International Journal of Gynecological Pathology

31:364368, Lippincott Williams & Wilkins, Baltimore

r 2012 International Society of Gynecological Pathologists

Case Report

Molecular Genetic Analysis of Nongestational

Choriocarcinoma in a Postmenopausal Woman:
A Case Report and Literature Review

Yukihiro Hirata, M.D., Nozomu Yanaihara, M.D., Ph.D., Satoshi Yanagida, M.D.,
Kenji Fukui, M.D., Ph.D., Kimiharu Iwadate, M.D., Ph.D.,
Takako Kiyokawa, M.D., Ph.D., and Tadao Tanaka, M.D., Ph.D.

Summary: Choriocarcinoma is a highly malignant tumor of trophoblastic origin. Most

cases occur in association with preceding gestational events. However, on very rare
occasions, nongestational choriocarcinoma arises from germ cell or trophoblastic
dierentiation in dierent types of carcinoma. This article reports the case of a 58-year-
old woman with primary nongestational choriocarcinoma of the uterus that developed
19 years after her nal pregnancy and 4 years after menopause. A total abdominal
hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological
examination showed choriocarcinoma of the uterus without components of other germ
cell tumors. Karyotype analysis of the tumor cells demonstrated XX. We conrmed its
nongestational origin by DNA polymorphism analysis at 15 short tandem repeat loci.
After surgery, the patient was given four courses of combination chemotherapy. She is
still alive and there has been no evidence of recurrence 3 years after surgery. Key Words:
Nongestational choriocarcinomaPostmenopausalDNA polymorphism analysis.

Gestational trophoblastic diseases comprise a spec-
trum of related disorders including benign trophoblastic
lesions, premalignant hydatidiform moles, clinically
malignant invasive hydatidiform moles, and neoplastic
disease. The term gestational trophoblastic neoplasia
encompasses a diverse group of interrelated but distinct
tumors that include choriocarcinomas, placental-site
trophoblastic tumors, and epithelioid trophoblastic
tumors. Gestational trophoblastic neoplasia, unique
From the Departments of Obstetrics and Gynecology (Y.H.,
N.Y., S.Y., T.T.); Forensic Medicine (K.F., K.I.), The Jikei
University School of Medicine, Nishi-Shinbashi, Minato-ku,
Tokyo; and Department of Molecular Pathology (T.K.), Chiba
University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
The authors declare no conicts of interest.
Address correspondence and reprint requests to: Tadao Tanaka,
MD, PhD, Department of Obstetrics and Gynecology, The Jikei
University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-
ku, Tokyo 105-8461, Japan. E-mail: tanaka3520@jikei.ac.jp.
among human neoplastic diseases, is highly curable even
in the presence of a widely metastatic disease because
they are genetically related to fetal tissues (1). Chorio-
carcinoma, a tumor that shows biphasic proliferation of
cytotrophoblastic and syncytiotrophoblastic cells, is a
highly malignant tumor of trophoblastic origin and is
classied as either gestational or nongestational (2). It
commonly occurs in women of reproductive age and
progresses rapidly. The incidence of choriocarcinoma
varies widely among dierent regions of the world.
Although its frequency is approximately 1 in 20,000 to
40,000 pregnancies in the United States and Europe, it is
found in 1 in 500 to 3000 pregnancies in south-east Asia.
Lately, the rigorous management of molar pregnancy
and the improvement of socioeconomic conditions have
resulted in the decreased frequency of choriocarcinoma
in all populations. Gestational choriocarcinoma arises in
association with preceding gestational events including
normal deliveries, abortions, ectopic pregnancies, and

