Ovary: Choriocarcinoma

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home Genes Leukemias Solid Tumors Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Ovary: Choriocarcinoma

Written	2008-09	Eiko Yamamoto
		Department of Obstetrics, Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya city, Aichi pref 466-8550, Japan

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C569 OVARY

Atlas_Id 5219

Phylum Female organs: Ovary::Germ cell tumor
WHO/OMS Classification Female organs

Other names Choriocarcinoma of the ovary
Ovarian choriocarcinoma
Note Choriocarcinoma of the ovary is a highly malignant ovarian tumor which is characterized pathologically by the presence of trophoblastic malignant cells, and biochemically by the production of the pregnancy hormone human chorionic gonadotrophin (hCG) in the absence of an ongoing pregnancy. Choriocarcinoma tends to be invasive and to metastasize early and widely through both the venous and lymphatic systems. This disease is classified two types in origin, gestational choriocarcinoma and nongestational germ cell tumor. Nongestational pure choriocarcinoma is so rare that the prognosis, chemo-sensitivity, and genetics analysis of nongestational type have not been decided compared with that of gestational type. It is necessary, but difficult to distinguish nongestational choriocarcinoma from gestational choriocarcinoma except by DNA analysis.

Classification

Classification of choriocarcinoma of the ovary is based on gestational or not. It is very difficult to differentiate a pure ovarian carcinoma with a non-gestational origin from a gestational one using histopathological investigation. It can be diagnosed with only in a patient who is sexually immature, unable to conceive, or has never had sexual intercourse, unless DNA analysis is not performed.

The gestational type includes an ovarian metastasis from primary uterine choriocarcinoma which occurs in association with a normal pregnancy or spontaneous abortion, complete hydatidiform mole, or partial mole, and primary gestational ovarian choriocarcinoma which arises from ectopic pregnancy in the ovary.
The nongestational type is as a component of a mixed germ cell tumor and a pure ovarian choriocarcinoma is a very rare malignant tumor.

Clinics and Pathology

Etiology By far the most important risk factor for gestational choriocarcinoma is the nature of the preceding pregnancy. A hydatidiform mole carries with it a 1,000 - to 2,000 fold increased risk of choriocarcinoma, one of the most striking cancer risk factors identified in humans. In nongestational choriocarcinoma, no factors have been associated with the etiology of germ cell tumor, apart from an increased incidence associated with dysgenetic gonads.

Epidemiology
Gestational type
Women over the age of 40 are at increased risk for gestational choriocarcinoma. The reported prevalence of choriocarcinoma varies widely throughout the world, being greatest in Asia, Africa, and Latin America and substantially lower in North America, Europe, and Australia. Choriocarcinoma occurs with a frequency of 1:20,000 to 1:40,000 pregnancies in the United States and Europe. Estimates for the incidence in Asia, Africa, and Latin America have generally been higher; rates as high as 1 per 500 to 1,000 pregnancies have been reported, although marked regional variations do occur. Gestational choriocarcinoma follows normal pregnancy (25%), spontaneous abortion (25%), and hydatidiform mole (50%), but only about 3-5% of all molar pregnancies eventuate in choriocarcinoma. Gestational primary ovarian choriocarcinoma is extremely rare, with an estimated incidence of 1 in 3.7 x 10⁸ pregnancies.

Nongestational type
Nongestational choriocarcinoma arises in women under 40 years old because of germ cell tumor, and the frequency is reported less than 0.6% of all ovarian tumors. Goswami et al. reported the mean age 13.6 +/- 6.9 years old.

Clinics Clinical symptoms are variety in gestational type, because choriocarcinoma is likely to metastasis to multiple organs, such as lung, liver, and brain. More than 90% of patients with extrauterine gestational choriocarcinoma will have lung metastasis. In nongestational type, predominant presenting symptom is lower abdominal pain. Common complains includes atypical genital bleeding, amenorrhea, nausea, and vomiting because of high level of hCG. Choriocarcinoma is often diagnosed by the finding of an elevated hCG level in association with metastatic lesion detected radiaographically. The levels of serum or urine beta-hCG are good tumor marker for the progression or remission of disease.

Pathology There is no difference in pathological appearances between gestational type and nongestational pure choriocarcinoma. On gross examination, a circumscribed hemorrhagic mass is observed. Microscopically, hemorrheage and necrosis are found, and tumor cells resemble placental trophoblastic cells: cytotrophoblast (CT), intermediate trophoblast (IT), and syncytiotrophoblast (ST). The CT and IT tend to grow in clusters and sheets separated by ST. The typical pattern of choriocarcinoma has been called two cell pattern, biphasic-terms that reflect the relatively regular, alternating arrangement of CT and ST in the tumor interspread with intermediate trophoblast. Nuclear plemorphism, hyperchromasia and nuclei are prominent. Immunohistochemically, beta-hCG is expressed in syncytiotrophoblastic cells, but not cytotrophoblastic cells.

