Complete Hydatidiform Mole

Synonyms: Hydatidiform Mole

Complete mole showing large villi with stromal edema and marked trophoblastic proliferation.

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Definition

Genetically abnormal placenta with hyperplastic trophoblast, without fetus or embryo.

Clinical Features

Incidence:
- 1 in 2000 deliveries for young healthy women in United States:1
  - at least four to five times greater in South-east Asia2,3
- 1 in 200 deliveries in Mexico
- 1 in 173 deliveries in Philippines
- 1 in 160 deliveries in India
- 1 in 125 deliveries in Taiwan
- 1 in 82 deliveries in Indonesia 4
Tend to be >30 years of age
Likely to have diet deficient in vitamin A precursors:
- may explain some geographic differences5
Risk:
- reduced by:
  - increased consumption of carotene
  - history of previous term birth
- greatly increased by:
  - history of a previous mole:3,6,7
    - ‘repetitive’ moles usually complete type 8
Uterus disproportionately large for stage of pregnancy9
Serum hCG levels continue to rise after 14th week:
- as opposed to drop of normal gestation
Frequently evidence of toxemia of pregnancy during early stages of the pregnancy, i.e.:
- hypertension
- edema
- albuminuria
Exceptionally hyperthyroidism:
- as a result of a thyroid stimulator secreted by the molar tissue, perhaps in hCG molecule itself10–12
May be vaginal bleeding:
- a sign that the mole has begun to abort spontaneously

Pathogenesis

Caused by abnormal gametogenesis and fertilization
Trophoblastic cells:
- all cytoplasmic DNA is maternally derived 13,14
Usually normal chromosomal number:
- 85% 46, XX
- 15% 46, XY
Hypothesized that:
- supported by genetic analysis of molar mitochondrial DNA 15
In a minority, DNA pattern is tetraploid:
- generally in an older age group16

Gross Pathology

Typically described as a ‘bunch of grapes', with all or nearly all villi showing hydropic degeneration
Individual vesicles 1–30∼mm diameter
Total weight usually >200 g
In a hysterectomy specimen swollen villi fill and distend the uterus
Characteristically no identifiable:
- embryo
- cord
- amniotic membranes
Exceptionally an embryo is present:
- almost invariably represents a twin gestation17,18

Histopathology

Two constant features:
- Severity:
  - may be difficult to appreciate in very early cases 19
- Sometimes:
  - villi are surrounded by an attenuated layer of degenerating trophoblast
  - trophoblast forms large hyperplastic sheets of cells (Fig. 1
    Fig. 1: Complete mole showing large villi with stromal edema and marked trophoblastic proliferation.
    )
- Distended core of the villus is traversed by widely separated broken strands of fibrillar material (‘cistern’ formation)
- Vessels:
  - seem absent or scanty in hematoxylin–eosin-stained sections even if they do not seem very diminished in number in CD34-stained preparations20
Trophoblastic hyperplasia:
- characteristically a circumferential but haphazard arrangement around the individual villi:
  - as opposed to polar proliferation in normal first-trimester villi
- also with atypia at the implantation site:
  - to much greater degree than in hydropic villi of abortion or partial moles21
Ultrastructurally
- molar trophoblast closely resembles that seen during first trimester of a normal pregnancy22

Special Stains and Immunohistochemistry

hCG:
- widely distributed
PLAP:
- patchily distributed in molar syncytiotrophoblast regardless of gestational age
hPL:
- tends to increase with increased gestational age23,24
α and β subunits of inhibin:
- in molar syncytiotrophoblast 25,26
p57kip2 protein:
- absent or markedly decreased in complete moles, even during early development 27–30
p53:
- intensity of staining in complete mole is therefore:
  - lower than in choriocarcinoma 31
- some staining also in:
  - normal trophoblast of early pregnancy
  - hydropic villi of spontaneous abortion32,33
Also expressed:
- myc, ras, and sis oncogenes
- epidermal growth factor

Other Investigations

Highly sensitive techniques for monitoring serum hCG levels 34,35

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Complete Hydatidiform Mole

Plexiform pattern of intermixed syncytiotrophoblast and cytotrophoblast of choriocarcinoma does not occur

