USA HCG REFERENCE SERVICE
QUIESCENT GTD, GESTATIONAL TROPHOBLASTIC NEOPLASM 

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Cole LA, Khanlian SA, Butler SA, Seckl M, Kohorn EI. Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a Reliable Marker of Active Neoplasia. Gynecologic Oncology, in press, 2006

Cole LA, Khanlian SA, Giddings A, Butler SA, Muller CY, Hammond C, Kohorn E. Gestational trophoblastic diseases: 4. Presentation with Persistent Low Positive Human Chorionic Gonadotropin Gynecologic Oncology, in press 2006

 

hCG-H in the Management of Gestational Trophoblastic Diseases

          Quiescent gestational trophoblastic disease is a benign or inactive form of GTN or choriocarcinoma, marked by persistent low hCG results, persisting for periods ranging from 3 months to 16 years (45-51). It may also be considered as a pre-malignant state in that approximately 1 in 5 cases transform into gestational trophoblastic neoplasm (GTN) or choriocarcinoma (44-51). We have reviewed the histology slides from two cases undergoing surgery for this condition.  In both cases, intermediate and highly differentiated syncytiotrophoblast cells were observed, with a clear absence of cytotrophoblast cells that mark most cases of choriocarcinoma (45, 46). Differentiated syncytiotrophoblast cells can be slow growing cells, and not invasive cells. It is inferred that the presence of syncytiotrophoblast cells with the absence of invasive cytotrophoblast cells is the nature of quiescent gestational trophoblastic disease. In the absence of cytotrophoblast cells, the hCG-H producing cells, no hCG-H can be detected. That is, syncytiotrophoblast cells remaining after treatment of an ectopic pregnancy, or parturition or abortion, or following evacuation of a hydatidiform mole.  Alternatively, slow growing syncytiotrophoblast cells can remain after chemotherapeutic resolution of cytotrophoblasts or following treatment of GTN or choriocarcinoma, where these cells may persist.  

          The USA hCG Reference Service has consulted on 69 cases with persistent low “real” (not false positive) hCG results (44). In all cases the persistent low levels persisted for 3 month or greater with minimal fluctuation and no clear upward or downward hCG trend. hCG-H was measured using the Nichols Advantage test as a proportion of total hCG in the DPC Immulite test (% hCG-H) as a marker for invasive cytotrophoblast cells. In 67 of the 69 cases (44-51), no hCG-H was detected whatsoever. In the two remaining cases, 10% and 12% hCG-H was detected.  In both, detectable hCG persisted for greater that 6 months with minimal fluctuation. Considering these histories, and that in these exceptional cases the proportion of hCG-H was below those of 79 GTN or choriocarcinoma cases referred to the Service, the diagnosis of quiescent gestational trophoblastic disease was conferred. As shown Table 1), proportion of hCG-H is a near absolute test for differentiating active (GTN or choriocarcinoma) and inactive (quiescent GTD) disease. The published cut-off for quiescent disease is 6%. At this cut-off 100% of 82 active disease cases can be detected at 1.5% false positive or error rate Table 1).

         hCG-H is also a marker for the early detection of recurrent GTN or choriocarcinoma. Demonstrating the presence of invasive disease weeks or months prior to rising hCG levels or the detection of tumor (52).  This data shows the utility of hCG-H as seemingly an absolute marker for differentiating quiescent and invasive disease. Considering that hCG-H is only produced by cytotrophoblast cells (3-4), the absence of hCG-H in quiescent gestational trophoblast disease confirms its origin from syncytiotrophoblast in the absence of cytotrophoblast cells.

          Of the 69 identified cases, 33 followed evacuation of a hydatidiform mole, 15 followed successful treatment of GTN or choriocarcinoma, and 21 following a spontaneously aborted, ectopic or term pregnancy. We examined the medical records of these 69 identified quiescent gestational trophoblastic disease cases. While 42 had received chemotherapy, combination chemotherapy, hysterectomy or other surgery for assumed active disease, none fully responded to the therapy, including chemotherapy.  We have interpreted this to mean that these cases have slowly growing dispersed syncytiotrophoblast cells, that are too slow growing to respond to chemotherapy.  In all treated cases, hysterectomy partially but never completely suppressed the hCG result. We have interpreted this to mean that syncytiotrophoblast cells commonly remain outside of the uterus after a gestational event or, alternatively, are transposed through the fallopian isthmus by an endometriosis-like mechanism. With a 100% summary of records indicating that therapy does not work, and similar findings by others (50,51), it is inferred that treating physicians should refrain from using chemotherapy or surgery in these cases.