Treatment Gestational choriocarcinoma is treated with methotrexate-based chemotherapy, for example MEA (methotrexate, etoposide and actinomycin-D), EMA/CO (methotrexate, etoposide, actinomycin-D, cyclophosphamide and vincristine), or EP/EMA (etoposide, cisplatin, methotrexate and actinomycin-D). However, nongestational ovarian choriocarcinoma (germ cell tumor) is so rare that there is lack information on therapeutic options. Germ cell tumors of the ovary are treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. A complete staging operation is indispensable for management and prognostication. In young patients, stage I germ cell tumors can be treated with conservative surgery, i.e., unilateral oophorectomy or salpingo-oophorectomy. Postoperative chemotherapy is recommended by combination chemotherapy with the BEP (bleomycin, etoposide and cisplatin) or methotrexate-based regimen.

Prognosis The prognosis of gestational choriocarcinoma is getting better by advances of combination chemotherapy. The survival rate is increasing and 96.4% in 15 years since 1985. Nongestational pure choriocarcinoma of the ovary is so rare that it is not known whether the prognosis is worse than gestational choriocarcinoma or not. Some papers reported that nongestational choriocarcinoma of the ovary has worse prognosis and is less sensitive to methotrexate-based chemotherapeutic regimens than gestational neoplasm. But they did not diagnose definitely by DNA polymorphism analysis. It is important to clarify whether the tumor arose from a gestational or nongestational origin in order to understand the prognosis of this disease accurately.

Genetics

Note To differentiate gestational from nongestational tumors, it is necessary to determine whether a paternal contribution is present in the genome of the tumor. Examination of genetic polymorphisms from the tumor and comparison with those found in the patient and her partner should define the presence or absence of paternal DNA and establish whether or not a tumor is gestational. An extensive literature search including Medline demonstrated only five reported cases of nongestational ovarian pure choriocarcinoma diagnosed with DNA polymorphic analysis from 1985 to 2007.

Cytogenetics

Note Gestational choriocarcinoma shows wider variations in karyotype, most being aneuploid, with some in the hyperdiploid and hypotetraploid range. Many forms of chromosomal gains, losses and rearrangements are observed, but no specific chromosomal abnormality has yet been identified.

Cytogenetics
Morphological
Gestational type
A study by Matsuda et al. suggested that chromosome 7 contained a putative tumor suppressor gene for choriocarcinoma. Furthermore, by using a panel of microsatellite markers located on chromosome 7, they identified the critical region on chromosome 7 (7p12-7q11.23) which was biallelically deleted in choriocarcinomas. Another study by Ahmed et al., using the comparative genomic hybridization technique, demonstrated amplification of 7q21-q31 and loss of 8p12-p21 in choriocarcinomas which did not occur in hydatidiform moles.

Genes involved and Proteins

Note
Gestational type
In the tumor suppressor genes, p53 (located on chromosome 17 and encodes for a 53 kDa nuclear phosphoprotein that binds to DNA and inhibits the progression of the cell cycle from G1 to S phase), the p21WAF1/CIP1 (a downstream effector of p53 and mediates growth arrest by inhibiting the G1 cyclin-dependent kinase), the retinoblastoma (Rb) gene (a reaction to the inactivation of Rb protein by forming a complex with over-expressed mdm2 proteins) were upregulated in choriocarcinoma than in normal placenta, and the DOC-2/hDab2 gene was downregulated. In oncogenes, the expression of c-myc, c-erb-B-2, c-fms and bcl-2 oncoproteins were studied in normal placenta, partial and complete moles, and choriocarcinoma. The study suggested that synergistic up-regulation of c-myc, c-erb-B-2, c-fms and bcl-2 oncoproteins may be important in the pathogenesis of complete mole and choriocarcinoma.

Bibliography

Gestational Trophoblastic Disease.

Edited by Szulman AE, Buchsbaum HJ; 1987. Springer-Verlag. New York Inc.

Comparative genomic hybridization studies in hydatidiform moles and choriocarcinoma: amplification of 7q21-q31 and loss of 8p12-p21 in choriocarcinoma.

Ahmed MN, Kim K, Haddad B, Berchuck A, Qumsiyeh MB.

Cancer Genet Cytogenet. 2000 Jan 1;116(1):10-5.

PMID 10616525

Malignant trophoblastic neoplasms with different modes of origin.

Arima T, Imamura T, Sakuragi N, Higashi M, Kamura T, Fujimoto S, Nakano H, Wake N.

Cancer Genet Cytogenet. 1995 Nov;85(1):5-15.

PMID 8536237

The epidemiology of molar pregnancy and choriocarcinoma.

Buckley JD.

