- Email: [email protected]
First confirmation by genotyping of transplacental choriocarcinoma transmission
Case Report
www.AJOG .org
First confirmation by genotyping of transplacental choriocarcinoma transmission Pierre-Adrien Bolze, MD; Be´atrice Weber, MD, PhD; Rosemary A. Fisher, MD, PhD; Michael J. Seckl, MD, PhD; Franc¸ois Golfier, MD, PhD 18
A mother developed multimetastatic gestational choriocarcinoma 13 months after delivery, and her infant died aged 11 months from the same tumor. The transplacental choriocarcinoma transmission was confirmed by genotyping. Henceforth, we recommend a 2-year maternal human chorionic gonadotropin follow-up after neonatal choriocarcinoma and extensive imaging if the human chorionic gonadotropin rises. Key words: choriocarcinoma, chorionic gonadotropin, genotyping, gestational trophoblastic disease, neoplasm metastasis
C
horiocarcinoma following a live birth is a rare variant of gestational trophoblastic neoplasia and occurs in about 1 per 50,000 births.1 Typically, children with infantile choriocarcinoma become symptomatic at a median age of 1 month, whereas maternal disease commonly presents several months postterm with vaginal bleeding and multiple metastases.2-4 To date, transplacental choriocarcinoma transmission has already been suspected in several cases but never been confirmed by genotyping.5
From the Department of Obstetrics and Gynecology, French Trophoblastic Disease Reference Center, Lyon Sud University Hospital, Lyon 1 Claude Bernard University, Pierre-Bénite, France (Drs Bolze and Golfier); Cancer Center Alexis Vautrin, Vandoeuvre-les-Nancy, France (Dr Weber); Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital, Campus of Imperial College London, London, United Kingdom (Drs Fisher and Seckl). Received Feb. 16, 2013; revised June 1, 2013; accepted July 1, 2013. This study was supported by French Institut National du Cancer (to the French Reference Center for Trophoblastic Diseases). The authors report no conflict of interest. Reprints: François Golfier, MD, PhD, Bat 3B Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, Pierre-Bénite 69495, France. francois.golfi[email protected]. 0002-9378/free ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.07.002
C ASE R EPORT In November 2008, a 5-month male infant was admitted to the hospital because of dyspnea and anemia (68 g/L). The clinical diagnosis of choriocarcinoma was established based on an elevated human chorionic gonadotropin (hCG) serum level of 27,860 IU/L, the presence of a liver mass, enlarged mediastinal lymph nodes, and pulmonary metastases. The placenta was no longer available for examination because it was macroscopically normal at the time of delivery. Chemotherapy with etoposide, ifosfamide, and cisplatinum was initiated. After 3 courses, hCG decreased to 16 IU/L but then rose despite a second (1 course of bleomycin, vinblastine, and high-dose methotrexate) and a third line (2 courses of cisplatinium and liposomal doxorubicin) chemotherapy regimens. An extended hepatectomy was performed but hCG levels continued to increase. Histopathological examination revealed choriocarcinoma. Although a fourth line palliative chemotherapy (gemcitabine and oxaliplatinum) was given, the infant died aged 11 months. The mother was 35 years old and had no previous history of molar pregnancy. Her hCG remained normal apart from a transient increase to 16 IU/L (Figure). However, a consistent increase to 107 IU/L was discovered 13 months after delivery when she also described intermittent headache and partial loss of vision. Whole-body computerized and
e4 American Journal of Obstetrics & Gynecology OCTOBER 2013
F-fluorodeoxyglucose-positron emission tomography showed a left occipital brain lesion, multiple pulmonary, and a left adrenal metastasis but normal pelvis. Magnetic resonance imaging of the pelvis was also normal. The brain lesion was resected, and histology was consistent with necrotic metastasis of choriocarcinoma (International Federation Gynecology and Obstetrics stage IV score 14). Chemotherapy (combination of etoposide, actinomycin D, and cisplatinum) was initiated. Her hCG levels returned to normal after the first of 3 courses of chemotherapy, which were followed by stereotactic brain irradiation (39 Grays in 13 fractions). The lung nodules disappeared after chemotherapy but not the adrenal lesion, which persisted and was resected to avoid relapse. Histopathological examination found no viable cells in an adrenal metastasis from the choriocarcinoma. Three years after her diagnosis, hCG monitoring, magnetic resonance imaging, and positron emission tomography scan evaluations showed no evidence of relapse. To determine the origin of the tumor in the mother, we genotyped with their agreement the patient and her partner (peripheral blood), tissue from the infant’s liver, and the mother’s brain metastases (Table). Deoxyribonucleic acid (DNA) was amplified using the AmpFlSTR Identifiler Plus kit (Applied Biosystems, Foster City, CA). Polymerase chain reaction products were separated by gel electrophoresis using the ABI 3100 and analyzed using GeneMapper Software (Applied Biosystems). This resulted in fluorescently labeled alleles for 15 autosomal loci on different chromosomes and a sex chromosome marker. The tumor in the infant’s liver showed loss of heterozygosity for a number of markers. However, there were no alleles present in the tumor that were not present in the child, confirming the tumor had
Case Report
www.AJOG.org
FIGURE
Maternal hCG follow-up
Postpartum hCG serum levels in the mother monitored weekly after diagnosis of choriocarcinoma in her infant. The hCG is expressed in international units per liter. CC, gestational choriocarcinoma; hCG, human chorionic gonadotropin. Bolze. Transplacental choriocarcinoma transmission. Am J Obstet Gynecol 2013.
