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GYNECOLOGIC ONCOLOGY

Persistently Elevated hCG in Nonpregnant Patients

Donald P. Goldstein, MD; Ebony Boyce, MD; Ross S. Berkowitz, MD

An elevated human chorionic gonadotropin (hCG) level in a nonpregnant patient occurs in 1 in 1,000 to 10,000 tests.1 This often results in unnecessary surgical and medical interventions. The various forms of hCG are noted in the Sidebar on the next page. The clinical vignettes here illustrate the various conditions in which nonpregnancy hCG elevations are encountered, as well as how to evaluate and manage these conditions.2,3

Clinical Scenario #1: Positive hCG without evidence of pregnancy

A 36-year-old G3P2 presented to her ObGyn with irregular menses. An hCG level ordered as part of the routine work-up was 78 mIU/mL. A repeat hCG level 48 hours later was 76 mIU/mL. A pelvic ultrasound was negative for intrauterine pregnancy or adnexal mass. An endometrial biopsy was negative for villi. She received methotrexate (MTX) 50 mg/m2 for a presumed ectopic pregnancy, with resulting day 4 and day 7 hCG values of 69 and 60 mIU/mL, respectively. A second dose of MTX was administered, with a resulting day 14 hCG of 61 mIU/mL. After medical management failed, the patient underwent a diagnostic laparoscopy, which was negative for tubal pregnancy.

Clinical Question: What was the source of her hCG?

Phantom hCG is the term used to describe any proteolytic enzyme that mimics hCG or heterophilic antibody in the serum that interferes with the hCG immunoassay by competing to bind the capture and label antibodies together without the presence of real hCG, thus creating a false-positive result. Since the occurrence of this phenomenon is rare, discriminating between the sources of persistently elevated hCG in nonpregnant patients is often confusing.

There are several diagnostic clues in this vignette that the diagnosis is likely phantom hCG. The first is that the hCG values are low (typically <150 mIU/mL) and the sequence of events does not make sense clinically.1 The patient’s hCG values are not consistent with her clinical or operative findings, as they remain unchanged both over time and after therapy. As soon as a discrepancy becomes apparent between the laboratory data and the clinical scenario, a urine hCG should be ordered, which in this case was negative and would have supported the diagnosis of phantom hCG. This occurs because heterophilic antibodies, the source of phantom hCG, are such large glycoproteins that they are not filtered through the renal glomeruli into the urine. Reference laboratories may help confirm the diagnosis with additional tests.4

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Clinical Scenario #2: Positive hCG in a perimenopausal patient

A 51-year-old, sexually active G2P2 with her last menstrual period 3 months prior presented to the emergency department (ED) complaining of abdominal pain. As part of the routine work-up, an hCG level was 15 mIU/mL. A repeat hCG value at her ObGyn’s office 48 hours later was 14 mIU/mL. Pelvic ultrasound was negative for an intrauterine or ectopic pregnancy.

Clinical Question: What was the source of the hCG?

This vignette illustrates a well-known phenomenon of pituitary hCG production in perimenopausal and postmenopausal women. As menopause approaches and estrogen and progesterone production decreases, gonadotropin-releasing hormone (GnRH) is released from its positive and negative feedback loop, resulting in elevations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The α subunits are identical for hCG, thyroid-stimulating hormone, FSH, and LH, while the β subunit gene of LH is found in a sequence of 7 hCG β subunit genes. For this reason, uncontrolled GnRH stimulation may lead to hCG production by pituitary gonadotrope cells of perimenopausal and postmenopausal women.5 Pituitary hCG production can be diagnosed by 2 to 3 weeks of a combined oral contraceptive pill to regulate GnRH and, in turn, suppress hCG production.3

