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Current advances in the management of gestational trophoblastic disease
Gynecologic Oncology 128 (2013) 3–5
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Clinical Commentary
Current advances in the management of gestational trophoblastic disease
Introduction Gestational trophoblastic disease (GTD) includes a group of interrelated diseases arising from the placenta with varying tendencies for local invasion and metastases [1,2]. GTD includes complete mole (CM) and partial mole (PM), choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor. Our understanding of GTD has advanced considerably in recent years and this article will review several of these advances in the area of both biology and clinical management. Biology of GTD Genetics Molar pregnancy (MP) is composed of two separate entities, PM and CM, which are distinguished by their distinct chromosomal patterns and histopathology [3,4]. CMs generally have a 46, XX karyotype and all of the chromosomes are of paternal origin [5]. Most CMs are homozygous and arise from the fertilization of an anuclear ovum by a 23, X haploid sperm which then duplicates its own chromosomes [6]. Because CMs generally do not have maternal chromosomes, paternally imprinted, maternally expressed gene products are generally not expressed in complete moles [7,8]. In contrast, PMs result from fertilization of an apparently normal ovum by two spermatozoa [9]. Studies have reported that certain patients with recurrent MP had biparental CM rather than the usual androgenetic CM. Many of these cases had a strong familial history [10]. Genetic mapping studies in these patients showed that the related genes were located on chromosome 19q 13.3–13.4 and subsequent analysis showed mutations in NLRP7 in this region [11,12]. Biparental CMs with NLRP7 mutations also exhibit imprinting abnormalities with the lack of expression of paternally imprinted, maternally expressed gene products [13]. Studies have shown that mutations in NLRP7 are clustered in a leucine-rich region which may be crucial for normal function [14]. NLRP7 mutations have also been reported in some androgenetic diploid CM and in triploid PM [15]. While most families with familial biparental hydatidiform mole (FBHM) have a mutation in NLRP7, not all such families have this mutation identified. A mutation in C6orf221 has also been recently implicated in a family with FBHM [16]. FBHM appears to result from a failure to establish maternal imprints at multiple genome-wide loci [17,18]. Molecular biology Matrix metalloproteinases (MMPs) are an important class of proteases that are involved in the metabolism of the extracellular matrix which is critical in both invasion of malignancy and normal trophoblastic 0090-8258/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ygyno.2012.07.116
invasion of maternal tissues [19–21]. MMPs and their inhibitors have recently been studied in both GTD and normal placenta [22]. CCA was characterized by high levels of expression of several MMPs (MMP-1, -2, -21, and ‐28) and low levels of expression of tissue inhibitors of MMPs which may contribute to the invasiveness of CCA. In contrast, PSTT has low levels of expression of MMPs. Drug resistant CCA may be effectively treated with matrix metalloproteinase inhibitors and synthetic inhibitors are currently being developed and clinically tested [23]. Angiogenesis is critical in tumor development and vascular endothelial growth factors and their receptors are key regulators of angiogenesis [24,25]. Recently the expression of vascular endothelial growth factors and their receptors and regulators was investigated in GTD and normal placenta [26]. Importantly, PSTT exhibited a high level of expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 and ‐2. PSTT may be relatively resistant to chemotherapy and inhibition of VEGF may provide a novel and useful treatment [27,28].