originated in the same pregnancy as the infant. Genotyping confirmed the maternal brain metastasis was from a gestational trophoblastic tumor. Moreover, the liver metastases in the infant and the brain metastasis in the patient were derived from the same tumor.
C OMMENT Infantile choriocarcinoma is a highly malignant tumor requiring rapid initiation of chemotherapy.2 The different interval between delivery and maternal or neonatal diagnosis may be linked to the maturity of the host immune
response to cancer cells, but this remains to be further investigated. Maternal diagnosis of postpartum gestational choriocarcinoma can be difficult and established several months after delivery. This report mandates the consideration of the possibility of transplacental transmission in any case of pediatric or neonatal choriocarcinoma. The mother should therefore be placed on hCG follow-up and imaged extensively if the hCG rises, even in the absence of symptoms. It is unclear how frequently or long hCG follow-up should continue, but because most maternal cases occur within 6 months of delivery, we recommend once every 2 weeks for 6 months and monthly thereafter to 2 years after the onset of disease in the neonate.2 ACKNOWLEDGMENT Written permission for publication was obtained from the patient.
TABLE
Fluorescent microsatellite genotyping of normal and tumor tissue DNA samples Locus D8S1179 D21S11
Chromosome 8 21
Mother a
12 -15 29
Infant 13-15 29-30
Liver tumor infant
Brain tumor patient
Father
b
13-15
13
b
b
15
30
30
30-31.2
D7S820
7
10-12
10-12
10-12
10-12
10
CSF1PO
5
10-11
10-12
10-12
10-12
10-12
D3S1358
3
14-16
14-20
14-20
20b
14-20
b
THO1
11
7-9
7-9
7
D13S317
13
8-14
8-14
8-14
7
b
8 >14 b
D16S539
16
10-12
10-11
10-11
11
D2S1338
2
18-20
18-19
18 >19
18 <19b b
7-8 12-14 11 17-19
D19S433
19
13.2-14
13.2-15
13.2-15
15
vWA
12
17-19
19
19
19
19
TPOX
2
8-11
11
11
11
8-11
14-15
D18S51
18
12-15
12-15
12-15
12-15
12
AMEL
Sex
X
XY
Xb
Xb
XY
D5S818
5
11-12
11-12
11-12
11-12
12
FGA
4
21
21-24
21-24
21-24
24
a
Specific allele, the figures representing the number of short tandem repeats for each allele; b Loci showing loss of heterozygosity in tumor tissue; greater than or less than indicates allelic imbalance.
Bolze. Transplacental choriocarcinoma transmission. Am J Obstet Gynecol 2013.
OCTOBER 2013 American Journal of Obstetrics & Gynecology
e5
Case Report REFERENCES 1. Bagshawe KD, Dent J, Webb J. Hydatidiform mole in England and Wales, 1973-83. Lancet 1986;2:673-7. 2. Blohm MEG, Göbel U. Unexplained anaemia and failure to thrive as initial symptoms of
www.AJOG.org infantile choriocarcinoma: a review. Eur J Pediatr 2004;163:1-6. 3. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376:717-29. 4. Avril MF, Mathieu A, Kalifa C, Caillou C. Infantile choriocarcinoma with cutaneous
e6 American Journal of Obstetrics & Gynecology OCTOBER 2013
tumors. An additional case and review of the literature. J Am Acad Dermatol 1986;14: 918-27. 5. Fisher RA, Newlands ES. Gestational trophoblastic disease. Molecular and genetic studies. J Reprod Med 1998;43:87-97.
