Persistent low level hCG

1. Persistent low level hCG

2. four values or more of hCG plateau over at least three weeks (days 1, 7, 14, and 21 rise in hCG of 10% or greater for three or more values over at least two weeks (days 1, 7, and 14) (or a rise in hCG-H >20 percent)

3. Trophoblastic causes of low level hCG GTN - active GTN, choriocarcinoma - quiescent GTN placental site trophoblastic tumors (PSTTs)

4. Active GTN, Choriocarcinoma • HyperglycosylatedhCG(hCG-H) • hCG produced by syncytiotrophoblasts • (H -hCG) synthesized by cytotrophoblast

5. the important proportion of total hCG forms absolute marker of ongoing invasion or malignancy indicated as active disease requiringtherapy

6. Use of total hCG and hCG-H(%) (hCG-H as a proportion of total hCG) to discriminate gestational trophoblastic diseases a Measuring hCG, no significant difference is observed between quiescent gestational trophoblastic disease or self-resolving hydatidiform mole cases (control categories) and the “early” choriocarcinoma/GTN cases (P > 0.05). Measuring hCG-H(%), a significant difference is observed (P < 0.0000001 and P < 0.0000001). L.A. Cole et al. Gynecol Oncol 102 (2006) 151–159

7. Quiescent GTN constant, low level of hCG, at low concentrations <100 IU/L without evidence of a primary or metastatic malignancy persisting for periods 3 months to 16 years slow-growing no respond well to chemotherapy or Surgery

8. exception potential to transform into active GTN ( choriocarcinoma, or PSTT) need to followed with frequent hCG levels(montly) - if the hCG level is rising, confirm by measuring hCG-H at least two consecutive rising hCG need therapy

9. Placenta site trophoblastic tumor ( PSTT) - often remotely following a normal pregnancy, spontaneous abortion, or hydatidiform mole The mean interval between the occurrence of PSTT and the antecedent GTN (2 ~ 5 years) definitive diagnosis hysterectomy significantly low hCG levels < 200 mIU/ml that free β subunit- useful marker

10. Phantom hCG false positive serum hCG

11. A useful way of identifying a false positive serum hCG result is to send the serum to two laboratories using different commercial assays. If the assay results vary greatly or are negative in one or both alternative tests, then a false positive hCG can be presumed

12. Patients who have false positive hCG test results are at risk for recurrent false positive hCG assay results .They are also at risk for other false positives, such as CA-125 and thyroid antibodies . They should make their future health care providers aware of this problem and it should be noted in their medical records

13. Because few cytotrophoblasts are present, little or no hCG-H is produced: the ratio of hCH-H to total hCG is usually less than 2 percent

14. Regular hCG levels are low; the levels are always below 212 mIU/mL with no more than two-fold natural variation over time (at least three weeks).

15. Imaging studies will be negative since total hCG <212 mIU/mL represents a minuscule trophoblast cell mass; >2000 mIU/mL is required before a tumor can be seen by magnetic resonance imaging

16. recommend that women with quiescent disease be placed on oral contraceptive pills and avoid pregnancy until hCG has been undetectable for six months

17. False-positive hCG The more than 5- differences in serum hCG results with alternative immunoassays (essential criterion) The finding that dilution of samples 2- 10 times does not diluted results close to 2- 10 times varying hCG results (more than 5- times) or negative results in 3 or more hCG tests. 2. The presence of hCG in serum and absence of detectable hCG or hCG related molecule in urine 4. The finding that a heterophilic antibody blocking agent

18. Interfering antibodies can be of 2 types: human antianimal antibodies (HAAA) or heterophile antibodies

19. HAAAs are specific antigen and may be produced after treatment with therapeutic antibodies or exposure to animal antigens Heterophile antibodies nonspecific interaction with numerous different antigens and are believed to be caused by B cells that have not completed appropriate somatic mutation These antibodies interfere with immunometric assays , leading to falsely increased results

20. Causes of false-positive HCG results

21. -persistently low levels of hCG to outside of pregnancy cross-reactivity with (LH)

22. Pituitary hCG in the serum of normal men and women hCG was secreted in a pulsatile fashion that paralleled the LH in nonpregnant suppressed by estrogen and progestin therapy OCPs higher levels of hCG in postmenopausal than premenopausal cutoffs for a “negative hCG” 14 IU/L / 5 IU/L The level of hCG attributable to pituitary production ranges from 1 to 32 mIU/mL establishing the diagnosis of pituitary hCG peri- or post-menopause or BSO, with low level hCG, should take HRT or oral contraceptives if pituitary origin after 2–3 weeks, suppress hCG production

23. Nongynecologic tumors with positive serum β-hCG levels

24. Guidelines for the management of patients with persistent low level hCG rule out pregnancy and ectopic pregnancy • determine if the hCG is biologically real • False-positive hCG • - 1. the presence of hCG immunoreactivity in serumbut not urine • - 2. varying hCG results (more than 5-fold) or negative results in 3 or more hCG tests • - 3. the suppression of result by a heterophilic antibody blocking agent • determine if active GTN, PSTT, or non-trophoblastic malignancy is present • hCG-H is detectable, >1 ng/ml: active GTN/choriocarcinoma • hCGfree β-subunit is more than one third of hCG: PSTT or non-trophoblastic malignancy • hCG-H(-) or no significant hCG free β-subunit: quiescent GTD • peri- or post-menopause or BSO: pituitary hCG L.A. Cole et al Gynecol Oncol 102 (2006)

25. Thank you for your attention!