Mini Review
Genetic Characterization of Choriocarcinoma and Potential Clinical Implications
Izildinha Maestá1,2*, Luz Angela Correa Ramírez3, Julia Bette Homem de Mello4, Marilza Vieira Cunha Rudge1, Silvia R Rogatto5
1Department of Gynecology and Obstetrics, Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil
2Trophoblastic Diseases Center of the Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil
3Clinical Department, Caldas University, Manizales, Caldas, Colombia
4International Research Center - AC Camargo Cancer Center, Sao Paulo, SP, Brazil
5Department of Clinical Genetics, Vejle Sygehus and Institute of Regional Health, University of Southern Denmark, Vejle, Denmark
*Corresponding author: Izildinha Maestá, Department of Gynecology and Obstetrics, Botucatu Medical School, UNESP-Sao Paulo State University, Botucatu, SP, Brazil
Published: 07 Apr, 2017
Cite this article as: Maestá I, Ramírez LAC, de Mello JBH,
Rudge MVC, Rogatto SR. Genetic
Characterization of Choriocarcinoma
and Potential Clinical Implications. Clin
Oncol. 2017; 2: 1261
Abstract
Choriocarcinoma is a unique neoplasm that can occur after a pregnancy, as a component of germ cell
tumors, or follow the trophoblastic differentiation of neoplastic somatic cells that completely lose
their normal phenotype and produce hCG. Gestational Choriocarcinoma (GC) and Nongestational
Choriocarcinoma (NGC) are pathologically and morphologically similar, but differ in genetic origin,
immunogenicity, sensitivity to chemotherapy, and prognosis (with GC having a better prognosis
than NGC). GC can follow any type of pregnancy, while NGC usually arises from ovarian germ cell
tumors, or from any epithelial cancer.
Approximately equal numbers of GC cases follow molar or non-molar pregnancies. The genetic
make up of the tumor is determined by the nature of the antecedent pregnancy. Tumors resulting
from term pregnancies, nonmolar abortions, or partial hydatidiform moles will have both maternal
and paternal chromosomes, while those derived from complete hydatidiform moles will be
androgenetic in origin. Although choriocarcinoma karyotypic analyses have shown no consistent
chromosomal abnormalities, chromosomal gains, losses, and rearrangements have been identified.
Distinguishing between GC and NC is clinically important in determining the prognosis and
optimum management approach. The treatment of choice for GC is chemotherapy. Patients with
NGC frequently respond well to initial chemotherapy, but will not be ultimately cured and should
be managed more aggressively with surgical removaland multiagent chemotherapy.Although the
overall survival of patients with choriocarcinoma receiving chemotherapy is high, some women
still die due to chemoresistance. Identifying tumor origin by genetic parental analysesis essential to
determine the prognosis and most appropriate treatment.
Introduction
Choriocarcinoma is a unique neoplasm composed of cytotrophoblast and syncytiotrophoblast
that secrete Human Chorionic Gonadotrophin (hCG). It can occur after a pregnancy, as a component
of germ cell tumors, [1,2] or follow the trophoblastic differentiation of neoplastic somatic cells that
completely lose their normal phenotype and produce hCG [2,3].
Choriocarcinoma represents the most immature form of trophoblastic diseases. It resembles
the most primitive trophoblast at the first stage of placental development, and is characterized by
sheets of trophoblastic cells invading and permeating vessels and tissues [4,5]. Except in the rare case of choriocarcinoma with a term pregnancy, villi are absent. It shows considerable cellular atypia
with large pleomorphic nuclei, abnormal mitotic figures and bizarre cellular configuration. Central
hemorrhage and necrosis are present, with a rim of normal tissue around the interface of viable
tumor cells. In addition, diffuse and strong immunoreactivity for hCG is observed [5].
Most commonly, choriocarcinoma derives from term or preterm pregnancies, non-molar
abortions, and molar pregnancies. On rare occasions, choriocarcinoma occurs independent of
pregnancy, and is therefore called nongestational choriocarcinoma. Gestational choriocarcinoma
cannot be morphologically distinguished from nongestational choriocarcinoma [6,7].
Gestational Choriocarcinoma (GC) can follow any type of
pregnancy: 50% arise after hydatidiform mole, 25% after spontaneous
abortion, 22.5% after a normal pregnancy, and 2.5% following ectopic
pregnancy [1].
Nongestational Choriocarcinoma (NGC) most commonly arises
from ovarian germ cell tumors, but can originate from any epithelial
cancer, including those from lung, gastric and bowel [8]. In some
instances, there are mixed tumors comprising epithelial elements
and choriocarcinoma, but in others they may have completely lost
their epithelial phenotype [9]. The incidence of NGC is still unknown,
being reported as a very rare tumor.
Genetic Origin
Although gestational and nongestational choriocarcinoma are
pathologically and morphologically similar, they differ in genetic
origin, immunogenicity, sensitivity to chemotherapy, and prognosis,
with Gestational Choriocarcinoma (GC) having a better prognosis
than Nongestational Choriocarcinoma (NGC).
Genetically, NGC is similar to other tumors. It originates entirely
from the patient and, consequently, has poor immunogenicity that
results in lower sensitivity to chemotherapy. GC contains material
from the paternal genome that induces a vigorous reaction of the
maternal immune system, and is considered to be a semiallograft
[4,10]. The remarkable curability of GC with chemotherapy reflects
the underlying immune response of the mother to paternal antigens
expressed on the surface of the tumor [10].
Approximately equal numbers of GC cases follow molar
or non-molar pregnancies. The genetic make up of the tumor
is determined by the nature of the antecedent pregnancy [11].
