GTD: Understanding the Spectrum of Normalcy
GTD: Understanding the Spectrum of Normalcy
Abstrct & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Synopsis: Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis.
Source: Cole LA, et al. Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results. Gynecol Oncol. 2006;102:165-172.
Persistent low levels of serum hCG in the absence of pregnancy or tumor is a perplexing problem that often leads to aggressive interventions including surgery and multi-agent cytotoxic chemotherapy. Given the low prevalence of true disease in these cases, it is not surprising these interventions provide little impact and may, and in fact, prove harmful. Cole and colleagues looked at their extensive database of hCG aliquots acquired as part of their service as a reference laboratory. The primary goals of this study were: (1) to address potential causes of persistent low-level hCG values and (2) to provide guidelines for interpretation in an attempt to prevent over-treatment. The definition of persistence was serial determinations over a period of at least 3 months.
One hundred seventy women were identified with hCG values ranging from 6.1 to 900 mIU/mL (mean, 102 ± 152 mIU/mL). Just 13 (7.6%) had true malignancies consisting of placental site trophoblastic tumor (PSTT), choriocarcinoma/invasive mole, and non-gestational trophoblastic malignancies. The remainder had false-positive determinations (n = 71, 42%), quiescent GTD (n = 69, 41%) or pituitary hCG (n = 17, 10%). However, 90 of these 157 women without true malignancy underwent chemotherapy and 18 underwent surgery. In no case did the intervention affect the natural course of disease. The authors suggest identified patients should have secondary hCG validation with sub-fraction hCG analysis to verify true disease from non-disease. They also provide guidelines to improve diagnostic precision in order to prevent over-treatment of this clinical scenario.
Commentary
The standards for management of GTD are well understood and therapy is fortunately associated with a good outcome in nearly all patients. The biomarker (hCG) is very reliable and reproducible and appears to provide clear guidance as to resolution, persistence or recurrence. In cases where serial evaluation suggests the latter two, more invasive intervention such as chemotherapy and/or surgery is warranted. Here too, nearly universal success is expected. However, notable exceptions1-3 are well documented in the literature (and elsewhere) and women, in 2006, still die of this disease—or from complications of its treatment. Careful consideration of the indications for treatment is necessary to avoid both over- and under-treatment as it is these situations which are most costly.
The authors of the current report provide some chilling case scenarios of patients in whom treatment was rendered for suspected disease only to discover false-positive determinations or quiescent GTD. The diagnosis of these cases was inferred from persistently elevated but relatively low levels of serial hCG values. The non-response to conventional therapy in many cases led to additional and more toxic therapy and surgery. Systematic evaluation by sampling the urine for hCG, and determining both the free subunit of hCG and its hyperglycosylated form was able to identify the confounding variables in these women.
Most strikingly was the incidence of false-positive values. Two of every 5 women with this clinical scenario had merely false elevation of hCG by heterophile antibodies. This diagnosis was confirmed by absent hCG in the urine, disappearance of hCG following coadministration of a heterophile blocking antibody and evaluation of the clinical course of serial hCG's documenting normal values on 3 or more occasions. Unfortunately, the vast majority of these patients went on to receive therapy. Nearly equivalent in number, the second most common clinical scenario underlying serially positive low level hCG was quiescent GTD. This is a relatively new recognized state characterized by the presence of syncytiotrophoblasts in the absence of a critical mass of active cytotrophoblasts. The condition is considered pre-malignant as 10-25% of these patients will develop rapidly escalating hCG values indicating transition to malignancy. However, therapy before this transition has yet to produce any response or hCG resolution.
Fortunately, the condition can be distinguished by quantifying the hyperglycosylated fraction, which is typically absent in quiescent GTD. The last category identified in this series consisted of menopausal or peri-menopausal women in whom a pituitary source of hCG was suspected. This situation occurs when gonadotrope cells in the anterior pituitary gland secrete hCG in response to low sex steroid levels in the hypothalamus. The diagnosis is confirmed by observing hCG resolution following treatment with oral contraceptives or steroid hormone replacement.
The paper is provocative, as it should call to mind careful consideration of therapeutic interventions and/or expert consultation in cases that don't follow the norm.
References
- Cole LA, et al. Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia. Gynecol Oncol. 2006;102:151-159.
- Seki K, et al. Advances in the clinical laboratory detection of gestational trophoblastic disease. Clin Chim Acta. 2004;349:1-13.
- Vladutiu AO, et al. Heterophilic antibodies interfering with radioimmunoassay. A false-positive pregnancy test. JAMA. 1982;248:2489-2490.
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