Changing epidemiology and natural history Changing clinical features of HM In 1995 a report from the New England Trophoblastic Disease Center documented dramatic changes in the clinical presentation of CM in recent years due to early diagnosis by the widespread use of pelvic ultrasound and serum hCG testing without a significant decrease in the incidence of postmolar gestational trophoblastic neoplasia (GTN) [29]. Changes in the clinical presentation of CM have also been recently reported from China and Thailand indicating a more global phenomenon. In a review of 113 Chinese patients during the years of 1989–2006 as compared to historic data from 1948 to 1975, Hou et al. concluded that because of early detection the traditional presenting signs and symptoms of preeclampsia, hyperemesis, trophoblastic embolization and theca lutein (TL) cysts were less frequently present even though the risk of developing postmolar GTN remained unchanged. Chemoprophylaxis was administered to patients with high‐risk factors for developing GTN such as maternal age >40, uterine size excessively greater than gestational age, pre-evacuation hCG level >100,000 mIU/ml, diameter of TL cysts >6 cm, and a history of prior mole with a significant decrease in the incidence of postmolar GTN [30]. Similar findings were also reported by Lertkhachonsuk et al. from Bangkok where over 3 decades the incidence of CM decreased, the diagnosis was made earlier and traditional clinical presentations were less frequent while the rate of postmolar GTN did not decrease [31]. Early clinical diagnosis, however, has made it more difficult to pathologically differentiate early CM and PM from a non-molar abortus. The use of immunohistochemical stains for paternally imprinted and maternally expressed p57 overcomes the limitations of routinely
4
Clinical Commentary
stained sections by differentiating PM and non-molar abortus from CM [7,8]. Changing trends in the management of GTN The current outcomes of treatment for patients with both low-risk and high-risk GTN have improved worldwide over the past 50 years as a result of increased efforts of trophoblast disease specialists to educate generalists in prompt recognition of the disease and establishment of general principles of management. An excellent example of this is the experience in the Philippines where an effort has been made to standardize data reporting, utilize established treatment protocols, and individualize care with a multidisciplinary approach [32]. Increasing communication among various treatment centers has also led to modification of accepted standards of treatment with comparable results to compensate for limitations in the availability of treatment facilities and chemotherapeutic drugs. There is a general consensus, however, that the increase in referral centers and treatment based on standardized staging and risk evaluation has led to significant improvements in outcomes particularly in patients with high-risk disease. Demographics Martin and Kim noted that significant demographic changes in GTD had occurred over four decades in South Korea including a decreased incidence and better outcomes due to improved medical care and to social, economic and educational changes [33]. Recent demographic studies from the United Kingdom [34], Italy [35], the Netherlands [36], Turkey [37,38], and Brazil [39] reflect wide discrepancies in incidence which may be due to the accuracy of data collection, increased maternal age, percent of conceptions in patients of Asian descent, and availability of improved diagnostic techniques. Interestingly, Savage et al. observed an increase in the incidence of molar pregnancy in England and Wales in recent years which likely results from increased numbers of conceptions occurring in women older than 40 [34]. Maternal age Maternal age has been well-known to be associated with both the incidence of MP and the risk of developing postmolar GTN. Recent studies have evaluated the natural history of CM in women in their 40's or older than 50 [40,41]. Following molar evacuation postmolar GTN developed in women in their 40's or older than 50 in 53% and 60%, respectively, and therefore hysterectomy may be considered as an appropriate treatment in these patients. Investigations have also been conducted recently to better understand the natural history of MP in adolescent patients [42,43]. Interestingly, adolescents