hCG Variants

Human chorionic gonadotropin is a glycoprotein made of α and β subunits that are noncovalently linked. It is a heterogeneous entity, because while most hCG is secreted into circulation by trophoblastic cells as an intact dimer, free α and β subunits and hCG degradation products (called “nicked hCG”) can also be found in the serum and urine. hCG is detected in the body fluids of pregnant women as well as women with trophoblastic disease or ovarian germ cell tumors and men with testicular cancer, in miscellaneous other tumors, and in rare cases that do not fit into any of these categories. There are multiple forms of hCG, and the immunoassays used by most clinical laboratories measure intact hCG, hCG free β subunit, and total β-hCG (intact hCG + hCG free β subunit). The following are the hCG variants most commonly found in serum samples2: Intact hCG (hCG)—produced by syncytiotrophoblast in pregnancy and noninvasive hydatidiform mole. Promotes production of progesterone by the corpus luteum and angiogenesis in the myometrial spiral arteries. Free β-hCG—promotes growth and invasion in nongestational malignancies; thus, leading to poor prognosis. Detected in blood and urine of more than 50% of gynecologic malignancies. Hyperglycosylated hCG (H-hCG)—produced by cytotrophoblast cells in early pregnancy and replaced by hCG almost entirely by the fourth week after conception. It is also produced by cytotrophoblasts in invasive gestational trophoblastic neoplasia (GTN) such as choriocarcinoma or an invasive mole. It is a structural variant of intact hCG with larger N-linked and O-linked sugar side chains and is essential for invasion to occur.

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Clinical Scenario #3: Persistent low-level hCG in a patient treated for molar pregnancy

A 24-year-old patient underwent evacuation of a complete mole and was assessed for hCG levels, which declined from 120,000 to 53 mIU/mL and remained between 50 and 80 mIU/mL for the next 6 weeks. Chest x-ray was negative for metastatic disease, and pelvic ultrasound was negative. The patient resumed regular menses. She was treated with MTX and then actinomycin D with no gonadotropin response.

Clinical Question: What was the source of her persistent low-level hCG?

Following molar pregnancy, patients may develop persistently low levels of hCG due to persistent GTN or, infrequently, quiescent gestational trophoblastic disease (GTD). Women with GTD have little or no hyperglycosylated hCG (H-hCG), which is the form produced by invasive cytotrophoblasts. Quiescent GTD is a benign form of the disease defined by low hCG results, marked by slow-growing differentiated syncytiotrophoblast cells rather than invasive cytotrophoblasts. This may be considered a premalignant state, because approximately 21% to 42% of quiescent GTD patients will ultimately give rise to persistent active GTN, while the remainder will regress spontaneously.6 It is, therefore, imperative that these patients be monitored closely with serial hCG assessments and the commercial Nichols Advantage test for H-hCG.5 Quiescent disease is consistent with an H-hCG value of less than 0.3 ng/mL.5 Therapy is not indicated until there is a steep increase in the H-hCG levels to 100 mIU/mL, at which time the residual trophoblastic cells become responsive to chemotherapy.

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Clinical Scenario #4: Positive hCG in a postpartum patient with amenorrhea

A 31-year-old G1P1 presents complaining of amenorrhea after having an uncomplicated vaginal delivery 6 months earlier. She stopped breastfeeding after 2 months, and multiple pregnancy tests at home were negative. She saw her ObGyn, and an hCG level was 7 mIU/mL with a negative pelvic ultrasound. She was followed with monthly hCG tests, with results that ranged from 5 to 8 mIU/mL. Repeat pelvic ultrasound 3 months later showed a slight thickening of the endometrium. A D&C was performed, and a diagnosis of placental site trophoblastic tumor (PSTT) was made.

Clinical Question: What is the nature of the hCG in PSTT?

PSTT is an uncommon variant of GTN. It is usually suspected because of findings of intramyometrial lesions on imaging in the setting of low hCG levels (usually <250 mIU/mL) and amenorrhea or irregular bleeding remotely after a normal pregnancy (average of 3.4 years), spontaneous abortion, or hydatidiform mole.6,7

PSTT is made up of malignant nonvillous intermediate trophoblastic tumor cells that do not have a predilection for widespread or early vascular invasion, which distinguishes it from other GTNs. PSTT tends to have low hCG levels that change slowly over time.

Immunohistochemical staining for human placental lactogen and hCG is helpful for the morphologic diagnosis of PSTT, but it is generally difficult to clinically discriminate PSTT from other GTNs, including quiescent disease. Studies by Cole et al show that PSTT can be distinguished from quiescent GTD and choriocarcinoma when the proportion of free β subunit in the serum is greater than 30%, because the β subunit is the predominant form of hCG produced by PSTT.6,8

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Clinical Scenario #5: Positive hCG in a patient with a nontrophoblastic neoplasm

A 48-year-old female G0 presented to the ED complaining of right chest pain. A chest x-ray revealed a 3-cm nodule in the right upper lobe, a screening pregnancy test was positive, and quantitative hCG was 200 mIU/mL. A pelvic ultrasound was negative for an intrauterine pregnancy.

