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Gestational Trophoblastic Tumors and Related Tumor-Like Lesions

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Blaustein’s Pathology of the Female Genital Tract

Abstract

Gestational trophoblastic disease (GTD) encompasses a heterogeneous group of lesions with specific clinical features, morphological characteristics, and pathogenesis. The World Health Organization classification of GTD includes complete and partial hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), epithelioid trophoblastic tumor, exaggerated placental site, and placental site nodule (Table 20.1 ) [145]. Some of these lesions are true neoplasms, whereas others represent abnormally formed placentas with a predisposition for neoplastic transformation of the trophoblast. Two benign entities, the exaggerated placental site and the placental site nodule, are included because they are trophoblastic lesions that must be distinguished from other entities with malignant potential. The literature on GTD is extensive and at times confusing because of inconsistencies in classification and terminology. In fact, the necessity of a morphologic classification has been questioned, because current management is largely medical and in the case of trophoblastic disease following a mole, treatment is often conducted in the absence of a histological diagnosis. Thus, all trophoblastic lesions are frequently combined under the rubric of GTD without applying specific pathological terms. However, recent studies demonstrate profound differences in the etiology, morphology, and clinical behavior of various forms of the disease. These studies underscore the importance of a uniform histological classification to facilitate standardized reporting of data and to ensure appropriate clinical management. Nonetheless, the term GTD has clinical utility, as the principles of human chorionic gonadotropin (hCG) monitoring in follow-up and the chemotherapy of metastatic or persistent disease are similar for all these entities.

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References

  1. Akbulut M, Tosun H, Soysal ME, Oztekin O (2008) Endometrioid carcinoma of the endometrium with choriocarcinomatous differentiation: a case report and review of the literature. Arch Gynecol Obstet 278:79–84

    Article  PubMed  Google Scholar 

  2. Allan RW, Algood CB, Shih Ie M (2009) Metastatic epithelioid trophoblastic tumor in a male patient with mixed germ-cell tumor of the testis. Am J Surg Pathol 33:1902–1905

    Article  PubMed  Google Scholar 

  3. Altieri A, Franceschi S, Ferlay J, Smith J, La Vecchia C (2003) Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 4:670–678

    Article  PubMed  Google Scholar 

  4. Ariel I, Boldes R, Weintraub A, Reinus C, Beller U, Arbel R (2009) Chorangiocarcinoma: a case report and review of the literature. Int J Gynecol Pathol 28:267–271

    Article  PubMed  Google Scholar 

  5. Arroyo MR, Podda A, Cao D, Rodriguez MM (2008) Placental site trophoblastic tumor in the ovary of a young child with isosexual precocious puberty. Pediatr Dev Pathol 12:73–76

    Article  Google Scholar 

  6. Azuma C, Saji F, Nobunaga T, Kamiura S, Kimura T, Tokugawa Y, Koyama M, Tanizawa O (1990) Studies on the pathogenesis of choriocarcinoma by analysis of restriction fragment length polymorphisms. Cancer Res 50:488–491

    PubMed  CAS  Google Scholar 

  7. Baergen RN, Rutgers J, Young RH (2003) Extrauterine lesions of intermediate trophoblast. Int J Gynecol Pathol 22:362–367

    Article  PubMed  Google Scholar 

  8. Baergen RN, Rutgers JL, Young RH, Osann K, Scully RE (2006) Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance. Gynecol Oncol 100:511–520

    Article  PubMed  Google Scholar 

  9. Bagshawe KD, Lawler SD, Paradinas FJ, Dent J, Brown P, Boxer GM (1990) Gestational trophoblastic tumours following initial diagnosis of partial hydatidiform mole. Lancet 335:1074–1076

    Article  PubMed  CAS  Google Scholar 

  10. Behtash N, Ghaemmaghami F, Hasanzadeh M (2005) Long term remission of metastatic placental site trophoblastic tumor (PSTT): case report and review of literature. World J Surg Oncol 3:34

    Article  PubMed  Google Scholar 

  11. Berkowitz RS, Im SS, Bernstein MR, Goldstein DP (1998) Gestational trophoblastic disease. Subsequent pregnancy outcome, including repeat molar pregnancy. J Reprod Med 43:81–86

    PubMed  CAS  Google Scholar 

  12. Berkowitz LW, Lage JM (1990) Persistent gestational trophoblastic tumor after partial hydatidiform mole. Gynecol Oncol 36:358–362

    Article  PubMed  Google Scholar 

  13. Bifulco C, Johnson C, Hao L, Kermalli H, Bell S, Hui P (2008) Genotypic analysis of hydatidiform mole: an accurate and practical method of diagnosis. Am J Surg Pathol 32:445–451

    Article  PubMed  Google Scholar 

  14. Brewer CA, Adelson MD, Elder RC (1992) Erythrocytosis associated with a placental-site trophoblastic tumor. Obstet Gynecol 79:846–849

    PubMed  CAS  Google Scholar 

  15. Burrows TD, King A, Loke YW (1994) Expression of adhesion molecules by endovascular trophoblast and decidual endothelial cells: implications for vascular invasion during implantation. Placenta 15:21–33

    Article  PubMed  CAS  Google Scholar 

  16. Carinelli SG, Verdola N, Zanotti F (1989) Placental site nodule: a report of 17 cases. Pathol Res Pract 185:30–34

    Google Scholar 

  17. Castrillon DH, Sun D, Weremowicz S, Fisher RA, Crum CP, Genest DR (2001) Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2. Am J Surg Pathol 25:1225–1230

    Article  PubMed  CAS  Google Scholar 

  18. Chang YL, Chang TC, Hsueh S, Huang KG, Wang PN, Liu HP, Soong YK (1999) Prognostic factors and treatment for placental site trophoblastic tumor: report of 3 cases and analysis of 88 cases. Gynecol Oncol 73:216–222