with CM have a lower risk of developing GTN than adults, and if they do develop GTN they have no difference in disease stage or sensitivity to chemotherapy as compared to adults. Advances in chemotherapy Low-risk GTN Despite the extensive experience of treating low-risk GTN that has accumulated over the past 50 years and the more than 14 different regimens which have been described, there is no consensus regarding the optimal first-line treatment. In the absence of strong data demonstrating the clear superiority of one method, differences in treatment are arbitrarily used by different centers. Three basic regimens are most widely utilized: 1) weekly low-dose intramuscular Methotrexate (MTX) [44]; 2) pulsed doses of actinomycin D (Act-D) given every 2 weeks [45]; and 3) several other dosing regimens for single agent MTX with and without folinic acid (leucovorin) rescue [46]. A
recent prospectively randomized Gynecologic Oncology Group study showed that intravenous biweekly Act-D 1.25 mg/m [2] was statistically superior to weekly intramuscular MTX 30 mg/m [2] (Complete Response: 70% v 53%; p = .01) in low-risk GTN with World Health Organization (WHO) risk scores 0–4. However, both regimens were less effective if the WHO risk score was 5 or 6, or if the diagnosis was CCA [47]. Comparing the costs of the various regimens, Shah et al. created a decision-tree model as described by the cost-analysis guidelines of the National Information Center on Health Services Research and Health Care Technology and concluded that the 8-day MTX–folinic acid regimen as compared to weekly MTX or pulsed Act-D is consistently the least expensive strategy [48]. Clearly an optimal regimen would maintain a high cure rate while limiting toxicity and cost. Resistant disease and relapse rates Drug resistance and relapse are known to occur more frequently in high-risk rather than low-risk patients [49]. Recent studies report that the number of consolidation courses administered, the level of initial hCG, the extent of disease, and higher WHO risk scores appear to predispose to relapse and drug resistance [50,51]. Among patients with low-risk GTN relapse rates were significantly less in patients receiving 3 versus 2 consolidation courses of MTX (4.0 vs. 8.3% relapse rate, p b 0.006) [50]. Post-molar gonadotropin follow-up Patients with MP are followed with serial hCG levels to assure the early detection of GTN. Patients are often monitored with weekly hCG levels until undetectable (b 5 mIU/ml) for 3 weeks and then monthly levels until undetectable for 6 months. Recent data from multiple centers indicate that once the serum hCG level becomes undetectable, re-elevation of the hCG level occurs in less than 1% of patients. Since 2004, 8 centers have reported that only 2 of more than 2000 patients with a molar pregnancy developed persistent tumor after serum hCG levels became undetectable [52–59]. The interval of hCG monitoring after molar evacuation could likely be shortened without compromising patient's safety. Psychosocial consequences of GTD Studies have shown that despite a very favorable outcome, future fertility and pregnancy fears, mood disturbances and sexual disturbances can persist for years in patients with GTD [60]. Recent studies have broadened and deepened our understanding of the adverse psychosocial consequences of GTD across several cultures [61,62]. These studies emphasize the importance for clinicians to be mindful of the altered psychosocial functioning of these patients and the need to provide counseling and support. Conflict of interest statement No conflict of interest.
References [1] Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376: 717-29. [2] Lurain JR. Gestational trophoblastic disease. I: epidemiology, pathology, presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 2010;203:531-9. [3] Szulman AE, Surti U. The syndromes of hydatidiform mole. II. Morphologic evolution of the complete and partial mole. Am J Obstet Gynecol 1978;132:20-7. [4] Berkowitz RS, Goldstein DP. Clinical practice; molar pregnancy. N Engl J Med 2009;360:1639-45. [5] Kajii T, Ohama K. Androgenetic origin of hydatidiform mole. Nature 1977;268: 633-4. [6] Yamashita K, Wake N, Araki T, Ichinoe R, Makoto K. Human lymphocyte antigen expression in hydatidiform mole: androgenesis following fertilization by a sperm. Am J Obstet Gynecol 1979;135:597-600.
