Human Pathology (2013) 44, 2861–2864

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Case study

Ovarian complete hydatidiform mole: case study with molecular analysis and review of the literature☆,☆☆ Jennifer K. Sehn MD a,⁎, Lindsay M. Kuroki MD b , Margaret M. Hopeman MD b , Ryan E. Longman MD b , Colleen P. McNicholas DO b , Phyllis C. Huettner MD a a

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, 63110, USA

b

Received 30 May 2013; revised 7 June 2013; accepted 19 July 2013

Keywords: Ectopic pregnancy; Complete mole; Hydatidiform mole; Ovary; STR

Summary Ectopic complete molar pregnancy in the ovary is an exceptionally rare event. Here we present a case of ovarian complete hydatidiform mole in a 20-year-old gravida 2 para 1 woman. At presentation, the patient underwent excision of a hemorrhagic left ovarian cyst, with routine sections demonstrating a hemorrhagic corpus luteum with a single microscopic focus of detached atypical trophoblast, without chorionic villi. Subsequent left salpingo-oophorectomy for persistently elevated human chorionic gonadotropin led to a final diagnosis of complete hydatidiform mole arising in the ovary. The fallopian tube was unremarkable. Zygosity was determined using short tandem repeat analysis, confirming the diagnosis of monospermic complete mole. In the clinical setting of a markedly elevated human chorionic gonadotropin level and an ovarian mass, histopathologic examination is critical in distinguishing ectopic pregnancy from choriocarcinoma. Short tandem repeat analysis can be a useful adjunct to histologic diagnosis in challenging cases. © 2013 Elsevier Inc. All rights reserved.

1. Introduction The incidence of molar ectopic pregnancy is estimated to be 1.5 per 1,000,000 births [1]. Complete mole occurring in an ovarian ectopic pregnancy is vanishingly rare, with an estimated incidence of 1 in 50 million pregnancies, represented by only 13 cases reported in the literature since 1925 [1-13]. Complete molar pregnancy arises from fertilization of

an empty ovum by 2 sperm (dispermic 46XY, 10% of all complete molar pregnancies) or by a single sperm followed by duplication of the haploid paternal complement (monospermic 46XX, 90% of complete moles). Approximately 20% of patients with complete mole require chemotherapy for persistently elevated serum human chorionic gonadotropin (hCG) levels after removal of the molar tissue, and 2% to 3% of patients develop gestational choriocarcinoma [14]. Here we report a case of ovarian ectopic complete mole with molecular analysis and review of the literature.



Conflicts of interest: The authors have no conflicts of interest to declare. Sources of support: Funding for molecular analysis of this case came from the Department of Pathology and Immunology of Washington University in St. Louis, St. Louis, MO. ⁎ Corresponding author. Washington University School of Medicine, Department of Pathology and Immunology, Campus Box 8118. E-mail address: [email protected] (J. K. Sehn). ☆☆

0046-8177/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.humpath.2013.07.027

2. Clinical history and pathology A 20-year-old gravida 2 para 1 woman presented to the emergency department with a 7-day history of heavy vaginal

2862 bleeding and abdominal pain. Her hCG level was markedly elevated at 100, 355 mIU/mL. Transvaginal ultrasonography demonstrated a 3.0 × 2.7 × 2.2–cm complex left adnexal mass, with free fluid in the pelvis. No intrauterine pregnancy was identified. The patient underwent diagnostic laparoscopy with excision of a hemorrhagic cystic mass that was adherent to the left ovary and pelvic sidewall. The specimen was submitted entirely for histologic examination, which showed a single microscopic focus of atypical trophoblast along with a hemorrhagic corpus luteum. No other benign or malignant germ cell elements were identified. Choriocarcinoma could not be ruled out because of trophoblast atypia and the absence of chorionic villi. After discharge, the patient again presented on postoperative day 11 with persistent vaginal bleeding and abdominal pain. The serum hCG level at this time was elevated above the preoperative level, at 100, 680. Transvaginal ultrasonography showed enlargement of the complex adnexal mass, with no evidence of a gestational sac. Subsequently, the patient underwent laparoscopic left salpingo-oophorectomy. Gross examination of the specimen showed an unremarkable fallopian tube and a 5.5 × 4.1 × 2.5–cm aggregate of hemorrhagic, fragmented ovary with a prominent corpus luteum. Intraoperative frozen sections showed atypical trophoblast with no chorionic villi. Routine histologic sections showed an ectopic complete hydatidiform mole of the left ovary, with markedly enlarged, irregular villi with central cisterns, surrounded by abundant, circumferential atypical trophoblast proliferation (Fig. 1). The patient was followed with serial measurement of quantitative serum hCG levels until undetectable.