Clinical Question: What was the source of her elevated hCG level?

Human chorionic gonadotropin, usually in the form of free β-hCG, is produced by a variety of nontrophoblastic tumors and can be used as a tumor marker. The most common tumors that have been associated with the ectopic production of hCG include germ cell tumors of the ovary, testis, bladder, uterus, lung, liver, pancreas, and stomach.3 However, if the concentration of free β-hCG is below 100 mIU/mL, a nontrophoblastic cancer is not likely the diagnosis.9

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DISCUSSION

A basic understanding of the types of hCG molecules found in the serum and urine in a wide variety of nonpregnancy-related conditions, coupled with a heightened awareness of the presence of phantom hCG, will greatly reduce the morbidity associated with false-positive hCG test results leading to unnecessary surgery and chemotherapy. The most likely differential diagnosis of an hCG value that does not match the clinical scenario, as presented in the prior clinical vignettes, includes phantom hCG, pituitary hCG, quiescent GTD, PSTT, and nontrophoblastic neoplasms. A study by Khanlian and Cole on 170 patients with persistently low hCG showed that 10% were due to pituitary hCG, 42% were from phantom hCG, 41% were quiescent GTD, and 7.6% had an hCG-producing nontrophoblastic malignancy.10

The finding of persistently low levels of hCG often prompts the clinician to initiate a diagnostic work-up that has the potential to put the patient at risk, regardless of the antecedent history. The Table summarizes results of assays that can be used for the differential diagnosis of persistently elevated hCG levels in nonpregnant patients. This approach will enable the clinician to appropriately diagnose these patients and prevent potentially harmful treatments.

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TABLE. Assay Results for the Differential Diagnosis of Persistently Elevated hCG in Nonpregnant Patients

The authors report no actual or potential conflicts of interest in relation to this article.

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Donald P. Goldstein, MD, is Professor of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA; Ebony Boyce, MD, is Resident, Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston; and Ross S. Berkowitz, MD, is William H. Baker Professor of Gynecology, Harvard Medical School.

References

1. Braunstein GD. False-positive serum human chorionic gonadotropin results: causes, characteristics, and recognition. Am J Obstet Gynecol. 2002;187(1):217-224.
2. Muller CY, Cole LA. The quagmire of hCG and hCG testing in gynecologic oncology. Gynecol Oncol. 2009;112(3): 663-672.
3. Olsen TG, Barnes AA, King JA. Elevated hCG outside of pregnancy—diagnostic considerations and laboratory evaluation. Obstet Gynecol Surv. 2007;62(10):669-674.
4. Cole LA, Kohorn EI. The need for an hCG assay that appropriately detects trophoblastic disease and other hCG-producing cancers. J Reprod Med. 2006;51(10):793-811.
5. Cole LA, Kohorn E, Smith HO. Gestational trophoblastic diseases: management of cases with persistent low human chorionic gonadotropin results. Obstet Gynecol Clin North Am. 2005;32(4):615-626.
6. Cole LA, Khanlian SA, Muller CY. Blood test for placental site trophoblastic tumor and nontrophoblastic malignancy for evaluating patients with low positive human chorionic gonadotropin results. J Reprod Med. 2008;53(7): 457-464.
7. Feltmate CM, Genest DR, Goldstein DP, Berkowitz RS. Advances in the understanding of placental site trophoblastic tumor. J Reprod Med. 2002;47(5):337-341.
   
8. Cole LA, Khanlian SA, Muller CY, Giddings A, Kohorn E, Berkowitz R. Gestational trophoblastic disease: 3. Human chorionic gonadotropin-free β-subunit, a reliable marker of placental site trophoblastic tumors. Gynecol Oncol. 2006;102(2):160-164.
9. Marcillac I, Troalen F, Bidart JM, et al. Free human chorionic gonadotropin β subunit in gonadal and nongonadal neoplasms. Cancer Res. 1992;52(14):3901-3907.
10. Khanlian S, Cole LA. Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin. J Reprod Med. 2006;51(10): 812-818.

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