Clinical Commentary [7] Fukanaga M. Immunohistochemical characterization of p57 (KIP 2) expression in early complete moles. Hum Pathol 2002;33:1188-92. [8] Genest DR, Dorfman DM, Castrillon DH. Ploidy and imprinting in hydatidiform moles: complementary use of flow cytometry and immunochemistry of the imprinted gene product p57KIP2 to assist molar classification. J Reprod Med 2002;47:342-6. [9] Szulman AE, Surti U. The syndromes of hydatidiform mole. I. Cytogenetic and morphologic correlations. Am J Obstet Gynecol 1978;131:665-71. [10] Fisher R, Hodges MD, Newlands ES. Familial recurrent hydatidiform mole: a review. J Reprod Med 2004;49:595-601. [11] Moglabey YB, Kircheisen R, Seoud M, El-Mogharbel N, Van den Veyrer I, Slim R. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum Mol Genet 1999;8:667-71. [12] Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, et al. Mutations in NLRP7 cause recurrent hydatidiform moles and reproductive wastage in human. Nat Genet 2006;38:300-2. [13] Kou YC, Shao L, Peng HH, Rosetta R, del Gaudo D, Wagner AF, et al. A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod 2008;14:33-40. [14] Wang CM, Dixon PH, Decordova S, Hodges MD, Sebire NJ, Ozalp S, et al. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich area. J Med Genet 2009;46:569-75. [15] Deveault C, Qian JK, Chebaro W, Ao A, Gilbert L, Mehio A, et al. NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation. Hum Mol Genet 2009;18:888-97. [16] Parry DA, Logan CV, Hayward BE, Shirer M, Landols H, Diggle C, et al. Mutations causing familial biparental hydatidiform mole implicate C6 or f221 as a possible regulator of genomic imprinting in the human oocyte. Am J Hum Genet 2011;89:451-8. [17] Fisher RA, Hodges MD, Rees HC, Sebire NJ, Seckl MJ, Newlands ES, et al. The maternally transcribed gene p57 (KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum Mol Genet 2002;11:3267-72. [18] El-Maarri O, Seoud M, Coulline P, Herbiniau U, Oldenburg J, Rouleau G, et al. Maternal alleles acquiring paternal methylation patterns in biparental complete hydatidiform moles. Hum Mol Genet 2003;12:1405-13. [19] Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463-516. [20] Kessenbrock K, Plaks V, Werb Z. Mattrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010;141:52-67. [21] Bischof P, Marshall M, Campana A, Itoh Y, Ogata Y, Nagare H. Importance of matrix metalloproteinases in human trophoblast invasion. Early Pregnancy 1995;1:263-9. [22] Singh M, Kindelberger D, Nagymanyoki Z, Ng S-W, Quick CM, Elias KM, et al. Matrix metalloproteinases and their inhibitors and inducers in gestational trophoblastic diseases and normal placenta. Gynecol Oncol 2011;122:178-82. [23] Butler GS, Dean RA, Tam EM, Overall CM. Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: dynamics of membrane type 1 matrix metalloproteinase-mediated membrane protein shedding. Mol Cell Biol 2008;28: 4896-914. [24] Folkman J, Cole P, Zimmerman S. Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg 1966;164:491-502. [25] Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocrinol Rev 2004;25:581-611. [26] Singh M, Kindelberger D, Nagymanyoki Z, Ng S-W, Quick CM, Yamamoto H, et al. Vascular endothelial growth factors and their receptors and regulators in gestational trophoblastic diseases and normal placenta. J Reprod Med 2012;57:197-203. [27] Lurain JR. Gestational trophoblasic disease. II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 2011;204:11-8. [28] Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic disease. Gynecol Oncol 2009;112:654-62. [29] Soto-Wright V, Bernstein MR, Goldstein DP, Berkowitz RS. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol 1995;86:775-9. [30] Hou J, Wan X, Xiang Y, Qing-wdei Q, Xiu-yu Y. Changes of clinical features in hydatidiform mole: analysis of 113 cases. J Reprod Med 2008;53:629-33. [31] Lertkhachonsuk A-a, Israngura N, Tangtrakul S, Thanapprapasr D, Charakorn C, Chittithaworn S. Complete hydatidiform mole: change in clinical profile over 3 decades. J Reprod Med in press. [32] Cagayan MSFS. Changing trends in the management of gestational trophoblastic disease in the Philippines. J Reprod Med 2010;55:1225-32. [33] Martin BH, Kim JM. Changes in gestational trophoblastic tumors over four decades: a Korean experience. J Reprod Med 1998;43:60-8. [34] Savage P, Williams J, Wong S-L, Short D, Casalboni S, Catalano K, et al. The demographics of molar pregnancies in England and Wales from 2000 to 2009. J Reprod Med 2010;55:341-5. [35] Salerno A. The incidence of gestational trophoblastic disease in Italy: a multicenter study. J Reprod Med 2012;57:204-6. [36] Lybol C, Thomas CMG, Bulten J, van Dijck JAAM, Sweep FCGJ, Massuger LFAG. Increase in the incidence of gestational trophoblastic disease in the Netherlands. Gynecol Oncol 2011;121:334-8. [37] Ozalp SS. Regional perspective on gestational trophoblastic disease in Turkey. J Reprod Med 2008;53:639-42. [38] Oge T, Ozalp SS, Gungor T, Yildirim Y, Sanci M, Dogan A, et al. Hydatidiform mole in Turkey: results from 6 centers. J Reprod Med 2012;57:259-61. [39] Belfort P, Baptista AM, Valle Filho OC. Gestational trophoblastic disease: regional perspective in Rio de Janeiro, Brazil. J Reprod Med 2010;55:258-60.
