Hydatidiform mole

Gestational trophoblastic disease occurs in less than 1 per 1200 pregnancies in the United States. The spectrum of this disease ranges from benign hydatidiform mole to trophoblastic malignancy (placental-site trophoblastic tumor and choriocarcinoma). Benign gestational trophoblastic disease generally occurs in women of reproductive age and is extremely rare in postmenopausal women. To our knowledge, our case represents only the third description in the world literature of a benign complete hydatidiform mole in a woman with a history of amenorrhea greater than 1 year. We describe the case of a 61-year-old postmenopausal woman who underwent an emergent total abdominal hysterectomy due to uncontrollable vaginal bleeding associated with an increased serum [beta]an chorionic gonadotropin level. The resected uterus contained an endometrial, cystic, grapelike tumor. Microscopic examination demonstrated hydropic degenerated villi with a circumferential trophoblastic cell proliferation and moderate atypia, consistent with a complete hydatidiform mole. The morphologic and immunophenotypic characteristics are presented, as well as the results of a literature review.

(Arch Pathol Lab Med. 2004;128:1039-1042)

Gestational trophoblastic disease (GTD) encompasses a diverse group of lesions that includes placental villous abnormalities, known as hydatidiform moles, as well as neoplastic trophoblastic cell proliferations unaccompanied by chorionic villi (Table). The recognition and separation of these entities are important, as each disease has distinctive clinical manifestations, morphology, evolution, and, more importantly, different therapeutic approaches.

In the United States, the incidence of GTD is less than 1 per 1200 pregnancies.1 It generally occurs in women of reproductive age with an age range from 13 to 49 years.2 When it occurs in women older than 50 years, it frequently represents a malignant disease.1 To date, there are few series reported in the world literature of gestational diseases occurring in women older than 50 years. Even rarer are reports of benign trophoblastic disease in women of postmenopausal status. To our knowledge, our case represents the third description in the world literature of a complete hydatidiform mole (CHM) in a woman with a history of more than 1 year of amenorrhea since the first description by Jequier and Winterton in 1973.4

REPORT OF A CASE

A 61-year-old postmenopausal woman presented with a 16day history of vaginal bleeding. Her obstetrical history was significant for menarche at 14 years of age, 2 normal spontaneous vaginal deliveries (gravida 2, para 2, aborta 2), and amenorrhea for 1 year, during which time she was undergoing hormonal replacement therapy. The patient was also receiving atenolol to treat her hypertension. On admission, a pelvic ultrasound showed an enlarged uterus (12.2 × 6.7 × 9.6 cm) with 5.2-cm complex echoes in the uterine cavity. The serum [beta]-human chorionic gonadotropin (hCG) level was determined to be greater than 200 000 mIU/mL.

The patient underwent an endometrial curettage, which grossly revealed a large amount of vesicular tissue. Due to profuse bleeding equaling about 1 L of blood within 15 minutes and the clinical suspicion of choriocarcinoma, she subsequently underwent an emergent total abdominal hysterectomy with bilateral salpingo-oophorectomy. The patient had an uneventful postoperative recovery with a drop in her serum [beta]hCG level to 40154 mIU/mL within the immediate postoperative period and a negative workup for métastases, including chest radiograph and abdominal and pelvic computed tomographic scan. Follow-up with quantitative serum [beta]-hCG level testing was scheduled.

HISTOPATHOLOGIC FINDINGS

Three endometrial biopsy specimens were received, which consisted of multiple, tan, grapelike soft tissue fragments admixed with blood clots, measuring 16.0 × 10.5 × 3.8 cm in aggregate. The total abdominal hysterectomy specimen consisted of a 14.0 × 10.0 × 5.5-cm uterus with attached bilateral fallopian tubes and ovaries. Gross examination revealed an enlarged endometrial cavity containing blood clots and a fleshy, hemorrhagic, and edematous tissue with scanty grapelike clear vesicles measuring up to 0.2 cm in diameter (Figure 1). Microscopic examination of the endometrial biopsy specimens and the uterus revealed generalized hydropic villi with cisterns and circumferential proliferation of mildly atypical and hyperchromatic trophoblastic cells (Figure 2), which did not invade into the adjacent myometrium or blood vessels.

Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue. The syncytiotrophoblastic cells of the hydropic villi showed diffuse staining for hCG and human placental lactogen (Figure 3). Immunostaining for p57 was negative in the cytotrophoblasts and villi mesenchyme. Immunostaining for p53 was positive in approximately 70% of extravillous intermediate trophoblastic cells (Figure 4). Cytogenetic analysis was not performed. The histomorphology and immunophenotypic findings were consistent with a CHM.