J. K. Sehn et al. DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA) according to the manufacturer’s instructions, including optional RNAse treatment. DNA extracts were assessed for purity and quality using a spectrophotometer (NanoDrop, Wilmington, DE), fluorometer (Qubit, Grand Island, NY), and gel electrophoresis. Short tandem repeat (STR) microsatellite analysis was performed on 0.5 ng of input DNA following the protocol for the PowerPlex 16 HS assay kit (Promega, Madison, WI). Briefly, 15 STR loci and the amelogenin locus (used for sex determination) were amplified by multiplex polymerase chain reaction with fluorescent labeling. Capillary electrophoresis analysis was performed with an Applied Biosystems 3730xl DNA Analyzer using GeneMapper 4.0 software (Applied Biosystems, Grand Island, NY), followed by manual review of the STR peaks.

4. Results The ovary and products of conception showed differential allelic profiles at 14 of 16 evaluated loci, with no evidence of aneuploidy in the molar tissue (Fig. 2). Only 1 allele was present for each locus in the molar tissue. Two loci were uninformative, meaning that the single allele present in the molar tissue was also present in the ovarian tissue (ie, the mother and the father carry the same allele), including the X chromosome at the amelogenin locus. These STR findings confirm the diagnosis of a monospermic complete hydatidiform mole, showing duplication of a single set of paternally derived alleles with absence of a maternal genetic contribution.

3. Materials and methods Ovarian tissue was macrodissected from 5 unstained formalin-fixed, paraffin-embedded, 5-μm tissue sections. Molar trophoblast and villi were macrodissected from 20 unstained formalin-fixed, paraffin-embedded, 5-μm sections. DNA was extracted from both samples using the QIAamp

5. Discussion Ectopic complete mole of the ovary is vanishingly rare, with our case being only the 14th reported since 1925. Previous reports occurred in 25- to 46-year-old women,

Fig. 1 Microscopic findings. A, Histologic sections of the left ovary show massive, edematous villi with central cisterns (arrow) and circumferential trophoblast proliferation. B, Trophoblast shows marked atypia. C, A large corpus luteum (arrow) is seen in the ovarian parenchyma adjacent to atypical trophoblast (asterisk), which is highlighted in the inset.

Ovarian complete hydatidiform mole

2863

Fig. 2 Representative peaks from STR analysis. The molar tissue shows a single peak present at each of the evaluated loci, representing 1 allele at each locus (top row). At 14 of the 16 loci, the allele that was present in the molar tissue was different from the possible maternally derived alleles seen in the ovarian tissue (bottom row). One allele was shared between the father and the mother (asterisk). These findings indicate the duplication of a single paternally derived genetic complement, diagnostic of a monospermic complete hydatidiform mole.

villous edema and, as such, are often misdiagnosed as molar pregnancies; the presence of circumferential (ie, nonpolar) proliferation of definitively atypical trophoblast surrounding diffusely edematous villi differentiates a molar pregnancy from an early ectopic gestation [15]. In addition, the presence of villi virtually excludes a diagnosis of gestational choriocarcinoma, except in the case of intraplacental choriocarcinoma arising in term placentas. Still, histologic diagnosis of ectopic molar gestations is not straightforward; the histologic diagnosis of ectopic molar pregnancy was confirmed by expert review in only 6% cases referred to the United Kingdom Trophoblastic Disease Center [15]. Furthermore, gestational choriocarcinoma may

including primigravidas and multigravidas. Patients typically presented in the first trimester with abdominal pain, nausea, and vomiting. When available, reported serum hCG levels were elevated. Adnexal masses ranged from 4 to 20 cm at the time of initial presentation and usually occurred on the right side (Table) [1-15]. Only 1 patient had a documented history of a prior ectopic pregnancy or pelvic surgery [5]. Our case represents the first ectopic complete mole of the ovary to be confirmed with molecular analysis by STRs, demonstrating a monospermic complete hydatidiform mole. Microscopically, early ectopic gestations, as compared with early intrauterine gestations, characteristically show exaggerated extravillous trophoblastic proliferation and patchy

Table

Clinical characteristics of reported cases of complete mole in the ovary

Reference

Patient age (y)

Prior gestations

Gestational age

Side

Size (cm)

[1] [2]

46 29

3

[3]

33

3

[4] [5]

29

2

6 wk

R L

[6] [7] [8] [9] [10]

24

0

15 wk

R

16

27 38 35

0 5a

12 wk 1st trimester

L R R

14 4

[11]

25

0

8 wk

R

6

[12]

25

0

6 wk

R

10

[13]

25

2

3 mo

R

20

R

8 wk

Abbreviations: R, right; L, left. a Patient had a concurrent intrauterine hydatidiform mole.