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[40] Elias KM, Goldstein DP, Berkowitz RS. Complete hydatidiform mole in women older than age 50. J Reprod Med 2010;55:208-12. [41] Elias KM, Shoni M, Bernstein MR, Goldstein DP, Berkowitz RS. Complete hydatidiform mole in women aged 40 to 49 years. J Reprod Med 2012;57:254-8. [42] Braga A, Growdon WB, Bernstein MR, Maesta I, Rudge MV, Goldstein DP, et al. Molar pregnancy in adolescents. J Reprod Med 2012;57:225-30. [43] Rauh-Hain JA, Growdon WB, Braga A, Goldstein DP, Berkowitz RS. Gestational trophoblastic neoplasia in adolescents. J Reprod Med 2012;57:237-42. [44] Homesley HD. Single agent therapy for nonmetastatic and low-risk gestational trophoblastic disease. J Reprod Med 1998;43:69-74. [45] Twiggs LB. Pulse actinomycin-D scheduling in nonmetastatic gestational trophoblastic neoplasia: cost-effective chemotherapy. Gynecol Oncol 1983;16: 190-5. [46] Foulmann K, Guastalla JP, Caminet N, Trillet-Lenoir V, Raudrant D, Golfier F. What is the best protocol of single agent methotrexate chemotherapy in nonmetastatic or low-risk metastatic gestational trophoblastic tumors? A review of the evidence. Gynecol Oncol 2006;102:103-10. [47] Osborne RJ, Filiaci V, Schink JC, Mannel RS, Secord AA, Kelley JL, et al. Phase III trial of weekly methotrexate or pulsed Dactinomycin for low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study. J Clin Oncol 2011;29:825-31. [48] Shah NT, Barroilhet L, Berkowitz RS, Goldstein DP, Horowitz N. A cost analysis of first-line chemotherapy for low-risk gestational trophoblastic neoplasia. J Reprod Med 2012;57:211-8. [49] Mutch DG, Soper JT, Babcock CJ, Clarke-Pearson D, Hammond CB. Recurrent gestational trophoblastic disease. Cancer 1990;66:978-82. [50] Lybol C, Sweep FCGJ, Harvey R, Mitchell H, Short D, Thomas CMG, et al. Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia. Gynecol Oncol 2012;125: 576-9. [51] Chapman-Davis E, Hoekstra AV, Rademaker AW, Schink JC, Lurain JR. Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia:factors associated with resistance to single agent methotrexate chemotherapy. Gynecol Oncol 2012;125:572-5. [52] Kerkmeijer LG, Wielsma S, Massuger LF, Sweep FCGJ, Thomas CMG. Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in the Netherlands. Gynecol Oncol 2007;106:142-6. [53] Kerkmeijer L, Wielsma S, Bekkers R, Pyman J, Tan J, Quinn M. Guidelines following hydatidiform mole: a reappraisal. Aust N Z J Obstet Gynaecol 2006;46:112-8. [54] Pisal N, Tidy JA, Hancock BW. Gestational trophoblastic disease: is intensive follow-up essential in all women? Br J Obstet Gynaecol 2004;111:1449-51. [55] Wielsma S, Kerkmeijer L, Bekkers R, Pyman J, Tan J, Quinn M. Persistent trophoblastic disease following partial molar pregnancy. Aust N Z J Obstet Gynaecol 2006;46:119-23. [56] Bartorfi J, Vegh G, Szepesi J, Szigetvari I, Doszpod J, Fulop V. How long should patients be followed after molar pregnancy? Analysis of serum hCG follow-up data. Obstet Gynecol 2004;112:95-7. [57] Wolfberg AJ, Feltmate CM, Goldstein DP, Berkowitz RS, Lieberman E. Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004;104:551-4. [58] Wolfberg AJ, Growdon WB, Feltmate CM, Goldstein DP, Genest D, Chinchilla ME, et al. Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy. Obstet Gynecol 2006;108:393-6. [59] Lavie I, Rao GG, Castrillon DH, Miller DS, Schorge JO. Duration of human chorionic gonadotropin surveillance for partial hydatidiform moles. Am J Obstet Gynecol 2005;192:1362-4. [60] Wenzel L, Berkowitz RS, Habbal R, Newlands E, Hancock BW, Goldstein DP, et al. Predictors of quality of life among long-term survivors of gestational trophoblastic disease. J Reprod Med 2004;49:589-94. [61] Ferreira EGU, Maesta I, Michelin OC, de Paula RCC, Consonni M, Rudge MUC. Assessment of quality of life and psychologic aspects in patients with gestational trophoblastic disease. J Reprod Med 2009;54:239-44. [62] Caygayan MSFS, Llarena RT. Quality of life of gestational trophoblastic neoplasia survivors: a study of patients at the Philippine General Hospital Trophoblastic Disease section. J Reprod Med 2010;55:321-6.