DOI: 10.1097/PGP.0b013e318241d556 364

 ANALYSIS OF NONGESTATIONAL CHORIOCARCINOMA
hydatidiform moles. Very rarely, choriocarcinoma
originates from trophoblastic dierentiation of germ
cell tumors (teratoma, embryonic carcinoma, and yolk
sac tumor) and carcinoma (endometrioid adenocarci-
noma), or residual germ cells; this is known as
nongestational choriocarcinoma (3). Although gesta-
tional choriocarcinoma is generally sensitive to chemo-
therapy and has a good prognosis even in advanced
stages, nongestational choriocarcinoma is less sensitive
and has a poor prognosis (2). It is sometimes dicult to
distinguish the 2 types of choriocarcinoma by clinical
manifestations and histopathologic ndings alone (4).
Many biologic studies have extensively reported molec-
ular and cellular pathogenesis in the unique develop-
ment of choriocarcinoma (1). Recently, molecular
analysis has been used to identify the genetic origin of
choriocarcinoma. We report herein a case of nongesta-
tional choriocarcinoma in a postmenopausal woman on
whom molecular genetic analysis was performed.
CASE REPORT
A 58-year-old woman (gravida 6, para 3), whose
last pregnancy had been 19 years earlier, presented
with a history of postmenopausal vaginal bleeding.
Her last menstrual period had been 4 years before she
presented with these symptoms, and her medical,
surgical, and gynecologic histories were unremark-
able. Pelvic examination revealed a bulky uterus and
crumbly tumor tissue protruding from the uterine os.
Transvaginal sonograms detected a 46  27-mm
hypoechoic region from the uterine corpus to the
cervix with a thin endometrium, and a 50-mm mass in
the left adnexal region. Magnetic resonance imaging
showed a round nodule in the anterior wall and an
adenomyosis-like nodule in the posterior wall of the
uterus. Chest x-ray, chest and abdominal computed
tomography, and brain magnetic resonance imaging
showed no sign of metastatic lesions. Her laboratory
ndings were found to be within the normal range,
except for an increased serum human chorionic
gonadotropin (hCG) level, which was extremely high
(147578.7 mIU/mL). Carcinoembryonic antigen and
a-fetoprotein levels were 2.5 IU/mL and 7 IU/mL,
respectively. The biopsy of soft tissue egested from
within the uterus revealed choriocarcinoma.
The patient underwent a total abdominal hysterec-
tomy and bilateral salpingo-oophorectomy. The
postoperative serum hCG level continued to be as
high as 10140.3 mIU/mL, and the patient received 4
courses of MEA (methotrexate, 450 mg/body, day 1;
etoposide, 100 mg/body, days 15; actinomycin D,
365
0.5 mg/body, days 15). After the rst course of
chemotherapy, the serum hCG level decreased to
2618.1 mIU/mL and normalized after the second
course of chemotherapy. The hCG level remained
below the normal range (o0.1 mIU/mL) after 36 mo,
and there has been no evidence of tumor recurrence
during the follow-up period.
PATHOLOGIC FINDINGS
The uterus and bilateral adnexa weighed 452 g
(Fig. 1A), and the uterus measured 130  100  55
mm. A tumor with massive necrosis and hemorrhage,
measuring 9 cm in the greatest dimension, was found
in the endometrium of the lower uterine body and
cervix. The left ovary formed a monolocular cystic
tumor, measuring 5 cm in its greatest dimension.
Microscopic examination revealed proliferation of
highly atypical epithelioid tumor cells, growing in
sheets, which invaded into the myometrium. The
tumor cells constituted an intimate mixture of
cytotrophoblasts, syncytiotrophoblasts, and inter-
mediate trophoblasts (Fig. 1B). In the center of the
tumor, the spaces lled with red blood cells com-
pletely surrounded by trophoblastic cells devoid of
endothelial cells were appreciated (Fig. 1C). A
thorough sampling of the tumor found absence of
chorionic villi or nonchoriocarcinomatous neoplastic
component. The left ovarian cystic tumor showed
serous cystadenoma. The patient was diagnosed with
choriocarcinoma, which was classied as Interna-
tional Federation of Gynecology and Obstetrics
Stage I (pT1NxMx). The prognostic index score
was 12 (high-risk group) according to the Interna-
tional Federation of Gynecology and Obstetrics 2000
staging and risk factor scoring system.
DNA POLYMORPHISM ANALYSIS
DNA polymorphism analysis was performed to
determine the genetic origin of choriocarcinoma.
Genomic DNA was extracted from the tumor and
from peripheral blood leukocytes of the patient and
her husband with informed consent. DNA was
amplied using a commercially available analysis
tool, the AmpFISTR Identiler Polymerase Chain
Reaction Amplication Kit (Applied Biosystems,
Foster City, CA), with 15 short tandem repeat
markers including D8S1179, D21S11, D7S820,
CSF1PO, D3S1358, TH01, D13S317, D16S539,
D2S1338, D19S433, vWA, TPOX, D18S51,
D5S818, and FGA, and a sex determination marker.
Int J Gynecol Pathol Vol. 31, No. 4, July 2012
366 Y. HIRATA ET AL.

FIG. 1. Pathologic findings. (A) Gross examination of the specimen showed a necrotic and hemorrhagic mass (9 cm in diameter) located from
the uterine corpus to the cervix along with a left ovarian cystic tumor. (B) Microscopic examination showed that the tumor contained biphasic
proliferation of cytotrophoblastic and syncytiotrophoblastic cells (hematoxylin and eosin, 200  ). (C) Higher magnification showed the
spaces filled with red blood cells completely surrounded by trophoblastic cells devoid of endothelial cells (hematoxylin and eosin, 400  ).