www.AJOG .org
First confirmation by genotyping of transplacental choriocarcinoma transmission Pierre-Adrien Bolze, MD; Be´atrice Weber, MD, PhD; Rosemary A. Fisher, MD, PhD; Michael J. Seckl, MD, PhD; Franc¸ois Golfier, MD, PhD 18
A mother developed multimetastatic gestational choriocarcinoma 13 months after delivery, and her infant died aged 11 months from the same tumor. The transplacental choriocarcinoma transmission was confirmed by genotyping. Henceforth, we recommend a 2-year maternal human chorionic gonadotropin follow-up after neonatal choriocarcinoma and extensive imaging if the human chorionic gonadotropin rises. Key words: choriocarcinoma, chorionic gonadotropin, genotyping, gestational trophoblastic disease, neoplasm metastasis
C
horiocarcinoma following a live birth is a rare variant of gestational trophoblastic neoplasia and occurs in about 1 per 50,000 births.1 Typically, children with infantile choriocarcinoma become symptomatic at a median age of 1 month, whereas maternal disease commonly presents several months postterm with vaginal bleeding and multiple metastases.2-4 To date, transplacental choriocarcinoma transmission has already been suspected in several cases but never been confirmed by genotyping.5
From the Department of Obstetrics and Gynecology, French Trophoblastic Disease Reference Center, Lyon Sud University Hospital, Lyon 1 Claude Bernard University, Pierre-Bénite, France (Drs Bolze and Golfier); Cancer Center Alexis Vautrin, Vandoeuvre-les-Nancy, France (Dr Weber); Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital, Campus of Imperial College London, London, United Kingdom (Drs Fisher and Seckl). Received Feb. 16, 2013; revised June 1, 2013; accepted July 1, 2013. This study was supported by French Institut National du Cancer (to the French Reference Center for Trophoblastic Diseases). The authors report no conflict of interest. Reprints: François Golfier, MD, PhD, Bat 3B Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, Pierre-Bénite 69495, France. francois.golfi[email protected]. 0002-9378/free ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.07.002
C ASE R EPORT In November 2008, a 5-month male infant was admitted to the hospital because of dyspnea and anemia (68 g/L). The clinical diagnosis of choriocarcinoma was established based on an elevated human chorionic gonadotropin (hCG) serum level of 27,860 IU/L, the presence of a liver mass, enlarged mediastinal lymph nodes, and pulmonary metastases. The placenta was no longer available for examination because it was macroscopically normal at the time of delivery. Chemotherapy with etoposide, ifosfamide, and cisplatinum was initiated. After 3 courses, hCG decreased to 16 IU/L but then rose despite a second (1 course of bleomycin, vinblastine, and high-dose methotrexate) and a third line (2 courses of cisplatinium and liposomal doxorubicin) chemotherapy regimens. An extended hepatectomy was performed but hCG levels continued to increase. Histopathological examination revealed choriocarcinoma. Although a fourth line palliative chemotherapy (gemcitabine and oxaliplatinum) was given, the infant died aged 11 months. The mother was 35 years old and had no previous history of molar pregnancy. Her hCG remained normal apart from a transient increase to 16 IU/L (Figure). However, a consistent increase to 107 IU/L was discovered 13 months after delivery when she also described intermittent headache and partial loss of vision. Whole-body computerized and
e4 American Journal of Obstetrics & Gynecology OCTOBER 2013
F-fluorodeoxyglucose-positron emission tomography showed a left occipital brain lesion, multiple pulmonary, and a left adrenal metastasis but normal pelvis. Magnetic resonance imaging of the pelvis was also normal. The brain lesion was resected, and histology was consistent with necrotic metastasis of choriocarcinoma (International Federation Gynecology and Obstetrics stage IV score 14). Chemotherapy (combination of etoposide, actinomycin D, and cisplatinum) was initiated. Her hCG levels returned to normal after the first of 3 courses of chemotherapy, which were followed by stereotactic brain irradiation (39 Grays in 13 fractions). The lung nodules disappeared after chemotherapy but not the adrenal lesion, which persisted and was resected to avoid relapse. Histopathological examination found no viable cells in an adrenal metastasis from the choriocarcinoma. Three years after her diagnosis, hCG monitoring, magnetic resonance imaging, and positron emission tomography scan evaluations showed no evidence of relapse. To determine the origin of the tumor in the mother, we genotyped with their agreement the patient and her partner (peripheral blood), tissue from the infant’s liver, and the mother’s brain metastases (Table). Deoxyribonucleic acid (DNA) was amplified using the AmpFlSTR Identifiler Plus kit (Applied Biosystems, Foster City, CA). Polymerase chain reaction products were separated by gel electrophoresis using the ABI 3100 and analyzed using GeneMapper Software (Applied Biosystems). This resulted in fluorescently labeled alleles for 15 autosomal loci on different chromosomes and a sex chromosome marker. The tumor in the infant’s liver showed loss of heterozygosity for a number of markers. However, there were no alleles present in the tumor that were not present in the child, confirming the tumor had
Case Report
www.AJOG.org
FIGURE
Maternal hCG follow-up
Postpartum hCG serum levels in the mother monitored weekly after diagnosis of choriocarcinoma in her infant. The hCG is expressed in international units per liter. CC, gestational choriocarcinoma; hCG, human chorionic gonadotropin. Bolze. Transplacental choriocarcinoma transmission. Am J Obstet Gynecol 2013.