Our history with quiescent gestational trophoblastic disease cases is like that with false positive hCG cases- too many people receiving needless therapy for a poorly understood and only recently fully recognized condition that in fact, requires no therapy. In one case, a patient was shown by the Service on two separate occasions during the course of one year to have quiescent disease.  Despite our recommendations, additional combinations of chemotherapeutic agents were given. This patient tragically died from complications of pulmonary fibrosis following bleomycin chemotherapy.  Nevertheless, this case is important because it emphasizes the importance of making an accurate diagnosis of GTN/choriocarcinoma versus quiescent disease before initiating cytotoxic chemotherapy.  This requires all medical and gynecologic oncologists, and to some extent, whomever manages patients who undergo hCG-H determinations, to be able to recognize and diagnose the phenomenon of quiescent gestational trophoblastic disease.  If the diagnosis is in doubt or suspect, these data indicate the importance of referring such patients to centers with experience with this condition before therapy is initiated. 

          Published data show the value of hCG-H not just in the detection of quiescent disease, but in the earlier detection and differention of recurrent GTN/choriocarcinoma and in the staging of GTN/choriocarcinoma (44).

 

Table 1.  Use of total hCG and hCG-H(%) (hCG-H as a proportion of total hCG) to discriminate gestational trophoblastic diseases. Description of study categories are presented in Table 1. Values are mean ± standard deviation. Results are compared using Student’s t test.

 

Description	hCG (mIU/ml)	hCG-H(%)
Choriocarcinoma/GTN (n = 82)	16298 ± 70590 a	50% ± 39% a
range	5.2 - 597,000	7 - 100%
Quiescent gestational trophoblastic disease (n =69)	34 ± 58	0.47% ± 2.1%
range	1 - 212	0 - 10%

^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). 

 

 

REFERENCES

 

1. Cole LA, Dai D, Butler S, Muller CY, Leslie K, Kohorn E. Gestational Trophoblastic Diseases: 1. Pathophysiology of Hyperglycosylated hCG. Gynecol Oncol 2005; in press

 

2. Lei ZM, Taylor DD, Gercel-Taylor C, Rao CV. Human chorionic gonadotropin promotes tumorigenesis of choriocarcinoma JAR cells. Troph Res 1999;13:147-59.

 

3. Kovalevskaya G, Genbacev O, Fisher SJ, Caceres E, O’Connor JF. Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary source or choriocarcinoma-like hCG. Mol Cell Endocrinol 2002;94:147-55.

 

4. Cole LA, Shahabi S, Oz UA, Bahado-Singh RO, Mahoney MJ. Hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen) immunoassay: A new basis for gestational Down syndrome screening. Clin Chem 1999;45:2109-19.

 

5. Elliott MM, Kardana A, Lustbader JW, Cole LA. Carbohydrate and peptide structure of the a- and b-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma. Endocrine 1997;7:15-32.

 

6. Cole LA. The O-linked oligosaccharides are strikingly different on pregnancy and choriocarcinoma hCG. J Clin Endocrinol Metab 1987;65:811-13.

 

7. Amano J, Nishimura R, Mochizuki M, Kobata A. Comparative study of the mucin-type sugar chains of human chorionic gonadotropin present in the urine of patients with trophoblastic diseases and healthy pregnant women. J Biol Chem 1988;263:1157-65.

 

8. Kobata A, Takeuchi M. Structure, pathology and function of the N-linked sugar chains of human chorionic gonadotropin. Biochim Biophys Acta. 1999;1455:315-26

 

9. Cole LA. Immunoassay of human chorionic gonadotropin, its free subunits, and metabolites. Clin Chem 1997;43:2233-43.

10. Takamatsu S, Oguri S, Toba Minowa M, Yoshida A, Nakamura K, Takeuchi M, Kobata A.

Unusually High Expression of N-Acetylglucosaminyltransferase-IVa in Human Choriocarcinoma Cell Lines: A Possible Enzymatic Basis of the Formation of Abnormal Biantennary Sugar Chain

Cancer Res 1999;59:3949-3953.

 

11. Peters BP, Krzesicki RF, Hartle RJ, Perini F, Ruddon RW A kinetic comparison of the processing and secretion of the alpha beta dimer and the uncombined alpha and beta subunits of chorionic gonadotropin synthesized by human choriocarcinoma cells. J Biol Chem. 1984;259:15123-30.

 

12. Hussa RO. Immunologic and physical characterization of human chorionic gonadotropin and its subunits in cultures of human malignant trophoblast. J Clin Endocrinol Metab 1977;44:1154-62.

 

13. Mann K, Karl HJ. Molecular heterogeneity of human chorionic gonadotropin and its subunits in testicular cancer. Cancer 1983;52:654-60.