    Article  PubMed  CAS  Google Scholar 

  19. Cheung AN, Shen DH, Khoo US, Wong LC, Ngan HY (1998) p21WAF1/CIP1 expression in gestational trophoblastic disease: correlation with clinicopathological parameters, and Ki67 and p53 gene expression. J Clin Pathol 51:159–162

    Article  PubMed  CAS  Google Scholar 

  20. Chew SH, Perlman EJ, Williams R, Kurman RJ, Ronnett BM (2000) Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM). Hum Pathol 31:914–924

    Article  PubMed  CAS  Google Scholar 

  21. Chilosi M, Piazzola E, Lestani M, Benedetti A, Guasparri I, Granchelli G, Aldovini D, Leonardi E, Pizzolo G, Doglioni C et al (1998) Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease. Lab Invest 78:269–276

    PubMed  CAS  Google Scholar 

  22. Cole LA (1998) hCG, its free subunits and its metabolites. Roles in pregnancy and trophoblastic disease. J Reprod Med 43:3–10

    PubMed  CAS  Google Scholar 

  23. Cole LA (2009) New discoveries on the biology and detection of human chorionic gonadotropin. Reprod Biol Endocrinol 7:8

    Article  PubMed  CAS  Google Scholar 

  24. Cole ME, Broaddus R, Thaker P, Landen C, Freedman RS (2008) Placental-site trophoblastic tumors: a case of resistant pulmonary metastasis. Nat Clin Pract Oncol 5:171–175

    Article  PubMed  Google Scholar 

  25. Cole LA, Khanlian SA, Muller CY, Giddings A, Kohorn E, Berkowitz R (2006) Gestational trophoblastic diseases: 3. Human chorionic gonadotropin-free beta-subunit, a reliable marker of placental site trophoblastic tumors. Gynecol Oncol 102:160–164

    Article  PubMed  CAS  Google Scholar 

  26. Coukos G, Makrigiannakis A, Chung J, Randall TC, Rubin SC, Benjamin I (1999) Complete hydatidiform mole. A disease with a changing profile [In Process Citation]. J Reprod Med 44:698–704

    PubMed  CAS  Google Scholar 

  27. Coulson LE, Kong CS, Zaloudek C (2000) Epithelioid trophoblastic tumor of the uterus in a postmenopausal woman: a case report and review of the literature. Am J Surg Pathol 24:1558–1562

    Article  PubMed  CAS  Google Scholar 

  28. Czernobilsky B, Barash A, Lancet M (1982) Partial moles: a clinicopathologic study of 25 cases. Obstet Gynecol 59:75–77

    PubMed  CAS  Google Scholar 

  29. Datta T, Banerjee AK, Adeyemo AK, McCullough WL, Duncan A (2007) Intraplacental choriocarcinoma associated with pregnancy continuum: a diagnostic dilemma. J Obstet Gynaecol 27:731–732

    Article  PubMed  CAS  Google Scholar 

  30. Denny LA, Dehaeck K, Nevin J, Soeters R, van Wijk AL, Megevand E, Bloch B (1995) Placental site trophoblastic tumor: three case reports and literature review. Gynecol Oncol 59:300–303

    Article  PubMed  CAS  Google Scholar 

  31. Dotto J, Hui P (2008) Lack of genetic association between exaggerated placental site reaction and placental site trophoblastic tumor. Int J Gynecol Pathol 27:562–567

    Article  PubMed  Google Scholar 

  32. Eckstein RP, Paradinas FJ, Bagshawe KD (1982) Placental site trophoblastic tumour (trophoblastic pseudotumour): a study of four cases requiring hysterectomy including one fatal case. Histopathology 6:211–226

    Article  PubMed  CAS  Google Scholar 

  33. Elston C (1995) Gestational trophoblastic disease, 4th edn. New York, Churchill Linvingstone

    Google Scholar 

  34. Fadare O, Parkash V, Carcangiu ML, Hui P (2006) Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement. Mod Pathol 19:75–82

    Article  PubMed  CAS  Google Scholar 

  35. Feltmate CM, Genest DR, Goldstein DP, Berkowitz RS (2002) Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47:337–341

    PubMed  Google Scholar 

  36. Fisher RA, Paradinas FJ, Newlands ES, Boxer GM (1992) Genetic evidence that placental site trophoblastic tumours can originate from a hydatidiform mole or a normal conceptus. Br J Cancer 65:355–358

    Article  PubMed  CAS  Google Scholar 

  37. Folberg R, Hendrix MJ, Maniotis AJ (2000) Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156:361–381

    Article  PubMed  CAS  Google Scholar 

  38. Fox H, Laurini RN (1988) Intraplacental choriocarcinoma: a report of two cases. J Clin Pathol 41:1085–1088

    Article  PubMed  CAS  Google Scholar 

  39. Fraser GC, Blair GK, Hemming A, Murphy JJ, Rogers P (1992) The treatment of simultaneous choriocarcinoma in mother and baby. J Pediatr Surg 27:1318–1319

    Article  PubMed  CAS  Google Scholar 

  40. Fukunaga M, Ushigome S (1993) Malignant trophoblastic tumors: immunohistochemical and flow cytometric comparison of choriocarcinoma and placental site trophoblastic tumors. Hum Pathol 24:1098–1106

    Article  PubMed  CAS  Google Scholar 

  41. Fukunaga M, Ushigome S (1993) Metastasizing placental site trophoblastic tumor. An immunohistochemical and flow cytometric study of two cases. Am J Surg Pathol 17:1003–1010

    Article  PubMed  CAS  Google Scholar 

  42. Garg R, Russell J, Shih I-M, Bristow RE (2004) Have you ruled out a placental site nodule? Contempory Obst Gyn 49:18–20

    Google Scholar 

  43. Garner EI, Goldstein DP, Feltmate CM, Berkowitz RS (2007) Gestational trophoblastic disease. Clin Obstet Gynecol 50:112–122