Genetics

50% diploid
43% tetraploid
3.6% polyploid
1.7% triploid36,37

Management

Evacuation of uterus by curettage:38
- initial therapy
Sequential quantitative determination by radioimmunoassay of the β-subunit of hCG:39,40
- standard recommendation is to measure serum hCG 10, 20, 30, 45, and 60 days after termination
- in ≈80% of cases normal levels by day 60
Chemotherapy:
- necessary in ≈20% of cases 41
- said to respond very well to chemotherapy if:
  - interposition of fibrin-like material at tumor–host interphase
  - abundant syncytiotrophoblast34
- said to be relatively resistant to chemotherapy if:
  - compact growth of cytotrophoblast with little differentiation
- etoposide is associated with increased risk of second tumors42
- some recommend administration if a plateau of three high values of hCG over a 2-week period after evacuation (≈20–30% of cases)
- others recommend waiting for 4 weeks or even 2 months before initiating chemotherapy, especially if hCG levels are low43
- presence of villi or atypical trophoblast following evacuation indicates ‘persistent trophoblastic disease', but decision whether to give chemotherapy or not largely depends on hCG levels

Prognosis

With appropriate therapy cure rate ≈100%44
Claimed that the more pronounced the trophoblastic hyperplasia, the higher the risk of choriocarcinoma:
- many exceptions45
Of 738 patients:
- spontaneous regression in 81%
- 17% developed an invasive mole
- 2% developed choriocarcinoma46
Heterozygous (dispermic) moles including dispermic heterozygous XY moles associated with a higher incidence of persistent trophoblastic disease than homozygous (monospermic) moles
Proliferation index and DNA ploidy not statistically associated with outcome36

References

1 Hertig AT. Hydatidiform mole and chorionepithelioma. Meigs JV, Sturgis SH editor. Progress in gynecology. New York: Grune & Stratton; 1950.

2 Hsu CT, Chen TY, Chiu WH, Yang C-C, Lai C-H, Chancheng C-H, et al. Some aspects of trophoblastic diseases peculiar to Taiwan. Am J Obstet Gynecol. 1964;90:308–316.

3 Joint Project for Study of Choriocarcinoma and Hydatidiform Mole in Asia. Geographic variation in the occurrence of hydatidiform mole and choriocarcinoma. Ann NY Acad Sci. 1959;80:178–195.

4 Park WW. Choriocarcinoma. A study of its pathology. Philadelphia: F.A. Davis; 1971;.

5 Berkowitz RS. Recent advances in the biology and treatment of gestational trophoblastic diseases and germ cell tumors. Curr Opin Oncol. 1990;2:901–905.

6 Sand PK, Lurain JR, Brewer JI. Repeat gestational trophoblastic disease. Obstet Gynecol. 1984;63:140–144.

7 Shapter AP, McLellan R. Gestational trophoblastic disease. Obstet Gynecol Clin North Am. 2001;28:805–817.

8 Rice LW, Lage JM, Berkowitz RS, Goldstein DP, Bernstein MR. Repetitive complete and partial hydatidiform mole. Obstet Gynecol. 1989;74:217–219.

9 Atrash HK, Hogue CJR, Grimes DA. Epidemiology of hydatidiform mole during early gestation. Am J Obstet Gynecol. 1986;154:906–909.

10 Cave WT, Dunn JT. Choriocarcinoma with hyperthyroidism. Probable identity of the thyrotropin with human chorionic gonadotropin. Ann Intern Med. 1976;85:60–63.

11 Hershman JM, Higgins HP. Hydatidiform mole – a cause of clinical hyperthyroidism. Report of two cases with evidence that the molar tissue secreted a thyroid stimulator. N Engl J Med. 1971;284:573–577.

12 Narasimhan KL, Ghobrial MW, Ruby EB. Hyperthyroidism in the setting of gestational trophoblastic disease. Am J Med Sci. 2002;323:285–287.

13 Fulop V, Mok SC, Gati I, Berkowitz RS. Recent advances in molecular biology of gestational trophoblastic diseases. A review. J Reprod Med. 2002;47:369–379.

14 Kajii T, Ohama K. Androgenetic origin of hydatidiform mole. Nature. 1977;268:633–634.

15 Azuma C, Saji F, Tokugawa Y, Kimura T, Nobunaga T, Takemura M, et al. Application of gene amplification by polymerase chain reaction to genetic analysis of molar mitochondrial DNA. The detection of anuclear empty ovum as the cause of complete mole. Gynecol Oncol. 1991;40:29–33.