Ross S. Berkowitz ⁎ Donald Peter Goldstein New England Trophoblastic Disease Center, Donald P. Goldstein Trophoblastic Tumor Registry, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA ⁎Corresponding author at: Division of Gynecologic Oncology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Fax: +1 617 738 5124. E-mail address: [email protected]. 23 July 2012
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Clinical Commentary
Current advances in the management of gestational trophoblastic disease
Introduction Gestational trophoblastic disease (GTD) includes a group of interrelated diseases arising from the placenta with varying tendencies for local invasion and metastases [1,2]. GTD includes complete mole (CM) and partial mole (PM), choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor. Our understanding of GTD has advanced considerably in recent years and this article will review several of these advances in the area of both biology and clinical management. Biology of GTD Genetics Molar pregnancy (MP) is composed of two separate entities, PM and CM, which are distinguished by their distinct chromosomal patterns and histopathology [3,4]. CMs generally have a 46, XX karyotype and all of the chromosomes are of paternal origin [5]. Most CMs are homozygous and arise from the fertilization of an anuclear ovum by a 23, X haploid sperm which then duplicates its own chromosomes [6]. Because CMs generally do not have maternal chromosomes, paternally imprinted, maternally expressed gene products are generally not expressed in complete moles [7,8]. In contrast, PMs result from fertilization of an apparently normal ovum by two spermatozoa [9]. Studies have reported that certain patients with recurrent MP had biparental CM rather than the usual androgenetic CM. Many of these cases had a strong familial history [10]. Genetic mapping studies in these patients showed that the related genes were located on chromosome 19q 13.3–13.4 and subsequent analysis showed mutations in NLRP7 in this region [11,12]. Biparental CMs with NLRP7 mutations also exhibit imprinting abnormalities with the lack of expression of paternally imprinted, maternally expressed gene products [13]. Studies have shown that mutations in NLRP7 are clustered in a leucine-rich region which may be crucial for normal function [14]. NLRP7 mutations have also been reported in some androgenetic diploid CM and in triploid PM [15]. While most families with familial biparental hydatidiform mole (FBHM) have a mutation in NLRP7, not all such families have this mutation identified. A mutation in C6orf221 has also been recently implicated in a family with FBHM [16]. FBHM appears to result from a failure to establish maternal imprints at multiple genome-wide loci [17,18]. Molecular biology Matrix metalloproteinases (MMPs) are an important class of proteases that are involved in the metabolism of the extracellular matrix which is critical in both invasion of malignancy and normal trophoblastic 0090-8258/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ygyno.2012.07.116
invasion of maternal tissues [19–21]. MMPs and their inhibitors have recently been studied in both GTD and normal placenta [22]. CCA was characterized by high levels of expression of several MMPs (MMP-1, -2, -21, and ‐28) and low levels of expression of tissue inhibitors of MMPs which may contribute to the invasiveness of CCA. In contrast, PSTT has low levels of expression of MMPs. Drug resistant CCA may be effectively treated with matrix metalloproteinase inhibitors and synthetic inhibitors are currently being developed and clinically tested [23]. Angiogenesis is critical in tumor development and vascular endothelial growth factors and their receptors are key regulators of angiogenesis [24,25]. Recently the expression of vascular endothelial growth factors and their receptors and regulators was investigated in GTD and normal placenta [26]. Importantly, PSTT exhibited a high level of expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 and ‐2. PSTT may be relatively resistant to chemotherapy and inhibition of VEGF may provide a novel and useful treatment [27,28].
