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45,X complete hydatidiform mole
GYNECOLOGIC
ONCOLOGY
14, 279-283 (1982)
45,X Complete Hydatidiform Mole Ross S. BERKOWITZ, M.D.,’ MARY SANDSTROM,Ph.D., DONALD P. GOLDSTEIN, M.D., AND SHIRLEY G. DRISCOLL,M.D. New England Trophoblastic Disease Center, Divisions of Gynecologic Oncology and Genetics, Departments of Obstetrics and Gynecology and Pathology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115 Received February 1, 1982 This paper describes the clinical history and chromosomal analyses of a patient with a 45,X molar pregnancy and reviews the literature regarding cytogenetic studies of complete hydatidiform moles. The reported patient with a 45,X complete mole developed postmolar choriocarcinoma. Complete molar pregnancy appears to be the morphologic expression of a wide variety of chromosomal patterns. The risk of developing postmolar choriocarcinema may be related to the chromosomal pattern of the molar tissue.
Several investigators in recent years have studied the chromosomal patterns of complete hydatidiform mole to further elucidate the genesis of this neoplasm. Most complete hydatidiform moles have a 46,Xx karyotype and are of androgenetic origin [l-5]. However, approximately 3-13% of hydatidiform moles have been found to have a 46,XY karyotype [6,7]. As more molar tissues have been analyzed, it has become increasingly apparent that the genetic background of this gestational tumor is varied and complex. The present case represents the first report of a 45,X complete hydatidiform mole. This paper describes the clinical history and chromosomal analyses of a patient with a 45,X molar pregnancy and reviews the literature regarding cytogenetic studies of complete hydatidiform moles. CASE HISTORY
G.B., an l&year-old white female, gravida 1, para 0, had her last menstrual period on 7/9/80 and presented to her private obstetrician-gynecologist on 10/14/ 80 with a 3-week history of vaginal bleeding. The uterine size was appropriate for gestational age on physical examination. A pelvic ultrasound examination was performed, revealing a molar pregnancy with bilateral theta lutein ovarian cysts. The patient was then referred to the New England Trophoblastic Disease Center for further evaluation and treatment. On 10/15/80, the serum human chorionic gonadotropin (hCG) level was 250,000 mIU/ml and the admission chest ’ Ross S. Berkowitz, M.D. is an American Cancer Society Junior Faculty Clinical Fellow. Requests for reprints should be addressed to Donald P. Goldstein, M.D. 279
0090-8258/82/050279-05$01.00/O Copyright Q 1982 by Academic Press, Inc. All rights of reproduction in any form reserved.
280
BERKOWITZ
ET
AL.
roentgenogram was normal. Uterine suction and sharp curettage was performed on 10/16/80; pathologic review of the curettings revealed a Group IV/VI hydatidiform mole [S]. Fresh molar tissue was also promptly sent for chromosomal analysis. After molar evacuation, the patient was followed with weekly hCG titers. The hCG level fell to 104 mIU/ml on 11/24/80 but then rose to 180 mIU/ ml on 12/S/80. The patient was then readmitted for further evaluation and treatment of persistent gestational trophoblastic disease. Metastatic workup, including chest roentgenogram, liver function tests, liver isotope scan, head computed tomography scan, and laparoscopy, demonstrated no evidence of metastatic disease [9]. A pretreatment endometrial curettage was performed on 12/9/80; the curettings contained fragments of choriocarcinoma [lo]. The patient was then treated with one course of methotrexate and citrovorum factor rescue and subsequently achieved complete sustained gonadotropin remission [ Ill. CHROMOSOMAL
STUDIES
The molar tissue, analyzed cytogenetically by quinacrine and Giemsa-trypsin banding techniques, was found to have a 45,X karyotype (Fig. 1). All of the 24 counted cells from the molar tissue contained only one X chromosome. Peripheral blood was obtained from both the patient and her spouse for chromosomal analysis. Lymphocytes were studied by quinacrine and A3 methyl-green banding techniques. The karyotype of the patient was 46,Xx and the karyotype of her spouse was 46,XY. The “paternal” blood samples exhibited a very bright polymorphic region on one of the No. 22 chromosomes, but this distinctive polymorphic variant did not appear in the molar material. There were no other polymorphic variants in the molar tissue or the “parents’ ” blood. While striking polymorphisms were not present in the molar tissue, apparent heteromorphic differences were not visible in the D,G, or No. 3 chromosomes. Therefore, no definitive conclusion can be reached as to the chromosomal source (“maternal” and/or “paternal”) of the molar tissue. DISCUSSION Our understanding of the genesis of complete molar pregnancy has been advanced by recent cytogenetic studies. Kajii and Ohama analyzed the chromosomal patterns in 20 molar pregnancies and the karyotype was 46,Xx in all cases [l]. The mode of inheritance of the molar chromosomes was examined in seven of the cases using Q- and R-band polymorphisms as markers. The molar chromosomes were demonstrated to be completely of paternal origin. After performing Q-banding chromosomal studies in three molar pregnancies and their parents, Wake er al. also concluded that the molar chromosomes were strictly of paternal origin [3]. In order to determine the mechanism of androgenesis in complete molar pregnancy, Yamashita et al. analyzed 13 hydatidiform moles and lymphocytes from each parent for HLA (A and B loci) specificities [4]. Molar tissues expressed homozygous HLA A and B specificities identical to those of the fathers. These data suggested that a complete molar pregnancy develops from an ovum which has been fertilized by a haploid sperm which duplicated its own
CASE
REPORTS
281
282
BERKOWITZ
ET AL.