Clin Obstet Gynecol. 1984 Mar;27(1):153-9.

PMID 6705308

Gestational and nongestational trophoblastic tumors distinguished by DNA analysis.

Fisher RA, Newlands ES, Jeffreys AJ, Boxer GM, Begent RH, Rustin GJ, Bagshawe KD.

Cancer. 1992 Feb 1;69(3):839-45.

PMID 1346098

Nongestational pure ovarian choriocarcinoma with contralateral teratoma.

Goswami D, Sharma K, Zutshi V, Tempe A, Nigam S.

Gynecol Oncol. 2001 Feb;80(2):262-6.

PMID 11161870

Survival rates of patients with choriocarcinoma treated with chemotherapy without hysterectomy: effects of anticancer agents on subsequent births.

Goto S, Ino K, Mitsui T, Kikkawa F, Suzuki T, Nomura S, Mizutani S.

Gynecol Oncol. 2004 May;93(2):529-35.

PMID 15099974

A case of metastatic ovarian non-gestational choriocarcinoma: successful treatment with conservative type surgery and myeloablative chemotherapy.

Inaba H, Kawasaki H, Hamazaki M, Okugawa T, Uchida K, Honzumi M, Komada Y, Ito M, Toyoda N, Sakurai M.

Pediatr Int. 2000 Aug;42(4):383-5.

PMID 10986872

Gestational choriocarcinoma of the ovary diagnosed by analysis of tumour DNA.

Lorigan PC, Grierson AJ, Goepel JR, Coleman RE, Goyns MH.

Cancer Lett. 1996 Jun 24;104(1):27-30.

PMID 8640741

Update on the management of ovarian germ cell tumors.

Lu KH, Gershenson DM.

J Reprod Med. 2005 Jun;50(6):417-25.

PMID 16050566

Genetics and molecular markers in gestational trophoblastic disease with special reference to their clinical application.

Matsuda T, Wake N.

Best Pract Res Clin Obstet Gynaecol. 2003 Dec;17(6):827-36.

PMID 14614883

Combination chemotherapy with methotrexate, etoposide, and actinomycin D for high-risk gestational trophoblastic tumors.

Matsui H, Suzuka K, Iitsuka Y, Seki K, Sekiya S.

Gynecol Oncol. 2000 Jul;78(1):28-31.

PMID 10873405

Karyotypic analysis and chromosome polymorphisms in four choriocarcinoma cell lines.

Sheppard DM, Fisher RA, Lawler SD.

Cancer Genet Cytogenet. 1985 Apr 1;16(3):251-8.

PMID 4038916

DNA polymorphism analysis of a pure non-gestational choriocarcinoma of the ovary: case report.

Shigematsu T, Kamura T, Arima T, Wake N, Nakano H.

Eur J Gynaecol Oncol. 2000;21(2):153-4.

PMID 10843474

Nongestational choriocarcinoma in the postpartum period: a case report.

Suryanarayan K, O'Hanlan KA, Surti U, Ishwad CS, Nowels K, Letourneau D, Marina N.

J Pediatr Hematol Oncol. 1998 Mar-Apr;20(2):169-73.

PMID 9544172

A pure nongestational choriocarcinoma of the ovary diagnosed with DNA polymorphism analysis.

Tsujioka H, Hamada H, Miyakawa T, Hachisuga T, Kawarabayashi T.

Gynecol Oncol. 2003 Jun;89(3):540-2.

PMID 12798727

Chromosome and cellular origin of choriocarcinoma.

Wake N, Tanaka K, Chapman V, Matsui S, Sandberg AA.

Cancer Res. 1981 Aug;41(8):3137-43.

PMID 7195772

A pure nongestational choriocarcinoma of the ovary diagnosed with short tandem repeat analysis: case report and review of the literature.

Yamamoto E, Ino K, Yamamoto T, Sumigama S, Nawa A, Nomura S, Kikkawa F.

Int J Gynecol Cancer. 2007 Jan-Feb;17(1):254-8.

PMID 17291262

Citation

This paper should be referenced as such :

Yamamoto, E

Ovary: Choriocarcinoma

Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):683-685.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/OvaryChoriocarcID5219.html

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes PTN SSX2

External links

Home Genes Leukemias Solid Tumors Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us
jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C569 OVARY
Atlas_Id	5219
Phylum	Female organs: Ovary::Germ cell tumor
WHO/OMS Classification	Female organs

Other names	Choriocarcinoma of the ovary
	Ovarian choriocarcinoma
Note	Choriocarcinoma of the ovary is a highly malignant ovarian tumor which is characterized pathologically by the presence of trophoblastic malignant cells, and biochemically by the production of the pregnancy hormone human chorionic gonadotrophin (hCG) in the absence of an ongoing pregnancy. Choriocarcinoma tends to be invasive and to metastasize early and widely through both the venous and lymphatic systems. This disease is classified two types in origin, gestational choriocarcinoma and nongestational germ cell tumor. Nongestational pure choriocarcinoma is so rare that the prognosis, chemo-sensitivity, and genetics analysis of nongestational type have not been decided compared with that of gestational type. It is necessary, but difficult to distinguish nongestational choriocarcinoma from gestational choriocarcinoma except by DNA analysis.