    Article  PubMed  Google Scholar 

  44. Genest DR (2001) Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. Int J Gynecol Pathol 20:315–322

    Article  PubMed  CAS  Google Scholar 

  45. Golfier F, Raudrant D, Frappart L, Mathian B, Guastalla JP, Trillet-Lenoir V, Vaudoyer F, Hajri T, Schott AM (2007) First epidemiological data from the French Trophoblastic Disease Reference Center. Am J Obstet Gynecol 196(172):e171–e175

    Google Scholar 

  46. Golubovsky MD (2003) Postzygotic diploidization of triploids as a source of unusual cases of mosaicism, chimerism and twinning. Hum Reprod 18:236–242

    Article  PubMed  CAS  Google Scholar 

  47. Goto S, Yamada A, Ishizuka T, Tomoda Y (1993) Development of postmolar trophoblastic disease after partial molar pregnancy. Gynecol Oncol 48:165–170

    Article  PubMed  CAS  Google Scholar 

  48. Guschmann M, Schulz-Bischof K, Vogel M (2003) Incidental chorangiocarcinoma. Case report, immunohistochemistry and theories of possible histogenesis. Pathologe 24:124–127

    PubMed  CAS  Google Scholar 

  49. Hamazaki S, Nakamoto S, Okino T, Tsukayama C, Mori M, Taguchi K, Okada S (1999) Epithelioid trophoblastic tumor: morphological and immunohistochemical study of three lung lesions. Hum Pathol 30:1321–1327

    Article  PubMed  CAS  Google Scholar 

  50. Hancock BW, Nazir K, Everard JE (2006) Persistent gestational trophoblastic neoplasia after partial hydatidiform mole incidence and outcome. J Reprod Med 51:764–766

    PubMed  Google Scholar 

  51. Hando T, Ohno M, Kurose T (1998) Recent aspects of gestational trophoblastic disease in Japan. Int J Gynaecol Obstet 60(Suppl 1):S71–S76

    Article  PubMed  Google Scholar 

  52. Harvey RA, Pursglove HD, Schmid P, Savage PM, Mitchell HD, Seckl MJ (2008) Human chorionic gonadotropin free beta-subunit measurement as a marker of placental site trophoblastic tumors. J Reprod Med 53:643–648

    PubMed  CAS  Google Scholar 

  53. Hassadia A, Gillespie A, Tidy J, Everard RGNJ, Wells M, Coleman R, Hancock B (2005) Placental site trophoblastic tumour: clinical features and management. Gynecol Oncol 99:603–607

    Article  PubMed  Google Scholar 

  54. Hernandez L, Kozlov S, Piras G, Stewart CL (2003) Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation. Proc Natl Acad Sci USA 100:13344–13349

    Article  PubMed  CAS  Google Scholar 

  55. Hertig AT (1956) Tumors of the female sex organs. Part 1. Hydatidifrom mole and choriocarcinoma. In: Atlas of tumor pathology, section 9, fascicle 33. Armed Forces Institute of Pathology, Washington DC

    Google Scholar 

  56. Hoekstra AV, Keh P, Lurain JR (2004) Placental site trophoblastic tumor: a review of 7 cases and their implications for prognosis and treatment. J Reprod Med 49:447–452

    PubMed  Google Scholar 

  57. Houghton O, McCluggage WG (2009) The expression and diagnostic utility of p63 in the female genital tract. Adv Anat Pathol 16:316–321

    Article  PubMed  CAS  Google Scholar 

  58. How J, Scurry J, Grant P, Sapountzis K, Ostor A, Fortune D, Armes J (1995) Placental site trophoblastic tumor. Report of three cases and review of the literature. Int J Gynecol Cancer 5:241–249

    Article  PubMed  Google Scholar 

  59. Hsieh TY, Hsu KF, Kuo PL, Huang SC (2008) Uterine choriocarcinoma accompanied by an extremely high human chorionic gonadotropin level and thyrotoxicosis. J Obstet Gynaecol Res 34:274–278

    Article  PubMed  Google Scholar 

  60. Huettner PC, Gersell DJ (1994) Placental site nodule: a clinicopathologic study of 38 cases. Int J Gynecol Pathol 13:191–198

    Article  PubMed  CAS  Google Scholar 

  61. Hui P, Parkash V, Perkins AS, Carcangiu ML (2000) Pathogenesis of placental site trophoblastic tumor may require the presence of a paternally derived X chromosome. Lab Invest 80:965–972

    Article  PubMed  CAS  Google Scholar 

  62. Hui P, Riba A, Pejovic T, Johnson T, Baergen RN, Ward D (2004) Comparative genomic hybridization study of placental site trophoblastic tumour: a report of four cases. Mod Pathol 17:248–251

    Article  PubMed  CAS  Google Scholar 

  63. Ilancheran A (1998) Optimal treatment in gestational trophoblastic disease. Ann Acad Med Singapore 27:698–704

    PubMed  CAS  Google Scholar 

  64. Ino K, Suzuki T, Uehara C, Nagasaka T, Okamoto T, Kikkawa F, Mizutani S (2000) The expression and localization of neutral endopeptidase 24.11/CD10 in human gestational trophoblastic diseases. Lab Invest 80:1729–1738

    Article  PubMed  CAS  Google Scholar 

  65. Jacobs PA, Hunt PA, Matsuura JS, Wilson CC, Szulman AE (1982) Complete and partial hydatidiform mole in Hawaii: cytogenetics, morphology and epidemiology. Br J Obstet Gynaecol 89:258–266

    Article  PubMed  CAS  Google Scholar 

  66. Jacques SM, Qureshi F, Ramirez NC, Lawrence WD (1997) Retained trophoblastic tissue in fallopian tubes: a consequence of unsuspected ectopic pregnancies. Int J Gynecol Pathol 16:219–224

    Article  PubMed  CAS  Google Scholar 

  67. Janni W, Hantschmann P, Rehbock J, Braun S, Lochmueller E, Kindermann G (1999) Successful treatment of malignant placental site trophoblastic tumor with combined cytostatic-surgical approach: case report and review of literature. Gynecol Oncol 75:164–169