chromosomes after meiosis. The authors speculated that the ovum nucleus was either absent or inactivated. Jacobs et al. performed cytogenetic studies of 24 complete moles and their parents to further elucidate the genesis of this neoplasm [12]. The molar and parental cells were analyzed using enzyme markers (phosphoglucomutase 1) and Q- and C-banding techniques. Twenty-one moles had a 46,Xx karyotype; one had a variable count with a mode of 85,XxXx; one had an additional medium-sized chromosome in a few cells; and one was 46,XY. The molar chromosomes were clearly of paternal origin in 22 cases. Analysis of enzyme markers was strongly supportive of a haploid sperm origin for most of the 46,Xx moles. However, in one 46,Xx complete mole, the molar chromosomes appeared to be derived from both paternal and maternal genomes. While most complete moles have a 46,Xx constitution, about 3-13% of hydatidiform moles have a 46,XY karyotype [6,7]. Surti et al. studied a case of 46,XY mole using polymorphic chromosomal and enzyme markers of the molar and parental genomes 161.The molar chromosomes were determined to be entirely of paternal origin. Another case of 46,XY molar pregnancy was examined by Patti110 et al. using Q-band chromosomal analysis [7]. Cytogenetic studies indicated that this 46,XY molar pregnancy was derived from fertilization of an ovum by two spermatozoa. The present paper reports the first case of a 45,X complete hydatidiform mole and therefore further expands the known chromosomal patterns of this neoplasm. Complete molar pregnancy does not result from a single chromosomal abnormality. As more molar tissues have been studied, the reported chromosomal constitution of complete mole has become increasingly complex and diverse. Complete molar pregnancy appears to be the morphologic expression of a wide variety of chromosomal patterns. The risk of developing postmolar choriocarcinoma may be related to the chromosomal pattern of the molar tissue. The present patient with a 45,X hydatidiform mole developed choriocarcinoma and required chemotherapy to achieve gonadotropin remission. Unfortunately, most cytogenetic analyses of molar pregnancies have ignored the clinical course of the examined patients. Cytogenetic studies should be continued to further understand the genesis of molar pregnancy and to determine whether molar chromosomal patterns are related to the risk of developing persistent trophoblastic disease. ACKNOWLEDGMENT The authors wish to express their appreciation to Margaret M. Powers for her technical work in performing the chromosomal studies.
REFERENCES 1. Kajii, T., and Ohama, K. Androgenetic origin of hydatidiform mole, Nature (Lo&~n) 268, 633-634 (1977). 2. Jacobs, P. A., Hassold, T. J., Matsuyama, A. M., and Newlands, I. M. Chromosome constitution of gestational trophoblastic disease, Lancer 2, 49 (1978). 3. Wake, N., Takagi, N., and Sasaki, M. Androgenesis as a cause of hydatidiform mole, J. Nat. Cancer Inst. 60, 51-53 (1978). 4. Yamashita, K., Wake, N., Araki, T., Ichinoe, K., and Makoto, K. Human lymphocyte antigen expression in hydatidiform mole: Androgenesis following fertilization by a haploid sperm, Amer. J. O&et. Gynecol. 135, 597-600 (1979).