Polymerase chain reaction products were separated
with an ABI PRISM 3130 Genetic Analyzer (Applied
Biosystems). Polymerase chain reaction product siz-
ing was accomplished using an ABI GeneMapper ID
v3.2 (Applied Biosystems). Karyotype analysis of
tumor cells demonstrated XX. The results of the
DNA polymorphism analysis showed an identical
polymorphic pattern between the tumor and patients
alleles at all 15 dierent short tandem repeat loci,
suggesting that this tumor is a nongestational
choriocarcinoma (Table 1).
DISCUSSION
Choriocarcinoma is divided into gestational or
nongestational, based on clinical presentation, histo-
pathologic features, and genetic features. Gestational
choriocarcinoma mostly derives from all kinds of
preceding pregnancy-related events in women of
reproductive age. In contrast, nongestational chorio-
carcinoma almost always occurs with another tumor
component, such as teratoma, embryonic carcinoma,
yolk sac tumor, and endometrioid adenocarcinoma.
Sixteen cases of uterine carcinoma with choriocarci-
nomatous dierentiation have been reported in the
literature; the mean age of the patients was 68.9 yr;
they were multigravida, and the most commonly
associated histologic type was endometrioid adeno-
carcinoma (3). Lack of a nonchoriocarcinomatous
component with thorough sampling in our case
suggested that the tumor might not be derived
from preexisting carcinoma such as endometrioid

Int J Gynecol Pathol Vol. 31, No. 4, July 2012

 ANALYSIS OF NONGESTATIONAL CHORIOCARCINOMA 367

TABLE 1. The short tandem repeat genotype of choriocarcinoma. Previously, nongestational chorio-
choriocarcinoma carcinoma was diagnosed by the patients reproduc-
No. maternal-paternal alleles tive history or menstrual status without molecular
Locus designation Tumor Patient Husband techniques. Recently, DNA polymorphism analysis
D8S1179 13-15 13-15 12-13 has been used successfully to identify the genetic
D21S11 29-30 29-30 30-32.2 origin of choriocarcinoma. Tsujioka et al. (5) re-
D7S820 11-11 11-11 12-12 ported that the genomic origin could be determined
CSF1PO 9-12 9-12 12-13
D3S1358 15-16 15-16 14-16 using 2 or 3 appropriate variable number of tandem
TH01 6-9 6-9 6-9 repeat loci because the condence of identical alleles
D13S317 11-11 11-11 8-9 was o1%. Nongestational choriocarcinoma is ex-
D16S539 9-12 9-12 9-9
D2S1338 19-20 19-20 24-25 clusively demonstrated by the existence of only
D19S433 12-14 12-14 15-16.2 maternal alleles. In our report, DNA proles from
vWA 17-18 17-18 17-18 the tumor and the patients peripheral blood demon-
TPOX 8-11 8-11 11-11
D18S51 13-15 13-15 15-15 strated an identical polymorphic allele pattern with all
D5S818 11-11 11-11 11-11 15 dierent short tandem repeat markers, suggesting
FGA 22-24 22-24 23-23 that the tumor was a nongestational uterine chorio-
Amelogenin X-X X-X X-Y
carcinoma. Recently, Shih (6) reported the presence of
vascular channels lined purely by neoplastic tropho-
adenocarcinoma. Rarely, nongestational choriocarci- blasts designated as trophoblastic vasculogenic mimi-
noma derives from germ cells without other neo- cry in gestational choriocarcinoma. It is noteworthy
plastic components. The possibility has been that the same phenomenon was seen in our case,
suggested that residual germ cells that failed to suggesting that trophoblastic vasculogenic mimicry
migrate to the gonads may undergo neoplastic may be a characteristic feature of both gestational and
transformation. There are several dierent clinical nongestational choriocarcinoma.
features that dierentiate gestational choriocarcino- The management of choriocarcinoma is well
ma from nongestational choriocarcinoma, such as established by the International Federation of Gyne-
genetic origin, chemosensitivity, and frequency of cology and Obstetrics 2000 staging and risk factor
metastasis (2). However, it is still dicult to scoring system. Patients with nonmetastatic and low-
determine whether the case is gestational or non- risk metastatic gestational trophoblastic disease can
gestational choriocarcinoma on the basis of histo- be treated with single-agent chemotherapy using
pathologic analysis alone. Therefore, it is necessary to methotrexate or actinomycin D, resulting in an
establish useful methods for the precise diagnosis of almost 100% survival rate. Patients categorized as