Other histologic findings included Arias-Stella reaction of the endometrial glands and decidualized stroma, consistent with the hormonal effects of a molar pregnancy and exogenous hormonal therapy, and a 1.2-cm luteoma of pregnancy in the left ovary. Cytologic examination of the peritoneal washing revealed no evidence of malignant cells.

COMMENT

In the world literature, it is well established that the occurrence of GTD in women older than 50 years is rare, but it can occur. Premenopausal or perimenopausal patients in this age group may develop benign or malignant trophoblastic disease, whereas in postmenopausal women, GTD is usually malignant.3-5 In 1985, Tsukamoto et al5 reported 20 cases of trophoblastic disease in women aged 50 or older. Five patients (25%) were diagnosed with a choriocarcinoma, 7 patients (35%) were diagnosed with a hydatidiform mole, and 8 patients (40%) were diagnosed with invasive mole. However, none of the patients with hydatidiform mole was postmenopausal. The 3 amenorrheic patients (12, 18, and 27 months of amenorrhea) had a choriocarcinoma.5

In 1997, Davidson et al6 described the case of a perimenopausal 60-year-old woman diagnosed with a molar pregnancy after only 3 months of amenorrhea. Rabczynski et al7 in 2000 reported a case of CHM in a 59-year-old woman; however, the history of amenorrhea was not addressed.

In the largest series, Jequier and Winterton4 reviewed 109 cases of GTD in women older than 50 years. They found malignant disease in 28.4% (31 patients), benign moles in 47.7% (52 patients), and an unclear pathologic diagnosis in the remaining 23.9%. The age of the patients with benign moles and malignant neoplasms ranged from 50 to 59 years (mean, 52.2 years) and 51 to 64 years (mean, 54.2 years), respectively. The available data of the amenorrhea period ranged from 0 to 22 years (mean, 33 months; median, 12 months) among the patients with a malignant disease, while that of the patients with benign moles ranged from O to 10 years (mean, 7.6 months; median, 4 months). There were only 2 (1.8%) postmenopausal patients who had a documented period of amenorrhea greater than 1 year and were diagnosed with a benign mole. These patients were aged 50 and 54 years and were amenorrheic for 18 months and 10 years, respectively.4 To our knowledge, our case represents the third case in the world literature of a CHM in a postmenopausal woman with a history of more than 1 year of amenorrhea.

Numerous studies support the fact that benign GTD is extremely rare in postmenopausal women. Patients in the sixth decade are not expected to be pregnant, and a physician may not even think of checking a [beta]-hCG level. Therefore, the diagnosis of pregnancy and, moreover, hydatidiform mole may be missed. On the other hand, in women of reproductive age, the possibility of GTD may be considered for those patients who present with abnormal vaginal bleeding. In a retrospective study, Coukos et al2 found 24 complete molar pregnancies out of 2431 cases of abnormal pregnancy. These patients presented with abnormal vaginal bleeding (75%), excessive uterine size (54%), and a markedly elevated serum [beta]hCG level for the gestational age (100%). A transvaginal ultrasound was diagnostic in 60% of the patients showing an enlarged uterus containing cystic amorphous material in conjunction with the absence of a normal gestational sac within the endometrial cavity.2 Similarly, Gemer et al8 retrospectively studied 41 patients with CHM who presented with vaginal bleeding (58%), excessive uterine size (15%), anemia (2%), and hyperemesis (2%). Complete hydatidiform mole was diagnosed by ultrasound in 88% of the cases.8 In the older, amenorrheic patients, abnormal vaginal bleeding is more likely to raise the possibility of malignant disease.

Gestational trophoblastic tumors hypersecrete [beta]-hCG, and the serum level of the hormone is proportional to the volume of the tumor. This offers a diagnostic confirmation of GTD and represents a fundamental basis for the patients' follow-up.

The diagnosis of benign CHM needs to be distinguished from other trophoblastic diseases (Table). The hydatidiform mole can be complete or partial and represents a malformed placenta caused by genetic aberration of the villous trophoblast. The CHM shows generalized hydropic degeneration of the chorionic villi with circumferential proliferation of trophoblastic cells and no development of a fetus or embryo. Most complete moles are diploid, with a 46,XX karyotype. The partial hydatidiform mole consists of hydropic villi interspersed with normal chorionic villi and typically has a triploid karyotype. Both types of molar pregnancies can become invasive and involve the adjacent myometrium and/or the blood vessels. Choriocarcinoma is a biphasic malignant proliferation of syncytiotrophoblastic cells and atypical cytotrophoblastic or intermediate trophoblastic cells, which exhibits marked nuclear pleomorphism. Placental-site trophoblastic tumor is composed predominantly of polyhedral and vacuolated, multinucleated intermediate trophoblastic cells that infiltrate the myometrium with extensive deposition of fibrinoid material. Unlike the hydatidiform moles, choriocarcinomas and placental-site trophoblastic tumors lack chorionic villi.