originated in the same pregnancy as the infant. Genotyping confirmed the maternal brain metastasis was from a gestational trophoblastic tumor. Moreover, the liver metastases in the infant and the brain metastasis in the patient were derived from the same tumor.
C OMMENT Infantile choriocarcinoma is a highly malignant tumor requiring rapid initiation of chemotherapy.2 The different interval between delivery and maternal or neonatal diagnosis may be linked to the maturity of the host immune
response to cancer cells, but this remains to be further investigated. Maternal diagnosis of postpartum gestational choriocarcinoma can be difficult and established several months after delivery. This report mandates the consideration of the possibility of transplacental transmission in any case of pediatric or neonatal choriocarcinoma. The mother should therefore be placed on hCG follow-up and imaged extensively if the hCG rises, even in the absence of symptoms. It is unclear how frequently or long hCG follow-up should continue, but because most maternal cases occur within 6 months of delivery, we recommend once every 2 weeks for 6 months and monthly thereafter to 2 years after the onset of disease in the neonate.2 ACKNOWLEDGMENT Written permission for publication was obtained from the patient.
TABLE
Fluorescent microsatellite genotyping of normal and tumor tissue DNA samples Locus D8S1179 D21S11
Chromosome 8 21
Mother a
12 -15 29
Infant 13-15 29-30
Liver tumor infant
Brain tumor patient
Father
b
13-15
13
b
b
15
30
30
30-31.2
D7S820
7
10-12
10-12
10-12
10-12
10
CSF1PO
5
10-11
10-12
10-12
10-12
10-12
D3S1358
3
14-16
14-20
14-20
20b
14-20
b
THO1
11
7-9
7-9
7
D13S317
13
8-14
8-14
8-14
7
b
8 >14 b
D16S539
16
10-12
10-11
10-11
11
D2S1338
2
18-20
18-19
18 >19
18 <19b b
7-8 12-14 11 17-19
D19S433
19
13.2-14
13.2-15
13.2-15
15
vWA
12
17-19
19
19
19
19
TPOX
2
8-11
11
11
11
8-11
14-15
D18S51
18
12-15
12-15
12-15
12-15
12
AMEL
Sex
X
XY
Xb
Xb
XY
D5S818
5
11-12
11-12
11-12
11-12
12
FGA
4
21
21-24
21-24
21-24
24
a
Specific allele, the figures representing the number of short tandem repeats for each allele; b Loci showing loss of heterozygosity in tumor tissue; greater than or less than indicates allelic imbalance.
Bolze. Transplacental choriocarcinoma transmission. Am J Obstet Gynecol 2013.
OCTOBER 2013 American Journal of Obstetrics & Gynecology
e5
Case Report REFERENCES 1. Bagshawe KD, Dent J, Webb J. Hydatidiform mole in England and Wales, 1973-83. Lancet 1986;2:673-7. 2. Blohm MEG, Göbel U. Unexplained anaemia and failure to thrive as initial symptoms of
www.AJOG.org infantile choriocarcinoma: a review. Eur J Pediatr 2004;163:1-6. 3. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376:717-29. 4. Avril MF, Mathieu A, Kalifa C, Caillou C. Infantile choriocarcinoma with cutaneous
e6 American Journal of Obstetrics & Gynecology OCTOBER 2013
tumors. An additional case and review of the literature. J Am Acad Dermatol 1986;14: 918-27. 5. Fisher RA, Newlands ES. Gestational trophoblastic disease. Molecular and genetic studies. J Reprod Med 1998;43:87-97.