 

14. Birken S, Krichevsky A, O’Connor J, Schlatterer J, Cole LA, Kardana A, Canfield R. Development and characterization of antibodies to a nicked and hyperglycosylated form of hCG from a choriocarcinoma patient: generation of antibodies that differentiate between pregnancy hCG and choriocarcinoma hCG. Endocrine 1999;10:137-44.

 

15. Pandian R, Lu J, Ossolinska-Plewnia J. Fully automated chemiluminometric assay for hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen). Clin Chem 2003;49:808-10.

 

16. Cole LA, Khanlian SA, Sutton JM, Davies S, Stephens N. hCG-H (Invasive Trophoblast Antigen, hCG-H) a Key Antigen for Early Pregnancy Detection. Clin Biochem, 2003;36:647-655

 

17. Khanlian SA, Smith HO, Cole LA. Persistent Low Levels of hCG: A Pre-malignant gestational trophoblastic disease. Am J Obstet Gynecol, 188: 1254-1259, 2003.

 

18. O’Connor JF, Ellish N, Kakuma T, Schlatterer J, Kovalevskaya G. Differential urinary gonadotropin profiles in early pregnancy and early pregnancy loss. Prenat Diagn 1998;18:1232–40.

 

19. Butler SA, Khanlian SA, Cole LA. Detection of early pregnancy forms of human chorionic gonadotropin by home pregnancy test devices. Clin Chem 2001;47:2131-06.

 

20. Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy tests at the time of missed menses. Am J Obstet Gynecol 2004;190:100-05.

 

21. Genbacev O. DiFederico E. McMaster M. Fisher SJ. Invasive cytotrophoblast apoptosis in pre-eclampsia. Human Reproduction. 1999;2:59-66.

 

22. Tarrade A. Goffin F. Munaut C. Lai-Kuen R. Tricottet V. Foidart JM. Vidaud M. Frankenne F. Evain-Brion D. Effect of matrigel on human extravillous trophoblasts differentiation: modulation of protease pattern gene expression. Biology of Reproduction. 2002;67:1628-37

 

23. Paradinas FJ, Sbire NJ, Rees HC. Pathology. In: Hancock BW, Newlands ES, Berkowitz RS, Cole LA eds. Gestational Trophoblastic Disease. Sheffield University, Sheffield UK,  2003, pp. 77-129.

 

24. Tarrade A. Goffin F. Munaut C. Lai-Kuen R. Tricottet V. Foidart JM. Vidaud M. Frankenne F. Evain-Brion D. Effect of matrigel on human extravillous trophoblasts differentiation: modulation of protease pattern gene expression. Biology of Reproduction. 2002;67:1628-37

 

25. Sutton JM, Cole LA. Sialic acid-deficient invasive trophoblast antigen (sd-hCG-H): a new urinary variant for gestational Down syndrome screening. Prenat Diagn. 2004; 24: 194-197 

 

26. Cole LA ,Sutton JM, Higgins TN, Cembrowski GS. Between-method variation in hCG test results, Clin Chem, 2004; 50:874-882.

27. Cole LA. O-Glycosylation of proteins in the normal and neoplastic trophoblast. Troph Res 1987;2:139-148.

 

28. Kovalevskaya G, Birken S, Kakuma T, Osaki N, Sauer M, Lindheim S, et al.  Differential expression of human chorionic gonadotropin (hCG) Glycosylation Isoforms in failing and continuing Pregnancies: Preliminary characterization of the hyperglycosylated hCG Epitope.  J Endocrinol 2002; 172: 497-506.

 

29. Sutton-Riley JM, Khanlian SA, Byrn FW, Cole LA. Hyperglycosylated hCG: A Single Serum Test for Measuring Early Pregnancy Outcome with High Predictive Value. Clin Biochem 2005; in press.

 

30. Byrn FW, Sutton-Riley JM, Cole LA. The Predictive Value of Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) in Evaluating Pregnancy Outcome. Fertil Steril 2005; in press.

 

31.     Cole, L.A., Cermik D., Bahado-Singh, R. Oligosaccharide variants of hCG-related molecules: Potential screening markers for Down syndrome. Prenat. Diagn. 1997;17:1188-1190. 

 

32.     Cole, L.A., Omrani, A., Cermik, D., Bahado-Singh, R.O., and Mahoney, R.O. Hyperglycosylated hCG, a potential alternative to hCG in down syndrome screening. Prenat. Diagn., 1998;18:926-933.

 

33.     Massin N Frendo JL, Luton D, Govagrandi Y, Muller F, Vidaud M, Evain-Brion D. Defect of syncytiotrophoblast formation and hCG expression in Down’s syndrome. Placenta 2001;22:S93-97.