    Article  PubMed  CAS  Google Scholar 

  68. Jauniaux E (1999) Partial moles: from postnatal to prenatal diagnosis. Placenta 20:379–388

    Article  PubMed  CAS  Google Scholar 

  69. Jauniaux E, Zucker M, Meuris S, Verhest A, Wilkin P, Hustin J (1988) Chorangiocarcinoma: an unusual tumour of the placenta. The missing link? Placenta 9:607–613

    Article  PubMed  CAS  Google Scholar 

  70. Jones WB, Romain K, Erlandson RA, Burt ME, Lewis JL Jr (1993) Thoracotomy in the management of gestational choriocarcinoma. A clinicopathologic study. Cancer 72:2175–2181

    Article  PubMed  CAS  Google Scholar 

  71. Kalhor N, Ramirez PT, Deavers MT, Malpica A, Silva EG (2009) Immunohistochemical studies of trophoblastic tumors. Am J Surg Pathol 33:633–638

    Article  PubMed  Google Scholar 

  72. Keep D, Zaragoza MV, Hassold T, Redline RW (1996) Very early complete hydatidiform mole. Hum Pathol 27:708–713

    Article  PubMed  CAS  Google Scholar 

  73. Khong TY (2000) Chorangioma with trophoblastic proliferation. Virchows Arch 436:167–171

    Article  PubMed  CAS  Google Scholar 

  74. Kim SY, Chang AS, Ratts VS (2005) Radiographic and hysteroscopic findings of a placental site nodule. Fertil Steril 83:213–215

    Article  PubMed  Google Scholar 

  75. Kim MJ, Kim KR, Ro JY, Lage JM, Lee HI (2006) Diagnostic and pathogenetic significance of increased stromal apoptosis and incomplete vasculogenesis in complete hydatidiform moles in very early pregnancy periods. Am J Surg Pathol 30:362–369

    PubMed  CAS  Google Scholar 

  76. Kim JH, Park DC, Bae SN, Namkoong SE, Kim SJ (1998) Subsequent reproductive experience after treatment for gestational trophoblastic disease. Gynecol Oncol 71:108–112

    Article  PubMed  CAS  Google Scholar 

  77. Kodama S, Kase H, Aoki Y, Yahata T, Tanaka K, Motoyama T, Dewa K (1996) Recurrent placental site trophoblastic tumor of the uterus: clinical, pathologic, ultrastructural, and DNA fingerprint study. Gynecol Oncol 60:89–93

    Article  PubMed  CAS  Google Scholar 

  78. Kuo K-T, Chen M-J, Lin M-C (2004) Epithelioid trophoblastic tumor of the broad ligament. Am J Surg Pathol 28:405–409

    Article  PubMed  Google Scholar 

  79. Kurman RJ (1991) The morphology, biology, and pathology of intermediate trophoblast: a look back to the present. Hum Pathol 22:847–855

    Article  PubMed  CAS  Google Scholar 

  80. Kurman RJ, Scully RE, Norris HJ (1976) Trophoblastic pseudotumor of the uterus: an exaggerated form of “syncytial endometritis” simulating a malignant tumor. Cancer 38:1214–1226

    Article  PubMed  CAS  Google Scholar 

  81. Kurman RJ, Young RH, Norris HJ, Main CS, Lawrence WD, Scully RE (1984) Immunocytochemical localization of placental lactogen and chorionic gonadotropin in the normal placenta and trophoblastic tumors, with emphasis on intermediate trophoblast and the placental site trophoblastic tumor. Int J Gynecol Pathol 3:101–121

    Article  PubMed  CAS  Google Scholar 

  82. Lage JM, Mark SD, Roberts DJ, Goldstein DP, Bernstein MR, Berkowitz RS (1992) A flow cytometric study of 137 fresh hydropic placentas: correlation between types of hydatidiform moles and nuclear DNA ploidy. Obstet Gynecol 79:403–410

    Article  PubMed  CAS  Google Scholar 

  83. Lathrop JC, Lauchlan S, Nayak R, Ambler M (1988) Clinical characteristics of placental site trophoblastic tumor (PSTT). Gynecol Oncol 31:32–42

    Article  PubMed  CAS  Google Scholar 

  84. Lee Y, Kim KR, McKeon F, Yang A, Boyd TK, Crum CP, Parast MM (2007) A unifying concept of trophoblastic differentiation and malignancy defined by biomarker expression. Hum Pathol 38:1003–1013

    Article  PubMed  CAS  Google Scholar 

  85. Leiserowitz GS, Webb MJ (1996) Treatment of placental site trophoblastic tumor with hysterotomy and uterine reconstruction. Obstet Gynecol 88:696–699

    Article  PubMed  CAS  Google Scholar 

  86. Lewin SN, Aghajanian C, Moreira AL, Soslow RA (2009) Extrauterine epithelioid trophoblastic tumors presenting as primary lung carcinomas: morphologic and immunohistochemical features to resolve a diagnostic dilemma. Am J Surg Pathol 33:1809–1814

    Article  PubMed  Google Scholar 

  87. Li J, Shi Y, Wan X, Qian H, Zhou C, Chen X (2010) Epithelioid trophoblastic tumor: a clinicopathological and immunohistochemical study of seven cases. Med Oncol (in press)

    Google Scholar 

  88. Li HW, Tsao SW, Cheung AN (2002) Current understandings of the molecular genetics of gestational trophoblastic diseases. Placenta 23:20–31

    Article  PubMed  Google Scholar 

  89. Lipata F, Parkash V, Talmor M, Bell S, Chen S, Maric V, Hui P (2010) Precise DNA genotyping diagnosis of hydatidiform mole. Obstet Gynecol 115:784–794

    Article  PubMed  Google Scholar 

  90. Macdonald MC, Palmer JE, Hancock BW, Tidy JA (2008) Diagnostic challenges in extrauterine epithelioid trophoblastic tumours: a report of two cases. Gynecol Oncol 108:452–454

