Hyperglycosylated hCG in the management of quiescent and chemorefractory gestational trophoblastic diseases

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Abstract

Introduction

The literature shows that hyperglycosylated hCG is the invasion stimulus in malignant gestational trophoblastic diseases. The USA hCG Reference Service has characterized 2 gestational trophoblastic disease conditions marked by low proportion of hyperglycosylated hCG. These are quiescent gestational trophoblastic disease, defined as inactive or benign invasive disease, and minimally invasive gestational trophoblastic disease, defined as slow growing or chemorefractory disease with hCG increasing very slowly (doubling rate 2–6 weeks). Here we examine the USA hCG Reference Service experience with both diseases.

Methods

Patient were referred to the USA hCG Reference Service, 133 cases shown to have quiescent gestational trophoblastic disease, 35 cases with aggressive and 30 with minimally invasive gestational trophoblastic disease.

Results

Quiescent or inactive gestational trophoblastic disease was demonstrated in 133 women. In 127 of these cases, no hyperglycosylated hCG was detected, and in 6 cases 4–27% hyperglycosylated hCG was detected. This is quiescent or inactive disease.

Only 1 of 35 cases with aggressive gestational trophoblastic disease (> 40% hyperglycosylated hCG) was chemorefractory. In contrast, 30 of 30 minimally invasive cases (< 40% hyperglycosylated hCG) were chemorefractory. In chemorefractory cases hyperglycosylated hCG ranged from < 1% to 39% of total hCG. The USA hCG Reference Service showed that proportions hyperglycosylated hCG significantly increases as total hCG rises. They recommended in minimally invasive cases to wait to hCG was > 3000 IU/L before commencing chemotherapy. This was successful in 10 of 10 minimally invasive cases.

Discussion

Measurement of hyperglycosylated hCG or invasiveness is a critical step in management of invasive gestational trophoblastic disease. Quiescent of inactive gestational trophoblastic disease requires no therapy. Minimally invasive disease in chemorefractory. The USA hCG Reference Service experience suggests waiting until hCG exceeds 3000 IU/L before commencing any chemotherapy.

Introduction

Low level hCG (human chorionic gonadotropin) plateaus outside of pregnancy can pose a difficult management dilemma for health care providers. As ELISA (Enzyme-linked immuno-spectrometric assay) assays evolved in the late 1990s, false positive hCG test results due to interfering heterophile antibodies were described and became a common cause for referral to the USA hCG Reference Service. Between 1999 and 2003 we consulted and subsequently reported many false positive hCG cases [1], [2], [3], [4]. As this phenomenon became better recognized, assays were corrected and practitioners became more confident in making the diagnosis. Today, we will consult on only 4 to 5 false positive cases each year. However, our group continues to receive many requests per year to evaluate persistent low level hCG cases. Between 2002 and 2003 we dealt with many cases of assumed false positive hCG tests by physicians. The problem with these cases was that they were truly positive for hCG, their only oddity was the absence of hyperglycosylated hCG [5], [6]. This led to the discovery of quiescent gestational trophoblastic disease in 2003. Today we look carefully at the cases with very low hyperglycosylated hCG and observe two disorders, quiescent gestational trophoblastic disease and minimally invasive gestational trophoblastic disease [7]. The USA hCG Reference Service experience with these two disorders is presented here.

Quiescent GTD (gestational trophoblastic disease) and minimally invasive GTD represent biologic phases of GTD diagnosed by clinical behavior and a biomarker signature. Critical to both disorders is the presence of minimal or absent hyperglycosylated hCG. As published by multiple authors, hyperglycosylated hCG is a variant of regular hCG with double size O-linked sugar units and larger triantennary N-linked sugar units boosting the size of hCG from 36,700 to > 40,000 molecular weight. It acts as an autocrine growth factor or cytokine to promote cytotrophoblast cell invasion and malignancy as occurs in implantation of pregnancy and in all invasion cases by trophoblast cells [8], [9], [10], [11], [12], [13]. Quiescent disease arises from highly differentiated trophoblast cells. Because of the minimal presence or absence of cytotrophoblast cells it does not produce hyperglycosylated hCG and is a stable non-malignant non-invasive condition.

We have noticed though the years that choriocarcinoma, GTN (gestational trophoblastic neoplasm, choriocarcinoma without pathology) and invasive mole can all be conditions that present with low proportions of hyperglycosylated hCG and commonly slow growing chemorefractory conditions. Based on follow-up data, we have discovered that avoiding therapy in these cases and allowing patients to advance to an hCG levels of approximately 3000 IU/L permits the advancement of the cytotrophoblast proportions of trophoblasts which elevate the percent of hyperglycosylated hCG [7]. Patients then have a better likelihood of complete response from chemotherapy [7]. We call this group of conditions minimally invasive gestational trophoblastic diseases. As the spectrum of GTD expands, the biomarker evaluation becomes more difficult to interpret. The problem now is that low concentrations of hyperglycosylated hCG overlap in quiescent and minimally invasive conditions. We present both disorders and their overlapping hyperglycosylated hCG results here.

Section snippets

Methods

The USA hCG Reference Service is a unique one-of-a-kind referral service specializing in gestational trophoblastic diseases and cases of positive hCG outside of pregnancy. They examine patients records and serum and urine samples, measuring specifically total hCG, hyperglycosylated hCG, free β-subunit, β-core fragment, nicked hCG, intact hCG with the β-subunit C-terminal peptide and intact hCG without the C-terminal peptide, luteinizing hormone and follicle stimulating hormone. From the patient

Results

From 1999 to the present, the USA hCG Reference Service has observed 133 cases diagnosed as quiescent or benign/inactive gestational trophoblastic disease (Fig. 1). All cases seemingly had low levels of hCG persisting for 3 months or longer and a history of documented gestational trophoblastic disease, 7 cases followed chemotherapy for choriocarcinoma, 62 cases followed evacuation or chemotherapy for complete hydatidiform mole, 9 cases followed the disappearance of hCG after treatment for

Discussion

The USA hCG Reference Service is a unique service that has been consulting on difficult cases of hCG interpretations by physicians responding to non-pregnant gestational events. Multiple cases have involved refractory gestational trophoblastic disease, invasive mole or choriocarcinoma, many of which demonstrate initial responsive disease but then showed low level plateaus using the commercially available total hCG tests. Our group has had a unique opportunity to study the majority of these

Conflict of interest statement

The authors declare that there are no conflicts of interest. The data presented in this manuscript present no conflict of interest with any company of other agency, no funds were received to promote this publication, and no company or agency has modified it in any way.

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