CASE
REPORTS
283
5. Yamashita, K., Wake, N., Araki, T., Ichinoe, K., and Makoto, K. A further HLA study of hydatidiform moles, Gynecol. Oncol. 11, 23-28 (1981). 6. Surti, U., Szulman, A. E., and O’Brien, S. Complete (classic) hydatidiform mole with 46,XY karyotype of paternal origin, Hum. Genet. 51, 153-155 (1979). 7. Pattillo, R. A., Sasaki, S., Katayama, K. P., Roesler, M. and Mattingly, R. F. Genesis of 46,XY hydatidiform mole, Amer. J. Obstet. Gynecol. 141, 104-105 (1981). 8. Hertig, A. T., and Mansell, H. Atlas of tumor pathology: Tumors of the female sex organs, Part I, Hydatidiform mole and choriocarcinoma, Armed Forces Inst. of Pathol., Washington, D.C., Sect. IX, Fast. 33 (1956). 9. Goldstein, D. P., and Berkowitz, R. S. Gestational trophoblastic neoplasms-Clinical principles of diagnosis and management, Saunders, Philadelphia (1982). 10. Berkowitz, R. S., Desai, U., Goldstein, D. P., Driscoll, S. G., Marean, A. R., and Bernstein, M. R. Pretreatment curettage-A predictor of chemotherapy response in gestational trophoblastic neoplasia, Gynecol. Oncol. 10, 39-43 (1980). 11. Berkowitz, R. S., and Goldstein, D. P. Methotrexate with citrovorum factor rescue for nonmetastatic gestational trophoblastic neoplasms, Obstet. Gynecol. 54, 725-728 (1979). 12. Jacobs, P. A., Wilson, C. M., Sprenkle, J. A., Rosenshein, N. B., and Migeon, B. R. Mechanism of origin of complete hydatidiform moles, Nature (London) 286, 714-716 (1980).
ONCOLOGY
14, 279-283 (1982)
45,X Complete Hydatidiform Mole Ross S. BERKOWITZ, M.D.,’ MARY SANDSTROM,Ph.D., DONALD P. GOLDSTEIN, M.D., AND SHIRLEY G. DRISCOLL,M.D. New England Trophoblastic Disease Center, Divisions of Gynecologic Oncology and Genetics, Departments of Obstetrics and Gynecology and Pathology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115 Received February 1, 1982 This paper describes the clinical history and chromosomal analyses of a patient with a 45,X molar pregnancy and reviews the literature regarding cytogenetic studies of complete hydatidiform moles. The reported patient with a 45,X complete mole developed postmolar choriocarcinoma. Complete molar pregnancy appears to be the morphologic expression of a wide variety of chromosomal patterns. The risk of developing postmolar choriocarcinema may be related to the chromosomal pattern of the molar tissue.
Several investigators in recent years have studied the chromosomal patterns of complete hydatidiform mole to further elucidate the genesis of this neoplasm. Most complete hydatidiform moles have a 46,Xx karyotype and are of androgenetic origin [l-5]. However, approximately 3-13% of hydatidiform moles have been found to have a 46,XY karyotype [6,7]. As more molar tissues have been analyzed, it has become increasingly apparent that the genetic background of this gestational tumor is varied and complex. The present case represents the first report of a 45,X complete hydatidiform mole. This paper describes the clinical history and chromosomal analyses of a patient with a 45,X molar pregnancy and reviews the literature regarding cytogenetic studies of complete hydatidiform moles. CASE HISTORY
G.B., an l&year-old white female, gravida 1, para 0, had her last menstrual period on 7/9/80 and presented to her private obstetrician-gynecologist on 10/14/ 80 with a 3-week history of vaginal bleeding. The uterine size was appropriate for gestational age on physical examination. A pelvic ultrasound examination was performed, revealing a molar pregnancy with bilateral theta lutein ovarian cysts. The patient was then referred to the New England Trophoblastic Disease Center for further evaluation and treatment. On 10/15/80, the serum human chorionic gonadotropin (hCG) level was 250,000 mIU/ml and the admission chest ’ Ross S. Berkowitz, M.D. is an American Cancer Society Junior Faculty Clinical Fellow. Requests for reprints should be addressed to Donald P. Goldstein, M.D. 279
0090-8258/82/050279-05$01.00/O Copyright Q 1982 by Academic Press, Inc. All rights of reproduction in any form reserved.