    Article  PubMed  CAS  Google Scholar 

  91. Machtinger R, Gotlieb WH, Korach J, Fridman E, Apter S, Goldenberg M, Ben-Baruch G (2005) Placental site trophoblastic tumor: outcome of five cases including fertility preserving management. Gynecol Oncol 96:56–61

    Article  PubMed  Google Scholar 

  92. Mao TL, Kurman RJ, Huang CC, Lin MC, Shih I-M (2007) Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis. Am J Surg Pathol 31:1726–1732

    Article  PubMed  Google Scholar 

  93. Mao TL, Kurman RJ, Jeng YM, Huang W, Shih I-M (2008) HSD3B1 as a novel trophoblast-associated marker that assists in the differential diagnosis of trophoblastic tumors and tumorlike lesions. Am J Surg Pathol 32:236–242

    Article  PubMed  Google Scholar 

  94. Mao TL, Seidman JD, Kurman RJ, Shih I-M (2006) Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor–an aid in differential diagnosis. Am J Surg Pathol 30:1105–1110

    Article  PubMed  Google Scholar 

  95. Matsui H, Iizuka Y, Sekiya S (1996) Incidence of invasive mole and choriocarcinoma following partial hydatidiform mole. Int J Gynaecol Obstet 53:63–64

    Article  PubMed  CAS  Google Scholar 

  96. Mazur MT (1989) Metastatic gestational choriocarcinoma. Unusual pathologic variant following therapy. Cancer 63:1370–1377

    Article  PubMed  CAS  Google Scholar 

  97. McConnell TG, Murphy KM, Hafez M, Vang R, Ronnett B (2009) Diagnosis and subclassification of hydatidiform moles using p57 immunohistochemistry and molecular genotyping: validation and prospective analysis in routine and consultation practice settings with development of an algorithmic approach. Am J Surg Pathol 33:805–817

    Article  PubMed  Google Scholar 

  98. McConnell TG, Norris-Kirby A, Hagenkord JM, Ronnett BM, Murphy KM (2009) Complete hydatidiform mole with retained maternal chromosomes 6 and 11. Am J Surg Pathol 33:1409–1415

    Article  PubMed  Google Scholar 

  99. Medeiros F, Callahan MJ, Elvin JA, Dorfman DM, Berkowitz RS, Quade BJ (2008) Intraplacental choriocarcinoma arising in a second trimester placenta with partial hydatidiform mole. Int J Gynecol Pathol 27:247–251

    PubMed  Google Scholar 

  100. Menczer J, Girtler O, Zajdel L, Glezerman M (1999) Metastatic trophoblastic disease following partial hydatidiform mole: case report and literature review. Gynecol Oncol 74:304–307

    Article  PubMed  CAS  Google Scholar 

  101. Meydanli MM, Kucukali T, Usubutun A, Ataoglu O, Kafkasli A (2002) Epithelioid trophoblastic tumor of the endocervix: a case report. Gynecol Oncol 87:219–224

    Article  PubMed  Google Scholar 

  102. Mi S, Lee X, Li X-P, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang X-Y, Edouard P, Howes S et al (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789

    Article  PubMed  CAS  Google Scholar 

  103. Milingos D, Doumplis D, Savage P, Seckl M, Lindsay I, Smith JR (2007) Placental site trophoblastic tumor with an ovarian metastasis. Int J Gynecol Cancer 17:925–927

    Article  PubMed  CAS  Google Scholar 

  104. Montes M, Roberts D, Berkowitz RS, Genest DR (1996) Prevalence and significance of implantation site trophoblastic atypia in hydatidiform moles and spontaneous abortions. Am J Clin Pathol 105:411–416

    PubMed  CAS  Google Scholar 

  105. Moore-Maxwell CA, Robboy SJ (2004) Placental site trophoblastic tumor arising from antecedent molar pregnancy. Gynecol Oncol 92:708–712

    Article  PubMed  Google Scholar 

  106. Morgan JM, Lurain JR (2008) Gestational trophoblastic neoplasia: an update. Curr Oncol Rep 10:497–504

    Article  PubMed  Google Scholar 

  107. Mosher R, Goldstein DP, Berkowitz R, Bernstein M, Genest DR (1998) Complete hydatidiform mole. Comparison of clinicopathologic features, current and past. J Reprod Med 43:21–27

    PubMed  CAS  Google Scholar 

  108. Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B et al (2006) Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet 38:300–302

    Article  PubMed  CAS  Google Scholar 

  109. Nagai Y, Kamoi S, Matsuoka T, Hata A, Jobo T, Ogasawara T, Aoki Y, Ohira S, Okamoto T, Nakamoto T et al (2007) Impact of p53 immunostaining in predicting advanced or recurrent placental site trophoblastic tumors: a study of 12 cases. Gynecol Oncol 106:446–452

    Article  PubMed  CAS  Google Scholar 

  110. Narita F, Takeuchi K, Hamana S, Ohbayashi C, Ayata M, Maruo T (2003) Epithelioid trophoblastic tumor (ETT) initially interpreted as cervical cancer. Int J Gynecol Cancer 13:551–554

    Article  PubMed  CAS  Google Scholar 

  111. Nayar R, Snell J, Silverberg SG, Lage JM (1996) Placental site nodule occurring in a fallopian tube. Hum Pathol 27:1243–1245

    Article  PubMed  CAS  Google Scholar 

  112. Newlands ES, Bower M, Fisher RA, Paradinas FJ (1998) Management of placental site trophoblastic tumors. J Reprod Med 43:53–59

    PubMed  CAS  Google Scholar 

  113. Newlands ES, Mulholland PJ, Holden L, Seckl MJ, Rustin GJ (2000) Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors. J Clin Oncol 18:854–859