TABLE 2. Reported cases of uterine choriocarcinoma in postmenopausal women

First
History of History of chemo- DNA
Case Age (yr) pregnancy GTD Type Surgery therapy analysis Outcome
ONeill et al. (8) 57 Yes No Gestational No surgery EMA-CO Yes NED
(43 mo)
Yildiz et al. (9) 65 Yes No Non- TAH, RSO EMA-CO No NED
gestational (420 mo)
Desai et al. (10) 73 Yes No ND No surgery EMA-CO No NED
(412 mo)
Mukherjee et al. (11) 54 Yes No ND TAH, BSO EMA-CO No REC
Chittenden et al. (12) 62 Yes No ND No surgery EMA-CO No DOD
Ramondetta et al. (13) 60 Yes No ND TAH, BSO, EMA-CO No REC
LND,
OMTX
Massenkeil et al. (14) 58 Yes No ND TAH, BSO MTX No DOD
Marcu et al. (15) 62 Yes No ND TAH, BSO ND No ND
Baykal et al. (16) 54 Yes ND ND TAH, BSO, EMA-CO No ND
LND
BSO indicates bilateral salpingo-oophorectomy; DOD, death due to disease; EMA-CO, etoposide, methotrexate, actinomycin D,
cyclophosphamide, vincristine; GTD, gestational trophoblastic disease; LND, lymph node dissection; MTX, methotrexate; ND, not
described; NED, no evidence of disease; OMTX, omentectomy; REC, recurrence; RSO, right oophorectomy; TAH, total abdominal
hysterectomy.

Int J Gynecol Pathol Vol. 31, No. 4, July 2012

368 Y. HIRATA ET AL.
being at high risk for metastatic disease should be
treated with a more aggressive regimen with multi-
agent chemotherapy, such as weekly cycles of EMA-
CO (etoposide, methotrexate, and actinomycin D,
followed by cyclophosphamide and vincristine),
which could result in an improvement in patient
prognosis (7). Meanwhile, nongestational choriocar-
cinoma may be resistant to methotrexate-based
single-agent chemotherapy. Therefore, irrespective
of the stage and risk factor score, nongestational
choriocarcinoma could be treated with multiagent
chemotherapy, such as EMA-CO, VAC (vincristine,
actinomycin D, cyclophosphamide), or BEP (bleo-
mycin, etoposide, cisplatin) regimens. The MEA
regimen was selected in our case, because it is
regarded as one of the most eective combination
chemotherapies and has equal eectiveness to EMA/
CO with fewer side eects in patients with high-risk
choriocarcinoma.
Choriocarcinoma in postmenopausal women,
whether gestational or nongestational, is extremely
rare (8). Previously reported cases of choriocarcino-
ma in postmenopausal women have been summarized
in Table 2 (816). The mean age of the 9 patients
studied was 60 yr and the longest period between
menopause and development of the tumor was
reported to be 23 yr (10). Gestational choriocarcino-
ma commonly occurs after hydatidiform mole and
the latency period is thought to be often o1 yr (17).
In a large study, only 8 (7.5%) of 106 patients with
gestational choriocarcinoma had a long latency
period of 42 yr from the previous gestational
period (18). Among the 9 patients, 1 was diagnosed
with gestational choriocarcinoma and 1 with non-
gestational choriocarcinoma; for the remaining 7
patients, the diagnosis was not certain (Table 2). Only
1 case reported by ONeill et al. (8) was diagnosed as
gestational choriocarcinoma using molecular genetic
analysis. Fisher et al. (4) reported that a tumor,
initially diagnosed as gestational choriocarcinoma on
the basis of evaluation of the clinical history and
presentation, was nally shown to be a nongesta-
tional choriocarcinoma with DNA analysis. There-
fore, further evaluation using molecular analysis may
be required to conrm the gestational or nongesta-
tional nature of choriocarcinoma in postmenopa-
usal women.
CONCLUSION
This case report describes a nongestational chorio-
carcinoma in a postmenopausal woman using molec-
Int J Gynecol Pathol Vol. 31, No. 4, July 2012
ular genetic analysis. To the best of our knowledge,
there are few case reports of uterine choriocarcinoma
in postmenopausal women in the global litera-
ture (816). The prognosis of nongestational chorio-
carcinoma is thought to be worse than that of
gestational choriocarcinoma; therefore, making a
signicant distinction between gestational and non-
gestational is clinically important. DNA polymor-
phism analysis has been proven to be a useful method
to determine the origin of choriocarcinoma.
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