, thus tests are always positive. They become slightly higher than normal when blood contains interfering HAMA or heterophilic antibodies. In terms of becoming false positive, however, hCG is a unique hormone. When indicating pregnancy, gestational trophoblastic disease, or cancer, hCG is either completely positive or completely negative. When HAMA/HAAA or heterophilic antibodies interfere with an estradiol, progesterone, LH, or hydrocortisone test, slightly elevated results occur, which is a minor issue. In contrast, if hCG is falsely positive due to heterophilic antibodies/HAAA/HAMA, it can create an emergency. False positive results can, for example, be interpreted as positive results indicative of cancer or gestational trophoblastic disease. Heterophilic antibodies and false positive tests can result from a family history of immunoglobulin-A deficiency syndrome or from protein crossing the stomach into the blood, such as in mononucleosis cases. This chapter also reviews the reported false positive hCG test result experiences of the USA hCG Reference Service and other laboratories.
Use of Hyperglycosylated hCG as a Unique Marker of Gestational Trophoblastic Neoplasms
2010, Human Chorionic Gonadotropin (hCG)
This chapter reviews the potential uses of hCG-H tests in gestational trophoblastic disease management. We examine an inactive form of disease called quiescent gestational trophoblastic disease. This is a relatively common inactive form of gestational trophoblastic disease and is seen all over the world. It is possibly the most common explanation for persistent low levels of hCG outside of pregnancy. This chapter also examines a widespread variant of gestational trophoblastic neoplasm and choriocarcinoma called minimally aggressive gestational trophoblastic neoplasm. New treatment protocols are proposed for this chemorefractory disorder. hCG-H, the promoter of trophoblast disease invasion, is considered as a new alternative marker to grade gestational trophoblastic diseases as opposed to the present World Health Organization (WHO) grading system. It is also noted that hCG-H determines which cases of gestational trophoblastic disease will respond to chemotherapy. In many ways, gestational trophoblastic disease is governed and regulated by the presence and predominance of hyperglycosylated hCG (hCG-H). It is the presence of unregulated hCG-H in humans that drives gestational trophoblastic neoplasms and causes people to get these human-specific diseases. hCG-H drives pregnancy implantation through regulatory mechanisms involving blockage of apoptosis, metalloproteinases, and collagenases. It is these same processes that drive invasion in gestational trophoblastic neoplasms including choriocarcinoma. This disease is the most malignant disease known to humans. It appears to be totally driven by hCG-H produced by cytotrophoblast cells and the pregnancy implantation-like invasion that it drives. If the woman is immediately treated with chemotherapy, this fast-growing disease can respond well and regress completely, with a 90% 5-year survival rate.
USA hCG reference service, 10-year report
2010, Clinical Biochemistry
The USA hCG Reference Service has been dealing with cases of persistent low levels of hCG and gestational trophoblastic diseases for 10 years. Here we present the complete experience.
Total hCG in serum and urine was measured using the Siemen's Immulite 1000 assay. Hyperglycosylated hCG, nicked hCG, free ß-subunit and ß-core fragment were measured using microtiterplate assays with antibodies B152, B151, FBT11 and B210, respectively.
The USA hCG Reference Service has identified 83 cases of false-positive hCG, 71 cases of aggressive gestational trophoblastic disease (GTD), 52 cases of minimally invasive GTD, 168 cases of quiescent GTD and 22 cases of placenta site trophoblastic tumor (PSTT). In addition, 103 cases of pituitary hCG have been identified, 60 cases of nontrophoblastic tumor, 4 cases of inherited hCG and 2 cases of Munchausen's syndrome. This is 565 cases total. Multiple new methods are described and tested for diagnosing all of these disorders.
The USA hCG Reference Service experience shows new methods for detecting multiple hCG-related disorders and recommends new approaches for detecting these hCG-related disorders.
Pre-evacuation hCG glycoforms in uneventful complete hydatidiform mole and persistent trophoblastic disease
2010, Gynecologic Oncology
To investigate whether the glycoform distribution patterns of human chorionic gonadotropin (hCG) obtained by chromatofocusing in pre-evacuation serum are different for patients who will eventually develop into persistent trophoblastic disease in case of complete hydatidiform mole pregnancy as compared to those patients for whom trophoblastic tissue will regress uneventfully.
Pre-evacuation blood samples were collected from women with complete hydatidiform mole with uneventful spontaneous regression after molar evacuation (n = 32), from women with complete hydatidiform mole who developed persistent trophoblastic disease after evacuation of their mole (n = 28) and, as a control group, from women during the first trimester of normal pregnancy (n = 22). The serum specimens were subjected to chromatofocusing, and hCG was determined in the fractions collected in the pH range 7.0–3.0.
Receiver operating characteristics (ROC) analysis revealed that 36% of complete hydatidiform mole patients with post-molar persistent trophoblastic disease development had different hCG glycoform profiles at 97% specificity (pH interval 6.3–5.1, hCG cutoff 9.9%). There was a significant difference between complete hydatidiform mole with and without persistent trophoblastic disease for the cumulative percent amounts of hCG in the pH interval 6.3–5.1 (p < 0.0003).
In 36% of the patients with complete hydatidiform mole with subsequent development of persistent trophoblastic disease, typical glycoform profiles for hCG are observed in pre-evacuation serum samples. This result suggests that hCG glycoform profiles are of potential use in the prediction of persistent trophoblastic disease.

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^☆: Reprint request to: Laurence A. Cole, PhD, Department Obstetrics and Gynecology, Division of Women's Health Research, USA hCG Reference Service, University of New Mexico, 2211 Lomas Blvd, NE, Albuquerque, NM 87131. E-mail: [email protected]

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General Obstetrics and Gynecology GynecologyPersistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease☆

Abstract

Section snippets

Methods

Results

Comment

Gynecol Oncol

Lancet

Gynecol Oncol

Utility of commonly used commercial hCG immunoassays in the diagnosis and management of trophoblastic diseases

Clin Chem

False positive or phantom hCG result: a serious problem

Clin Lab Int

Detection of hCG in trophoblastic disease: the USA hCG Reference Service experience

J Reprod Med

General Obstetrics and Gynecology Gynecology
Persistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease☆