    PubMed  CAS  Google Scholar 

  114. Ngan S, Seckl MJ (2007) Gestational trophoblastic neoplasia management: an update. Curr Opin Oncol 19:486–491

    Article  PubMed  Google Scholar 

  115. Niemann I, Hansen ES, Sunde L (2007) The risk of persistent trophoblastic disease after hydatidiform mole classified by morphology and ploidy. Gynecol Oncol 104:411–415

    Article  PubMed  Google Scholar 

  116. Noh HT, Lee KH, Lee MA, Ko YB, Hwang SH, Son SK (2008) Epithelioid trophoblastic tumor of paracervix and parametrium. Int J Gynecol Cancer 18:843–846

    Article  PubMed  CAS  Google Scholar 

  117. Nugent D, Hassadia A, Everard J, Hancock BW, Tidy JA (2006) Postpartum choriocarcinoma presentation, management and survival. J Reprod Med 51:819–824

    PubMed  Google Scholar 

  118. Numnum TM, Kilgore LC, Conner MG, Straughn JM Jr (2006) Fertility sparing therapy in a patient with placental site trophoblastic tumor: a case report. Gynecol Oncol 103:1141–1143

    Article  PubMed  Google Scholar 

  119. Ohira S, Yamazaki T, Hatano H, Harada O, Toki T, Konishi I (2000) Epithelioid trophoblastic tumor metastatic to the vagina: an immunohistochemical and ultrastructural study. Int J Gynecol Pathol 19:381–386

    Article  PubMed  CAS  Google Scholar 

  120. Oldt RJ 3rd, Kurman RJ, Shih I-M (2002) Molecular genetic analysis of placental site trophoblastic tumors and epithelioid trophoblastic tumors confirms their trophoblastic origin. Am J Pathol 161:1033–1037

    Article  PubMed  CAS  Google Scholar 

  121. Olsen JH, Mellemkjaer L, Gridley G, Brinton L, Johansen C, Kjaer SK (1999) Molar pregnancy and risk for cancer in women and their male partners. Am J Obstet Gynecol 181:630–634

    Article  PubMed  CAS  Google Scholar 

  122. Ordi J, Romagosa C, Tavassoli FA, Nogales F, Palacin A, Condom E, Torne A, Cardesa A (2003) CD10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic, and clear cell tumors. Am J Surg Pathol 27:178–186

    Article  PubMed  Google Scholar 

  123. Palmer JR (1994) Advances in the epidemiology of gestational trophoblastic disease. J Reprod Med 39:155–162

    PubMed  CAS  Google Scholar 

  124. Palmer JE, Macdonald M, Wells M, Hancock BW, Tidy JA (2008) Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53:465–475

    PubMed  CAS  Google Scholar 

  125. Papadopoulos AJ, Foskett M, Seckl MJ, McNeish I, Paradinas FJ, Rees H, Newlands ES (2002) Twenty-five years’ clinical experience with placental site trophoblastic tumors. J Reprod Med 47:460–464

    PubMed  Google Scholar 

  126. Parker A, Lee V, Dalrymple C, Valmadre S, Russell P (2003) Epithelioid trophoblastic tumour: report of a case in the fallopian tube. Pathology 35:136–140

    PubMed  CAS  Google Scholar 

  127. Patten DK, Lindsay I, Fisher R, Sebire N, Savage PM, Seckl MJ (2008) Gestational choriocarcinoma mimicking a uterine adenocarcinoma. J Clin Oncol 26:5126–5127

    Article  PubMed  Google Scholar 

  128. Pfeffer PE, Sebire N, Lindsay I, McIndoe A, Lim A, Seckl MJ (2007) Fertility-sparing partial hysterectomy for placental-site trophoblastic tumour. Lancet Oncol 8:744–746

    Article  PubMed  Google Scholar 

  129. Phippen NT, Lowery WJ, Leath CA 3rd, Kost ER (2010) Epithelioid trophoblastic tumor masquerading as invasive squamous cell carcinoma of the cervix after an ectopic pregnancy. Gynecol Oncol 117:387–388

    Article  PubMed  Google Scholar 

  130. Piura B (2006) Placental site trophoblastic tumor–a challenging rare entity. Eur J Gynaecol Oncol 27:545–551

    PubMed  CAS  Google Scholar 

  131. Piura B, Rabinovich A, Meirovitz M, Shaco-Levy R (2007) Placental site trophoblastic tumor: report of four cases and review of literature. Int J Gynecol Cancer 17:258–262

    Article  PubMed  CAS  Google Scholar 

  132. Popiolek DA, Yee H, Mittal K, Chiriboga L, Prinz MK, Caragine TA, Budimlija ZM (2006) Multiplex short tandem repeat DNA analysis confirms the accuracy of p57(KIP2) immunostaining in the diagnosis of complete hydatidiform mole. Hum Pathol 37:1426–1434

    Article  PubMed  CAS  Google Scholar 

  133. Randall TC, Coukos G, Wheeler JE, Rubin SC (2000) Prolonged remission of recurrent, metastatic placental site trophoblastic tumor after chemotherapy. Gynecol Oncol 76:115–117

    Article  PubMed  CAS  Google Scholar 

  134. Redline RW, Hassold T, Zaragoza MV (1998) Prevalence of the partial molar phenotype in triploidy of maternal and paternal origin. Hum Pathol 29:505–511

    Article  PubMed  CAS  Google Scholar 

  135. Reid A, Heyworth J, de Klerk N, Musk AW (2009) Asbestos exposure and gestational trophoblastic disease: a hypothesis. Cancer Epidemiol Biomarkers Prev 18:2895–2898

    Article  PubMed  CAS  Google Scholar 

  136. Rinne K, Shahabi S, Cole L (1999) Following metastatic placental site trophoblastic tumor with urine b-core fragment. Gynecol Oncol 74:302–303

    Article  PubMed  CAS  Google Scholar 

  137. Rodabaugh KJ, Bernstein MR, Goldstein DP, Berkowitz RS (1998) Natural history of postterm choriocarcinoma. J Reprod Med 43:75–80