Changing epidemiology and natural history Changing clinical features of HM In 1995 a report from the New England Trophoblastic Disease Center documented dramatic changes in the clinical presentation of CM in recent years due to early diagnosis by the widespread use of pelvic ultrasound and serum hCG testing without a significant decrease in the incidence of postmolar gestational trophoblastic neoplasia (GTN) [29]. Changes in the clinical presentation of CM have also been recently reported from China and Thailand indicating a more global phenomenon. In a review of 113 Chinese patients during the years of 1989–2006 as compared to historic data from 1948 to 1975, Hou et al. concluded that because of early detection the traditional presenting signs and symptoms of preeclampsia, hyperemesis, trophoblastic embolization and theca lutein (TL) cysts were less frequently present even though the risk of developing postmolar GTN remained unchanged. Chemoprophylaxis was administered to patients with high‐risk factors for developing GTN such as maternal age >40, uterine size excessively greater than gestational age, pre-evacuation hCG level >100,000 mIU/ml, diameter of TL cysts >6 cm, and a history of prior mole with a significant decrease in the incidence of postmolar GTN [30]. Similar findings were also reported by Lertkhachonsuk et al. from Bangkok where over 3 decades the incidence of CM decreased, the diagnosis was made earlier and traditional clinical presentations were less frequent while the rate of postmolar GTN did not decrease [31]. Early clinical diagnosis, however, has made it more difficult to pathologically differentiate early CM and PM from a non-molar abortus. The use of immunohistochemical stains for paternally imprinted and maternally expressed p57 overcomes the limitations of routinely
4
Clinical Commentary
stained sections by differentiating PM and non-molar abortus from CM [7,8]. Changing trends in the management of GTN The current outcomes of treatment for patients with both low-risk and high-risk GTN have improved worldwide over the past 50 years as a result of increased efforts of trophoblast disease specialists to educate generalists in prompt recognition of the disease and establishment of general principles of management. An excellent example of this is the experience in the Philippines where an effort has been made to standardize data reporting, utilize established treatment protocols, and individualize care with a multidisciplinary approach [32]. Increasing communication among various treatment centers has also led to modification of accepted standards of treatment with comparable results to compensate for limitations in the availability of treatment facilities and chemotherapeutic drugs. There is a general consensus, however, that the increase in referral centers and treatment based on standardized staging and risk evaluation has led to significant improvements in outcomes particularly in patients with high-risk disease. Demographics Martin and Kim noted that significant demographic changes in GTD had occurred over four decades in South Korea including a decreased incidence and better outcomes due to improved medical care and to social, economic and educational changes [33]. Recent demographic studies from the United Kingdom [34], Italy [35], the Netherlands [36], Turkey [37,38], and Brazil [39] reflect wide discrepancies in incidence which may be due to the accuracy of data collection, increased maternal age, percent of conceptions in patients of Asian descent, and availability of improved diagnostic techniques. Interestingly, Savage et al. observed an increase in the incidence of molar pregnancy in England and Wales in recent years which likely results from increased numbers of conceptions occurring in women older than 40 [34]. Maternal age Maternal age has been well-known to be associated with both the incidence of MP and the risk of developing postmolar GTN. Recent studies have evaluated the natural history of CM in women in their 40's or older than 50 [40,41]. Following molar evacuation postmolar GTN developed in women in their 40's or older than 50 in 53% and 60%, respectively, and therefore hysterectomy may be considered as an appropriate