Etiology	By far the most important risk factor for gestational choriocarcinoma is the nature of the preceding pregnancy. A hydatidiform mole carries with it a 1,000 - to 2,000 fold increased risk of choriocarcinoma, one of the most striking cancer risk factors identified in humans. In nongestational choriocarcinoma, no factors have been associated with the etiology of germ cell tumor, apart from an increased incidence associated with dysgenetic gonads.
Epidemiology	Gestational type Women over the age of 40 are at increased risk for gestational choriocarcinoma. The reported prevalence of choriocarcinoma varies widely throughout the world, being greatest in Asia, Africa, and Latin America and substantially lower in North America, Europe, and Australia. Choriocarcinoma occurs with a frequency of 1:20,000 to 1:40,000 pregnancies in the United States and Europe. Estimates for the incidence in Asia, Africa, and Latin America have generally been higher; rates as high as 1 per 500 to 1,000 pregnancies have been reported, although marked regional variations do occur. Gestational choriocarcinoma follows normal pregnancy (25%), spontaneous abortion (25%), and hydatidiform mole (50%), but only about 3-5% of all molar pregnancies eventuate in choriocarcinoma. Gestational primary ovarian choriocarcinoma is extremely rare, with an estimated incidence of 1 in 3.7 x 10⁸ pregnancies. Nongestational type Nongestational choriocarcinoma arises in women under 40 years old because of germ cell tumor, and the frequency is reported less than 0.6% of all ovarian tumors. Goswami et al. reported the mean age 13.6 +/- 6.9 years old.
Clinics	Clinical symptoms are variety in gestational type, because choriocarcinoma is likely to metastasis to multiple organs, such as lung, liver, and brain. More than 90% of patients with extrauterine gestational choriocarcinoma will have lung metastasis. In nongestational type, predominant presenting symptom is lower abdominal pain. Common complains includes atypical genital bleeding, amenorrhea, nausea, and vomiting because of high level of hCG. Choriocarcinoma is often diagnosed by the finding of an elevated hCG level in association with metastatic lesion detected radiaographically. The levels of serum or urine beta-hCG are good tumor marker for the progression or remission of disease.
Pathology	There is no difference in pathological appearances between gestational type and nongestational pure choriocarcinoma. On gross examination, a circumscribed hemorrhagic mass is observed. Microscopically, hemorrheage and necrosis are found, and tumor cells resemble placental trophoblastic cells: cytotrophoblast (CT), intermediate trophoblast (IT), and syncytiotrophoblast (ST). The CT and IT tend to grow in clusters and sheets separated by ST. The typical pattern of choriocarcinoma has been called two cell pattern, biphasic-terms that reflect the relatively regular, alternating arrangement of CT and ST in the tumor interspread with intermediate trophoblast. Nuclear plemorphism, hyperchromasia and nuclei are prominent. Immunohistochemically, beta-hCG is expressed in syncytiotrophoblastic cells, but not cytotrophoblastic cells.
Treatment	Gestational choriocarcinoma is treated with methotrexate-based chemotherapy, for example MEA (methotrexate, etoposide and actinomycin-D), EMA/CO (methotrexate, etoposide, actinomycin-D, cyclophosphamide and vincristine), or EP/EMA (etoposide, cisplatin, methotrexate and actinomycin-D). However, nongestational ovarian choriocarcinoma (germ cell tumor) is so rare that there is lack information on therapeutic options. Germ cell tumors of the ovary are treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. A complete staging operation is indispensable for management and prognostication. In young patients, stage I germ cell tumors can be treated with conservative surgery, i.e., unilateral oophorectomy or salpingo-oophorectomy. Postoperative chemotherapy is recommended by combination chemotherapy with the BEP (bleomycin, etoposide and cisplatin) or methotrexate-based regimen.
Prognosis	The prognosis of gestational choriocarcinoma is getting better by advances of combination chemotherapy. The survival rate is increasing and 96.4% in 15 years since 1985. Nongestational pure choriocarcinoma of the ovary is so rare that it is not known whether the prognosis is worse than gestational choriocarcinoma or not. Some papers reported that nongestational choriocarcinoma of the ovary has worse prognosis and is less sensitive to methotrexate-based chemotherapeutic regimens than gestational neoplasm. But they did not diagnose definitely by DNA polymorphism analysis. It is important to clarify whether the tumor arose from a gestational or nongestational origin in order to understand the prognosis of this disease accurately.