    PubMed  CAS  Google Scholar 

  138. Rotmensch S, Cole LA (2000) False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 355:712–715

    Article  PubMed  CAS  Google Scholar 

  139. Schmid P, Nagai Y, Agarwal R, Hancock B, Savage PM, Sebire NJ, Lindsay I, Wells M, Fisher RA, Short D et al (2009) Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374:48–55

    Article  PubMed  CAS  Google Scholar 

  140. Seckl MJ, Fisher RA, Salerno G, Rees H, Paradinas FJ, Foskett M, Newlands ES (2000) Choriocarcinoma and partial hydatidiform moles. Lancet 356:36–39

    Article  PubMed  CAS  Google Scholar 

  141. Seki K, Matsui H, Sekiya S (2004) Advances in the clinical laboratory detection of gestational trophoblastic disease. Clin Chim Acta 349:1–13

    Article  PubMed  CAS  Google Scholar 

  142. Sharkey AM, King A, Clark DE, Burrows TD, Loke YW (1999) Localization of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy. Biol Reprod 60:355–364

    Article  PubMed  CAS  Google Scholar 

  143. Shih I-M (1999) The role of CD146 (Mel-CAM) in biology and pathology. J Pathol 189:4–11

    Article  PubMed  CAS  Google Scholar 

  144. Shih I-M (2007) Trophogram, an immunohistochemistry-based algorithmic approach, in the differential diagnosis of trophoblastic tumors and tumorlike lesions. Ann Diagn Pathol 11:228–234

    Article  PubMed  Google Scholar 

  145. Shih I-M (2007) Gestational trophoblastic neoplasia—pathogenesis and potential therapeutic targets. Lancet Oncol 8:642–650

    Article  PubMed  CAS  Google Scholar 

  146. Shih I-M (2009) Gestational trophoblastic lesions. In: Nucci MR, Oliva E (eds) Gynecologic pathology. Churchill Livingstone Elsevier, London, pp 645–665

    Chapter  Google Scholar 

  147. Shih I-M, Hsu MY, Oldt RJ, Herlyn M, Gearhart JD, Kurman RJ (2002) The role of E-cadherin in the motility and invasion of implantation site intermediate trophoblast. Placenta 23:706–715

    PubMed  CAS  Google Scholar 

  148. Shih I-M, Kuo KT (2008) Power of the eternal youth: Nanog expression in the gestational choriocarcinoma. Am J Pathol 173:911–914

    Article  PubMed  CAS  Google Scholar 

  149. Shih I-M, Kurman RJ (1996) Expression of melanoma cell adhesion molecule in intermediate trophoblast. Lab Invest 75:377–388

    PubMed  CAS  Google Scholar 

  150. Shih I-M, Kurman RJ (1998) Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 22:1393–1403

    Article  PubMed  CAS  Google Scholar 

  151. Shih I-M, Kurman RJ (1998) Ki-67 labeling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma: a double immunohistochemical staining technique using Ki-67 and Mel-CAM antibodies. Hum Pathol 29:27–33

    Article  PubMed  CAS  Google Scholar 

  152. Shih I-M, Kurman RJ (1999) Immunohistochemical localization of inhibin-alpha in the placenta and gestational trophoblastic lesions. Int J Gynecol Pathol 18:144–150

    Article  PubMed  CAS  Google Scholar 

  153. Shih I-M, Kurman RJ (2001) The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 20:31–47

    Article  PubMed  CAS  Google Scholar 

  154. Shih I-M, Kurman RJ (2001) Placental site trophoblastic tumor–past as prologue. Gynecol Oncol 82:413–414

    Article  PubMed  CAS  Google Scholar 

  155. Shih I-M, Kurman RJ (2002) Molecular basis of gestational trophoblastic diseases. Curr Mol Med 2:1–12

    Article  PubMed  CAS  Google Scholar 

  156. Shih I-M, Kurman RJ (2004) p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations. Am J Surg Pathol 28:1177–1183

    Article  PubMed  Google Scholar 

  157. Shih I-M, Schnaar RL, Gearhart JD, Kurman RJ (1997) Distribution of cells bearing the HNK-1 epitope in the human placenta. Placenta 18:667–674

    Article  PubMed  CAS  Google Scholar 

  158. Shih I-M, Seidman JD, Kurman RJ (1999) Placental site nodule and characterization of distinctive types of intermediate trophoblast. Hum Pathol 30:687–694

    Article  PubMed  CAS  Google Scholar 

  159. Silva EG, Tornos C, Lage J, Ordonez NG, Morris M, Kavanagh J (1993) Multiple nodules of intermediate trophoblast following hydatidiform moles. Int J Gynecol Pathol 12:324–332

    Article  PubMed  CAS  Google Scholar 

  160. Singer G, Kurman RJ, McMaster M, Shih I-M (2002) HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Am J Surg Pathol 26(7):914–920

    Article  PubMed  Google Scholar 

  161. Siu MKY, Wong ESY, Chan H-Y, Ngan HYS, Chan KYK, Cheung ANY (2008) Overexpression of Nanog in gestational trophoblastic diseases. Effect on apoptosis, cell invasion and clinical outcome. Am J Pathol 173:1165–1172

    Article  PubMed  CAS  Google Scholar 

  162. Slim R, Mehio A (2007) The genetics of hydatidiform moles: new lights on an ancient disease. Clin Genet 71:25–34

    Article  PubMed  CAS  Google Scholar 

  163. Soper JT (2006) Gestational trophoblastic disease. Obstet Gynecol 108:176–187

    Article  PubMed  Google Scholar 

  164. Su YN, Cheng WF, Chen CA, Lin TY, Hsieh FJ, Cheng SP, Hsieh CY (1999) Pregnancy with primary tubal placental site trophoblastic tumor–A case report and literature review. Gynecol Oncol 73:322–325