This differential diagnosis of GTD may be supported with the use of immunohistochemical markers. Human chorionic gonadotropin is diffusely positive in the syncytiotrophoblasts of the complete mole and choriocarcinoma, but focally positive in the placental-site trophoblastic tumor. Human placental lactogen is moderately positive in the syncytiotrophoblasts of the hydatidiform mole and strongly positive in the intermediate trophoblasts of the placental-site trophoblastic tumor, but negative to weakly positive in the choriocarcinoma. p57 is a useful immunohistochemical marker for differentiating molar from nonmolar hydropic villi. The reaction for p57 is positive in the cytotrophoblasts and villi mesenchyme of hydropic nonmolar abortions, but negative in hydropic moles.9 p53 immunoreactivity is generally present in the extravillous intermediate trophoblasts of the complete moles, but absent in nonmolar pregnancies.10

In our case, choriocarcinoma and placental-site trophoblastic tumor were ruled out due to the presence of chorionic villi and the absence of tumor necrosis, extreme cytologic atypia, or invasion into the myometrium. The results of immunohistochemistry further supported the diagnosis of CHM in this older, amenorrheic patient. Partial hydatidiform mole was ruled out owing to the absence of fetal parts or embryo and the presence of a circumferential proliferation of trophoblastic cells in the hydropic chorionic villi.

The rarity of a molar pregnancy in a 61-year-old amenorrheic woman brings this patient's menopausal status into question. Menopause is clinically defined as the period that begins 12 months after the final episode of menstrual bleeding in women. Technically, serum luteinizing hormone and follicle-stimulating hormone levels are increased and the estradiol levels are decreased. While these laboratory tests may form part of the workup of an amenorrheic patient of reproductive age, one may not think of checking these serum markers in women older than 50 years with a 1-year history of amenorrhea. Even though this patient was amenorrheic for 1 year, she most likely was in a transitional period of progressive loss of ovarian function and sporadic ovulatory cycles.

In conclusion, even though CHM is rare in women older than 50 years with a history of amenorrhea longer than 1 year, it can and does occur. Therefore, a high level of suspicion must be maintained in order to establish the correct diagnosis.

References

1. Freedman R, Tortolero-Luna C, Pandey D, et al. Gestational trophoblastic disease. Obstet Cynecol Clin North Am. 1996;23:545-571.

2. Coukos G, Makrigiannakis A, Chung J, Randall T, Rubin S, Benjamin I. Complete hydatidiform mole: a disease with a changing profile. J Reprod Med. 1999; 44:698-704.

3. Yen S, MacMahon B. Epidemiologic features of trophoblastic disease. Am J Obstet Cynecol. 1968;101:126-132.

4. Jequier A, Winterton WR. Diagnostic problems of trophoblastic disease in women aged 50 or more. Obstet Gynecol. 1973:42:378-387.

5. Tsukamoto N, Iwasaka T, Kashimura Y, Uchino H, Kashimura M, Matsuyama T. Cestational trophoblastic disease in women aged 50 or more. Gynecol Oncol. 1985:20:53-61.

6. Davidson SA, Gottesfeld J, La Rosa FC. Molar pregnancy in a 60-year-old woman, Int J Gynecol Obstet. 1997:56:53-55.

7. Rabczynski J, Kochman A, Prudlak E, Lewandowski M. Hydatidiform mole in 59-year-old woman: a case report. Ginekot Pol. 2000:71:152-154.

8. Gemer O, Segal S, Kopmar A, Sassoon E. The current clinical presentation of complete molar pregnancy: the current clinical presentation of complete molar pregnancy. Arch Gynecol Obstet. 2000;264:33-34.

9. 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.

10. Al-Bozom IA. P53 and Bcl-2 oncoprotein expression in placentas with hydropic changes and partial and complete moles. APMIS. 2000:108:756-760.

Monica Garcia, MD; Rita L. Romaguera, MD; Carmen Gomez-Fernandez, MD

Accepted for publication April 23, 2004.

From the Department of Pathology, University of Miami School of Medicine, Miami, Fla.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Carmen Gomez-Fernandez, MD, Department of Pathology, Jackson Memorial Hospital, 1611 NW 12th Ave, Holtz Center, Room 2147, Miami, FL 33136 (e-mail: cgomez3@med.miami.edu).

Copyright College of American Pathologists Sep 2004
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