16 Bewtra C, Frankforter S, Marcus JN. Clinicopathologic differences between diploid and tetraploid complete hydatidiform moles. Int J Gynecol Pathol. 1998;16:239–244.

17 Baergen RN, Kelly T, McGinnis MJ, Jones OW, Benirschke K. Complete hydatidiform mole with a coexistent embryo. Hum Pathol. 1996;27:731–734.

18 Van de Kaa CA, Robben JC, Hopman AH, Hanselaar AG, Vooijs GP. Complete hydatidiform mole in twin pregnancy. Differentiation from partial mole with interphase cytogenetic and DNA cytometric analyses on paraffin embedded tissues. Histopathology. 1995;26:123–129.

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20 Qiao S, Nagasaka T, Nakashima N. Numerous vessels detected by CD34 in the villous stroma of complete hydatidiform moles. Int J Gynecol Pathol. 1998;16:233–238.

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

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23 Brescia RJ, Kurman RJ, Main CS, Surti U, Szulman AE. Immunocytochemical localization of chorionic gonadotropin, placental lactogen, and placental alkaline phosphatase in the diagnosis of complete and partial hydatidiform moles. Int J Gynecol Pathol. 1987;6:213–229.

24 Fukunaga M, Miyazawa Y, Sugishita M, Ushigome S. Immunohistochemistry of molar and non-molar placentas with special reference to their differential diagnosis. Acta Pathol Jpn. 1993;43:683–689.

25 Kommoss F, Schmidt D, Coerdt W, Olert J, Muntefering H. Immunohistochemical expression analysis of inhibin-alpha and -beta subunits in partial and complete moles, trophoblastic tumors, and endometrial decidua. Int J Gynecol Pathol. 2001;20:380–385.

26 Pelkey TJ, Frierson HF, Mills SE, Stoler MH. Detection of the alpha-subunit of inhibin in trophoblastic neoplasia. Hum Pathol. 1999;30:26–31.

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

28 Crisp H, Burton JL, Stewart R, Wells M. Refining the diagnosis of hydatidiform mole: image ploidy analysis and p57KIP2 immunohistochemistry. Histopathology. 2003;43:363–373.

29 Fukunaga M. Immunohistochemical characterization of p57KIP2 expression in early hydatidiform moles. Hum Pathol. 2003;33:1188–1192.

30 Jun S-Y, Ro JY, Kim K-R. P57KIP2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles. Histopathology. 2003;43:17–25.

31 Lee Y-S. p53 expression in gestational trophoblastic disease. Int J Gynecol Pathol. 1995;14:119–124.

32 Cheville JC, Robinson RA, Benda JA. P53 expression in placentas with hydropic change and hydatidiform moles. Mod Pathol. 1996;9:392–396.

33 Yasuda M, Kawai K, Serizawa A, Tang X, Osamura Y. Immunohistochemical analysis of expression of p53 protein in normal placentas and trophoblastic diseases. Appl Immunohistochem. 1995;3:132–136.

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35 Genest DR, Laborde O, Berkowitz RS, Goldstein DP, Bernstein MR, Lage J. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980–1990). Histologic grade lacks prognostic significance. Obstet Gynecol. 1991;78:402–409.

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

37 Lage JM, Popek EJ. The role of DNA flow cytometry in evaluation of partial and complete hydatidiform moles and hydropic abortions. Semin Diagn Pathol. 1993;10:267–274.

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41 Lewis JL. Diagnosis and management of gestational trophoblastic disease. Cancer. 1993;71:1639–1647.

42 Schorge JO, Goldstein DP, Bernstrein MR, Berkowitz RS. Recent advances in gestational trophoblastic disease. J Reprod Med. 2000;45:692–700.

43 Kohorn EI. Criteria toward the definition of nonmetastatic gestational trophoblastic disease after hydatidiform mole. Am J Obstet Gynecol. 1982;142:416–419.

44 Hancock BW, Tidy JA. Current management of molar pregnancy. J Reprod Med. 2002;47:347–354.

45 Jeffers MD, Richmond JA, Smith R. Trophoblast proliferation rate does not predict progression to persistent gestational trophoblastic disease in complete hydatidiform mole. Int J Gynecol Pathol. 1996;15:34–38.

46 Lurain JR, Brewer JI, Torok EE, Halpern B. Natural history of hydatidiform mole after primary evacuation. Am J Obstet Gynecol. 1983;145:591–595.

Last updated: 8 Mar 2006