    Article  PubMed  CAS  Google Scholar 

  165. Suzuki T, Goto S, Nawa A, Kurauchi O, Saito M, Tomoda Y (1993) Identification of the pregnancy responsible for gestational trophoblastic disease by DNA analysis. Obstet Gynecol 82:629–634

    PubMed  CAS  Google Scholar 

  166. Swisher E, Drescher CW (1998) Metastatic placental site trophoblastic tumor: long-term remission in a patient treated with EMA/CO chemotherapy. Gynecol Oncol 68:62–65

    Article  PubMed  CAS  Google Scholar 

  167. Szulman AE, Surti U (1982) The clinicopathologic profile of the partial hydatidiform mole. Obstet Gynecol 59:597–602

    PubMed  CAS  Google Scholar 

  168. Tavassoli FA, Devilee P (2003) WHO classification of tumors. In: Pathology and genetics tumors of the breast and female genital organs, IARC Press, Lyon, pp 113–161

    Google Scholar 

  169. Trask C, Lage JM, Roberts DJ (1994) A second case of “chorangiocarcinoma” presenting in a term asymptomatic twin pregnancy: choriocarcinoma in situ with associated villous vascular proliferation. Int J Gynecol Pathol 13:87–91

    Article  PubMed  CAS  Google Scholar 

  170. Tsai HW, Lin CP, Chou CY, Li CF, Chow NH, Shih I-M, Ho CL (2008) Placental site nodule transformed into a malignant epithelioid trophoblastic tumour with pelvic lymph node and lung metastasis. Histopathology 53:601–604

    PubMed  Google Scholar 

  171. Twiggs LB, Hartenbach E, Saltzman AK, King LA (1998) Metastatic placental site trophoblastic tumor. Int J Gynaecol Obstet 60(Suppl 1):S51–S55

    Article  PubMed  Google Scholar 

  172. Ueda SM, Mao TL, Kuhajda FP, Vasoontara C, Giuntoli RL, Bristow RE, Kurman RJ, Shih Ie M (2009) Trophoblastic neoplasms express fatty acid synthase, which may be a therapeutic target via its inhibitor C93. Am J Pathol 175:2618–2624

    Article  PubMed  CAS  Google Scholar 

  173. Urabe S, Fujiwara H, Miyoshi H, Arihiro K, Soma H, Yoshihama I, Mineo S, Kudo Y (2007) Epithelioid trophoblastic tumor of the lung. J Obstet Gynaecol Res 33:397–401

    Article  PubMed  Google Scholar 

  174. Vencken PM, Ewing PC, Zweemer RP (2006) Epithelioid trophoblastic tumour: a case report and review of the literature. J Clin Pathol 59:1307–1308

    Article  PubMed  CAS  Google Scholar 

  175. Wells M (2007) The pathology of gestational trophoblastic disease: recent advances. Pathology 39:88–96

    Article  PubMed  Google Scholar 

  176. Xu ML, Yang B, Carcangiu ML, Hui P (2009) Epithelioid trophoblastic tumor: comparative genomic hybridization and diagnostic DNA genotyping. Mod Pathol 22:232–238

    Article  PubMed  CAS  Google Scholar 

  177. Xue WC, Guan XY, Ngan HY, Shen DH, Khoo US, Cheung AN (2002) Malignant placental site trophoblastic tumor: a cytogenetic study using comparative genomic hybridization and chromosome in situ hybridization. Cancer 94:2288–2294

    Article  PubMed  Google Scholar 

  178. Yap KL, Hafez MJ, Mao TL, Kurman RJ, Murphy KM, Shih Ie M (2010) Lack of a y-chromosomal complement in the majority of gestational trophoblastic neoplasms. J Oncol 2010:364508

    Article  PubMed  CAS  Google Scholar 

  179. Young RH, Kurman RJ, Scully RE (1990) Placental site nodules and plaques. A clinicopathologic analysis of 20 cases. Am J Surg Pathol 14:1001–1009

    Article  PubMed  CAS  Google Scholar 

  180. Young RH, Scully RE (1984) Placental-site trophoblastic tumor: current status. Clin Obstet Gynecol 27:248–258

    Article  PubMed  CAS  Google Scholar 

  181. Young RH, Scully RE, McCluskey RT (1985) A distinctive glomerular lesion complicating placental site trophoblastic tumor: report of two cases. Hum Pathol 16:35–42

    Article  PubMed  CAS  Google Scholar 

  182. Yuan CC, Wang PH, Ng HT (1999) High hCG level is a risk factor for predicting the occurrence of brain and/or liver metastases from gestational choriocarcinoma. Int J Gynaecol Obstet 65:67–69

    Article  PubMed  CAS  Google Scholar 

  183. Zalel Y, Dgani R (1997) Gestational trophoblastic disease following the evacuation of partial hydatidiform mole: a review of 66 cases. Eur J Obstet Gynecol Reprod Biol 71:67–71

    Article  PubMed  CAS  Google Scholar 

  184. Zanetta G, Maggi R, Colombo M, Bratina G, Mangioni C (1997) Choriocarcinoma coexistent with intrauterine pregnancy: two additional cases and a review of the literature. Int J Gynecol Cancer 7:66–77

    Article  PubMed  CAS  Google Scholar 

  185. Zhang H-J, Xue W-C, Siu M, Liao X-Y, Ngan HY-S, Cheung AN-Y (2009) P63 expression in gestational trophoblastic disease: correlation with proliferation and apoptotic dynamics. Int J Gynecol Pathol 28:172–178

    Article  PubMed  Google Scholar 

  186. Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Kdjana E, Wheelock M, Damsky CH (1997) Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion? J Clin Invest 99:2139–2151

    Article  PubMed  CAS  Google Scholar 

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Shih, IM., Mazur, M.T., Kurman, R.J. (2011). Gestational Trophoblastic Tumors and Related Tumor-Like Lesions. In: Kurman, R.J., Ellenson, L.H., Ronnett, B.M. (eds) Blaustein’s Pathology of the Female Genital Tract. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0489-8_20

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