Elevated hCG and a high proportion of hCGβ in serum preceding the diagnosis of trophoblastic disease by seven months
Article first published online: 22 DEC 2003
BJOG: An International Journal of Obstetrics & Gynaecology
Volume 109, Issue 5, pages 589–590, May 2002
How to Cite
Vartiainen, J., Alfthan, H., Lehtovirta, P. and Stenman, U.-H. (2002), Elevated hCG and a high proportion of hCGβ in serum preceding the diagnosis of trophoblastic disease by seven months. BJOG: An International Journal of Obstetrics & Gynaecology, 109: 589–590. doi: 10.1111/j.1471-0528.2002.00195.x
- Issue published online: 22 DEC 2003
- Article first published online: 22 DEC 2003
- Accepted 20 August 2001
In April 1990 a 22 year old previously healthy woman was investigated for galactorrhea without menstrual disturbances. Her prolactin and thyroid function tests were normal, but her serum human chorionic gonadotrophin (hCG) was moderately elevated, increasing from 19 iu/L to 30 iu/L in two weeks. The upper reference limit is 3 iu/L as determined by the DELFIA assay (Wallac, Finland)1. She had been delivered of a healthy baby by caesarean section in February 1989. Her menstruation began three months later, after which she used contraception until the end of 1989.
A vaginal ultrasound scan suggested a submucosal fibroma. Histological examination of the endometrium showed only secretory phase endometrium. Her serum hCG increased to 66 iu/L in June 1990 (Fig. 1). Hysteroscopy indicated a decidual endometrial reaction suggesting ectopic pregnancy, but this was ruled out. hCGβ was determined with an in-house immunofluorometric assay2 (crossreaction with hCG is 0.1% on a molar basis). The proportion of hCGβ (hCGβ divided by hCG + hCGβ) was 7.1%–11.8%, indicating malignant trophoblastic disease3,4, but X-ray, angiography, computed tomography and magnetic resonance imaging were negative. The persistent hCG elevation and the high hCGβ:hCG ratio suggested choriocarcinoma, but due to the lack of histological confirmation, the hCG result was thought to be caused by non-specific interference by heterophilic antibodies. However, determination of hCG in urine confirmed the results and tests for heterophilic antibodies were negative. Chemotherapy was started in August, and after five courses of 0.5 mg actinomycin-D for five days, her serum hCG decreased from 67 to 20 iu/L, but remained at this level.
Because laparoscopy was normal and there were no other signs of trophoblastic disease than the moderately elevated hCG level, no further therapy was given. Serum hCG started to increase again and in December 1990 a tissue sample obtained by hysteroscopy from a suspicious area measuring 4 mm × 5 mm at the fundus of the uterus revealed choriocarcinoma. On the basis of her clinical history and the site of the tumour, this was most likely a placental site trophoblastic tumour. Combination chemotherapy with EMA/CO caused a slow decrease in hCG levels from 48 iu/L in January 1991 to 23 iu/L in March 1993 and biopsies obtained by hysteroscopy showed persisting choriocarcinoma. After seven courses of EMA/CO serum hCG and hCGβ were normal in May 1991 and have remained normal since. Hysteroscopy in June was also normal. The woman discontinued contraception in May 1992 and gave birth to a healthy baby in March 1993 and has had no signs of relapse since.
Choriocarcinoma after normal pregnancy usually causes abnormal vaginal bleeding5. In our case the presenting symptom was galactorrhoea, which is surprising considering the inhibitory effect of choriocarcinoma on the release of prolactin6. She had not experienced post-pill amenorrhoea, which may be associated with galactorrhoea, and she had normal menstruation throughout. The galactorrhoea stopped after the start of chemotherapy.
Choriocarcinoma may be detected on the basis of an elevated hCG at such an early stage that a histological diagnosis cannot be obtained. Although some experts recommend that therapy should be started on the basis of this finding7, many clinicians are reluctant to treat on account of a tumour marker in the absence of histological confirmation of the tumour. In our case the slight hCG elevation caused suspicion of a laboratory error. Therefore initial treatment was delayed by four months, and the first round of treatment was stopped although serum hCG had not decreased to normal. Combination chemotherapy was started only when the diagnosis had been confirmed histologically seven months after the first elevated hCG value.
The prognosis of choriocarcinoma has improved with combination chemotherapy7, but the mortality of choriocarcinoma after a live birth is still high (21%)5. hCG in serum is a very reliable marker of trophoblastic tumours8 and an elevated ratio of hCGβ to hCG indicates that the tumour is malignant3,4. Because hCG immunoreactivity is quite heterogenous, especially in gestational trophoblastic disease, the choice of an accurate hCG assay is important9. In our patient, the proportion of hCGβ was clearly elevated when we first saw her, preceding the histological diagnosis by seven months.
Falsely elevated immunoassay results may occasionally be caused by heterophilic antibodies and other serum proteins, but these are removed from the urine by glomerular filtration10. Therefore, if pregnancy is excluded, an elevated hCG value, measured by a sandwich assay specific for the αβ heterodimer in both serum and urine, is practically always due to trophoblastic disease. Thus if laboratory errors can be excluded as causes of elevated hCG values, we strongly agree with the recommendation to treat aggressively choriocarcinoma after pregnancy, even if the diagnosis has not been confirmed by histology11.
- 3Determination of chorionic gonadotropin in serum of nonpregnant subjects and patients with trophoblastic cancer by time-resolved immunofluorometric assay. Tumor Biology 1985;5: 97., , .
- 7From methotrexate to EMA/CO. In: SzulmanAE, BuchsbaumHJ, editor. Gestational Trophoblastic Disease. Springer-Verlag1987: 127–134.