Tumors that result from term pregnancies, nonmolar abortions, or
partial hydatidiform moles will have both maternal and paternal
chromosomes, while those derivedfrom complete hydatidiform
moles will be androgenetic in origin [6,11]. Trophoblastic neoplasms
are rare and often treated with chemotherapy without the surgical
removal of their active focus. As a result, tissue specimens, especially
those from fresh tumors, are rarely available for study [12]. Where
performed, cytogenetic analyses of choriocarcinoma cell lines and
tumor tissue usually reveal an aneuploid karyotype with modes in the
hyperdiploid and hypotetraploid range and chromosomal alterations
involving almost every chromosome. Choriocarcinoma karyotypic
analyses show no consistent chromosal abnormalities. However, a
range of abnormalities, including chromosomal gains, losses, and
rearrangements have been identified [6,11]. Molecular genetic studies
have identified frequent loss of specific regions of the genome. The
most significant of these are loss of 7p12–q11.2, [13] amplification
of 7q21–q31, [14] and loss of 8p12–p21 [12,14]. More recently, GC genetic profile has been demonstrated to be more heterogeneous
(losses of 9q33.1, 17q21.3 and 18q22.1; and gains of 1p36.33-p363.32
and 17q25.3), whereas NGC shows only a few abnormalities with
a homogeneous profile [7]. However, the specific genes involved
remain not identified.
NECC1, located on chromosome 4q11-q12 is one of the most
widely studied tumor suppressor gene in choriocarcinoma [15].
It is abundantly expressed in normal placental villi and absent in
choriocarcinoma. NECC1 transfection into choriocarcinoma cell
lines alters cell morphology and suppresses tumorigenesis, suggesting
that loss of NECC1 expression is involved in the malignant
transformation of normal trophoblast to choriocarcinoma [2,11].
The role of oncogenes in the development of choriocarcinoma is less
known. However, the amplification of 7q21-q31 observed in a series
of choriocarcinoma suggests a role for oncogenes located in this
region [6,11].
Clinical Implications
Given that choriocarcinomas tend to be fast-growing and the risk
of developing chemoresistant metastatic disease is high, establishing
the pathogenesis of these neoplasias is of substantial interest [4,16].
Distinguishing between GC and NC has a very important impact
on the clinical course and management of the patient. The type of
pregnancy in which a tumor arises and the time interval between
that pregnancy and the diagnosis of the tumor cannot be determined
morphologically but are clinically relevantin determining the
appropriate chemotherapeutic regimen. Studies have demonstrated
that the causative pregnancy of gestational choriocarcinoma is not
always the antecedent pregnancy [3,17-21]. In some cases, it may be a
much earlier pregnancy.
Comparing the microsatellite polymorphisms in the tumor
with the previous pregnancies can identify the causative pregnancy
and reveal the time interval in a woman who has had multiple
pregnancies.It can also inform whether the origin of a particular
tumor is gestational or nongestational [22].
The treatment of choice for GC is chemotherapy, [16,23] which
is tailored to each patient’s risk score (score 0-6 = low-risk, score ≥7
= high-risk) and response to treatment [24]. Among GC patients
treated with chemotherapy, the overall worldwide survival rate,
even for metastatic choriocarcinoma, is 80-90% [23]. Patients with
low-risk GC can normally be cured with single agent chemotherapy
(methotrexate or actinomycin D) [25]. Still, a minority of women
will have chemotherapy resistance or high-risk disease. Those with
high-risk GC require a multiagent chemotherapy regimen such as
EMA/CO (etoposide, methotrexate, actinomycin-D alternating with
cyclophosphamide and vincristine), [26] EP/EMA (Etoposide and
cisplatin / EMA) [27] or EP/EMA modified [28,29]. Studies have
shown that interferon alpha may be a useful biomarker for predicting
methotrexate resistance in gestational trophoblastic neoplasia. This
finding may provide a target for potential novel therapies for the
treatment of methotrexate resistance in the future [30].
On the other hand, patients with NGC frequently respond well to
initial chemotherapy, but will not be ultimately cured of their illness
and should be managed more aggressively with surgical removaland
multiagent chemotherapy. Unlike GC cases, NGCs are not categorized
according to a risk score system. Cases of NGC are usually treated
with surgical resection followed by chemotherapy [31]. However, the
prognosis of NGC is much less favorable despite advances in surgery
and chemotherapy regimens [32,33]. Indeed, molecular studies have
demonstrated that most patients with tumors containing no definite
paternal genes die of their disease(84% of the cases) [32].
NGC should be suspected in the presence of unusual features
such as metastases from unknown primary tumor, long interval since
a recognized pregnancy, uterine tumors with unusual pathology, and
primary ovarian choriocarcinoma [3,8].
Primary ovarian tumour
A Oladipo,
a
Mathew,
b
A Oriolowo,
c
I Lindsay,
d
R
Conclusion
Although the overall survival of patients with choriocarcinoma receiving chemotherapy is high, some women still die due to chemoresistance. Characterization of the molecular changes in choriocarcinoma would allow the target-based treatment of metastatic forms of this disease that are refractory to conventional therapy. The use of molecular genetic techniques to identify genomic imbalances in the tumor by array-based comparative genomic hybridization (aCGH) together with microarray analysis should facilitate these investigations. Identifying tumor origin by genetic parental analyses, such as polymorphic microsatellite markers, is essential to determine the prognosis and most appropriate treatment. Further genetic studies on choriocarcinomas are necessary to elucidatethe pathogenesis of this peculiar form of tumor.
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