treatment in these patients. Investigations have also been conducted recently to better understand the natural history of MP in adolescent patients [42,43]. Interestingly, adolescents with CM have a lower risk of developing GTN than adults, and if they do develop GTN they have no difference in disease stage or sensitivity to chemotherapy as compared to adults. Advances in chemotherapy Low-risk GTN Despite the extensive experience of treating low-risk GTN that has accumulated over the past 50 years and the more than 14 different regimens which have been described, there is no consensus regarding the optimal first-line treatment. In the absence of strong data demonstrating the clear superiority of one method, differences in treatment are arbitrarily used by different centers. Three basic regimens are most widely utilized: 1) weekly low-dose intramuscular Methotrexate (MTX) [44]; 2) pulsed doses of actinomycin D (Act-D) given every 2 weeks [45]; and 3) several other dosing regimens for single agent MTX with and without folinic acid (leucovorin) rescue [46]. A
recent prospectively randomized Gynecologic Oncology Group study showed that intravenous biweekly Act-D 1.25 mg/m [2] was statistically superior to weekly intramuscular MTX 30 mg/m [2] (Complete Response: 70% v 53%; p = .01) in low-risk GTN with World Health Organization (WHO) risk scores 0–4. However, both regimens were less effective if the WHO risk score was 5 or 6, or if the diagnosis was CCA [47]. Comparing the costs of the various regimens, Shah et al. created a decision-tree model as described by the cost-analysis guidelines of the National Information Center on Health Services Research and Health Care Technology and concluded that the 8-day MTX–folinic acid regimen as compared to weekly MTX or pulsed Act-D is consistently the least expensive strategy [48]. Clearly an optimal regimen would maintain a high cure rate while limiting toxicity and cost. Resistant disease and relapse rates Drug resistance and relapse are known to occur more frequently in high-risk rather than low-risk patients [49]. Recent studies report that the number of consolidation courses administered, the level of initial hCG, the extent of disease, and higher WHO risk scores appear to predispose to relapse and drug resistance [50,51]. Among patients with low-risk GTN relapse rates were significantly less in patients receiving 3 versus 2 consolidation courses of MTX (4.0 vs. 8.3% relapse rate, p b 0.006) [50]. Post-molar gonadotropin follow-up Patients with MP are followed with serial hCG levels to assure the early detection of GTN. Patients are often monitored with weekly hCG levels until undetectable (b 5 mIU/ml) for 3 weeks and then monthly levels until undetectable for 6 months. Recent data from multiple centers indicate that once the serum hCG level becomes undetectable, re-elevation of the hCG level occurs in less than 1% of patients. Since 2004, 8 centers have reported that only 2 of more than 2000 patients with a molar pregnancy developed persistent tumor after serum hCG levels became undetectable [52–59]. The interval of hCG monitoring after molar evacuation could likely be shortened without compromising patient's safety. Psychosocial consequences of GTD Studies have shown that despite a very favorable outcome, future fertility and pregnancy fears, mood disturbances and sexual disturbances can persist for years in patients with GTD [60]. Recent studies have broadened and deepened our understanding of the adverse psychosocial consequences of GTD across several cultures [61,62]. These studies emphasize the importance for clinicians to be mindful of the altered psychosocial functioning of these patients and the need to provide counseling and support. Conflict of interest statement No conflict of interest.
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Ross S. Berkowitz ⁎ Donald Peter Goldstein New England Trophoblastic Disease Center, Donald P. Goldstein Trophoblastic Tumor Registry, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA ⁎Corresponding author at: Division of Gynecologic Oncology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Fax: +1 617 738 5124. E-mail address: [email protected]. 23 July 2012