 

34.     Frendo JL, Vidaud M, Guibourdenche J, Luton D, Muller F, Belet D, Giovagrandi Y, Tarade A, Porquet D, Blot P, Evain-Brion D. Defect of villous cytotrophoblast differentiation in syncytiotrophoblast in Down’s syndrome. J Clin Endocr Metab 2000;85:3700-07,

 

35.     Evain-Brion D, Frendo JL, Vidaud M, Muller F,. Failure of differentiation of the trophoblast in trisomy 21. Bull Acad Natl Med 2000;184:1033-45.

 

36.     Cole, L.A. Shahabi, S., Rinne, K.M., Oz, U.A., Bahado-Singh, R.O., Mahoney, M.J. Urinary Screening Tests for Fetal Down Syndrome: II. Hyperglycosylated hCG. Prenat Diagn, 1999;19:351-359.

 

37.     Shahabi, S., Rinne, Oz, U.A., Bahado-Singh, R.O., Mahoney, M.J., Omrani, A., Baugarten, A., and Cole, L.A. Serum hyperglycosylated hCG a potential screening test for fetal Down syndrome. Prenat Diagn, 1999;19:488-489.

 

38.     Palomaki GE. Neveux LM. Knight GJ. Haddow JE. Pandian R. Maternal serum invasive trophoblast antigen (hyperglycosylated hCG) as a screening marker for Down syndrome during the second trimester. Clin Chem 2004; 50:1804-8.

 

39.     Cuckle, H.S., Shahabi, S., Sehmi, I., Jones, R., and Cole, L.A. Maternal urine hyperglycosylated hCG in pregnancies with Down’s Syndrome. Prenat Diagn 1999;19: 918-920.

 

40.     Weinans  JN, Butler SA, Mantingh A, Cole LA. Urinary hyperglycosylated hCG in first-trimester screening for chromosomal abnormalities. Prenat Diagn 2000;20:976-978

 

41. Reynolds TM. Down's syndrome screening: a controversial test, with more controversy to come! J Clin Path 2000;53:893-898

 

42. Strom CM, Palomaki GE,  Knight GJ, Cole LA, Pandian R. Maternal urine Invasive Trophoblast Antigen (ITA) is a useful marker for Down syndrome in the 1^st trimester. 51^st Ann Meet Am Soc Hum Gen, San Diego, 2001 (Abstract 2839).

 

43. Weinans MJ. Sancken U. Pandian R. van de Ouweland JM. de Bruijn HW. Holm JP. Mantingh A. Invasive trophoblast antigen (hyperglycosylated human chorionic gonadotropin) as a first-trimester serum marker for Down syndrome. 2005; Clin Chem 51:1276-9.

 

44. Cole LA, Butler SA, Khanlian SA, Giddings A, Seckl MJ,  Kohorn EI. Gestational Trophoblastic Diseases: 2. Hyperglycosylated hCG as a Reliable Marker of Active Neoplasia. Gyn Oncol 2005; in press.

 

45. Cole LA, Khanlian SA Inappropriate management of women with persistent low hCG results. J Reprod Med 2004; 49: 423-432.

 

46.  Khanlian SA, Smith HO, Cole LA. Persistent low levels of hCG: A Pre-malignant gestational trophoblastic disease. Am J Obstet Gynecol 2003; 188: 1254-1259.

 

47. Cole, LA, Sutton JM. hCG tests in the management of gestational trophoblastic diseases. Clin Obstet Gynecol 2003; 46: 533-540.

 

48. Cole LA. Use of hCG Tests for evaluating trophoblastic diseases: Choosing an appropriate hCG assay, false detection of hCG, unexplained elevated hCG, and quiescent trophoblastic disease. In: Gestational Trophoblastic Disease 2nd edition, eds. Hancock BW, Newlands ES, Berkowitz RS and Cole LA, Sheffield University Press, 130-155, 2003

 

49. Cole LA, Sutton JM: Selecting an Appropriate hCG test for management of gestational trophoblastic diseases and cancer cases. J Reprod Med, 2004; 49: 545-553.

 

50. Hancock BW, Tidy JA. Clinical management of persistent low level  hCGelevation. Trophobl Dis Upd 4: 5-6

 

51. Kohorn EI. Persistent low-level “real” human chorionic gonadotropin: a clinical challenge and a therapeutic dilemma. Gynecol Oncol, 2002; 85: 315-20

 

52. Cole LA, Khanlian SA, Butler SA, Seckl M, Kohorn EI. Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a Reliable Marker of Active Neoplasia. Gynecologic Oncology, in press, 2006