R

10

4.4

Presenting symptoms

Presenting hCG (IU/L)

Hemoperitoneum Abdominal pain, nausea, vomiting Right lower quadrant pain, nausea, vomiting

86, 000

Abdominal pain, vomiting, dysuria Right lower quadrant pain

3584

Weight loss, nausea, vomiting Vaginal bleeding Abdominal pain, vaginal bleeding Right lower quadrant pain, nausea, vomiting, breast tenderness Right lower quadrant pain, vaginal bleeding Abdominal enlargement, abdominal and back pain, nausea, vomiting

Prior ectopic No

No

Yes, left

44, 000

No

165, 000 54, 000

No No

No No

2864 subsequently arise from partial or complete molar pregnancies. In fact, Joneborg et al [1] described a case of gestational choriocarcinoma arising from an inadequately treated ectopic complete mole of the ovary, presenting with metastases to the lung and vagina. The differential diagnosis of atypical trophoblast in the ovary also includes nongestational (ie, germ cell) choriocarcinoma. However, the absence of other benign or malignant germ cell elements virtually excludes a nongestational choriocarcinoma; pure choriocarcinoma is an exceedingly rare form of germ cell tumor in the ovary. The clinical course of our patient emphasizes the importance of adequate tissue sampling when specimens are submitted for intraoperative frozen section consultations, where the pathologist has the opportunity to convey the adequacy of the collected specimen to the surgeon while the surgeon is able to obtain additional tissue. In the absence of villi, it is unclear whether clusters of atypical trophoblast represent the proliferative cells of a molar gestation or malignant cells in a choriocarcinoma. In addition, Leung et al [9] emphasized that the presence of an intrauterine pregnancy does not exclude the possibility of a synchronous ectopic pregnancy by describing the dramatic case of an ovarian hydatidiform mole that was coexistent with an intrauterine hydatidiform mole. Complete molar pregnancy, even when complicated by development of choriocarcinoma, fortunately has an excellent prognosis with surgical and/or medical intervention and close clinical follow-up of the serum hCG. In fact, all patients reported to date have been free of disease at the time of report. However, appropriate clinical management and counseling regarding future pregnancies are contingent upon arriving at the correct pathologic diagnosis. In the setting of histologically ambiguous or uncertain cases, STR analysis is a robust and reliable method of definitively differentiating complete molar pregnancies occurring in any site from other diagnoses in the differential, including early ectopic nonmolar gestations or nongestational choriocarcinoma.

J. K. Sehn et al.

Acknowledgment We thank Jennifer Stratman, Dorie Sherr, and the Genome Technology Access Center of the Washington University School of Medicine for DNA extraction and microsatellite testing.

References [1] Joneborg U, et al. Choriocarcinoma following ovarian hydatidiform mole: a case report. J Reprod Med 2011;56:511-4. [2] Adli AG. Primary ovarian hydatidiform mole. Int Surg 1978;63:103. [3] Barr FG, Oktay A. Primary ovarian hydatidiform mole: a case report. Am J Obstet Gynecol 1960;79:1088-90. [4] Bennett H. In: Novak E, editor. Gynecologic and obstetric pathology. 3rd ed. Philadelphia: WB Saunders Co; 1953. [5] Church E, et al. Ovarian molar pregnancy. J Obstet Gynaecol 2008;28: 660-1. [6] D'Aguillo AF, et al. Primary ovarian hydatidiform mole. HUM PATHOL 1982;13:279-81. [7] Fraser S. In: Novak E. Gynecologic and obstetric pathology. 3rd ed. Philadelphia: WB Saunders Co.; 1953. [8] Jock DE, Schwartz PE, Portnoy L. Primary ovarian hydatidiform mole: addition of a sixth case to the literature. Obstet Gynecol 1981;58:657-60. [9] Leung F, Terzibachian JJ, Lassabe C. One mole may hide another: the case of an ovarian hydatidiform mole coexistent with intrauterine hydatidiform mole. Eur J Obstet Gynecol Reprod Biol 2010;148:98-9. [10] Moller P, Als-Nielsen A. Cas de mole hydatideuse ovarienne. Acta Obstetricia et Gynecologica Scandinavica 1925;3:325. [11] Stanhope CR, Stuart GC, Curtis KL. Primary ovarian hydatidiform mole: review of the literature and report of a case. Am J Obstet Gynecol 1983;145:886-8. [12] Switzer JM, et al. Ovarian hydatidiform mole. J Ultrasound Med 1984;3:471-3. [13] Yenen E, Inanc FA, Babuna C. Primary ovarian hydatidiform mole. Report of a case. Obstet Gynecol 1965;26:721-4. [14] Mazur MT, Kurman RJ, Diagnosis of endometrial biopsies and curettings: a practical approach. 1995, New York: Springer-Verlag. [15] Sebire NJ, et al. Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies. Int J Gynecol Pathol 2005;24: 260-4.

Ovarian complete hydatidiform mole: case study with molecular analysis and review of the literature.

Ectopic complete molar pregnancy in the ovary is an exceptionally rare event. Here we present a case of ovarian complete hydatidiform mole in a 20-yea...
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