280
BERKOWITZ
ET
AL.
roentgenogram was normal. Uterine suction and sharp curettage was performed on 10/16/80; pathologic review of the curettings revealed a Group IV/VI hydatidiform mole [S]. Fresh molar tissue was also promptly sent for chromosomal analysis. After molar evacuation, the patient was followed with weekly hCG titers. The hCG level fell to 104 mIU/ml on 11/24/80 but then rose to 180 mIU/ ml on 12/S/80. The patient was then readmitted for further evaluation and treatment of persistent gestational trophoblastic disease. Metastatic workup, including chest roentgenogram, liver function tests, liver isotope scan, head computed tomography scan, and laparoscopy, demonstrated no evidence of metastatic disease [9]. A pretreatment endometrial curettage was performed on 12/9/80; the curettings contained fragments of choriocarcinoma [lo]. The patient was then treated with one course of methotrexate and citrovorum factor rescue and subsequently achieved complete sustained gonadotropin remission [ Ill. CHROMOSOMAL
STUDIES
The molar tissue, analyzed cytogenetically by quinacrine and Giemsa-trypsin banding techniques, was found to have a 45,X karyotype (Fig. 1). All of the 24 counted cells from the molar tissue contained only one X chromosome. Peripheral blood was obtained from both the patient and her spouse for chromosomal analysis. Lymphocytes were studied by quinacrine and A3 methyl-green banding techniques. The karyotype of the patient was 46,Xx and the karyotype of her spouse was 46,XY. The “paternal” blood samples exhibited a very bright polymorphic region on one of the No. 22 chromosomes, but this distinctive polymorphic variant did not appear in the molar material. There were no other polymorphic variants in the molar tissue or the “parents’ ” blood. While striking polymorphisms were not present in the molar tissue, apparent heteromorphic differences were not visible in the D,G, or No. 3 chromosomes. Therefore, no definitive conclusion can be reached as to the chromosomal source (“maternal” and/or “paternal”) of the molar tissue. DISCUSSION Our understanding of the genesis of complete molar pregnancy has been advanced by recent cytogenetic studies. Kajii and Ohama analyzed the chromosomal patterns in 20 molar pregnancies and the karyotype was 46,Xx in all cases [l]. The mode of inheritance of the molar chromosomes was examined in seven of the cases using Q- and R-band polymorphisms as markers. The molar chromosomes were demonstrated to be completely of paternal origin. After performing Q-banding chromosomal studies in three molar pregnancies and their parents, Wake er al. also concluded that the molar chromosomes were strictly of paternal origin [3]. In order to determine the mechanism of androgenesis in complete molar pregnancy, Yamashita et al. analyzed 13 hydatidiform moles and lymphocytes from each parent for HLA (A and B loci) specificities [4]. Molar tissues expressed homozygous HLA A and B specificities identical to those of the fathers. These data suggested that a complete molar pregnancy develops from an ovum which has been fertilized by a haploid sperm which duplicated its own
CASE
REPORTS
281
282
BERKOWITZ
ET AL.
chromosomes after meiosis. The authors speculated that the ovum nucleus was either absent or inactivated. Jacobs et al. performed cytogenetic studies of 24 complete moles and their parents to further elucidate the genesis of this neoplasm [12]. The molar and parental cells were analyzed using enzyme markers (phosphoglucomutase 1) and Q- and C-banding techniques. Twenty-one moles had a 46,Xx karyotype; one had a variable count with a mode of 85,XxXx; one had an additional medium-sized chromosome in a few cells; and one was 46,XY. The molar chromosomes were clearly of paternal origin in 22 cases. Analysis of enzyme markers was strongly supportive of a haploid sperm origin for most of the 46,Xx moles. However, in one 46,Xx complete mole, the molar chromosomes appeared to be derived from both paternal and maternal genomes. While most complete moles have a 46,Xx constitution, about 3-13% of hydatidiform moles have a 46,XY karyotype [6,7]. Surti et al. studied a case of 46,XY mole using polymorphic chromosomal and enzyme markers of the molar and parental genomes 161.The molar chromosomes were determined to be entirely of paternal origin. Another case of 46,XY molar pregnancy was examined by Patti110 et al. using Q-band chromosomal analysis [7]. Cytogenetic studies indicated that this 46,XY molar pregnancy was derived from fertilization of an ovum by two spermatozoa. The present paper reports the first case of a 45,X complete hydatidiform mole and therefore further expands the known chromosomal patterns of this neoplasm. Complete molar pregnancy does not result from a single chromosomal abnormality. As more molar tissues have been studied, the reported chromosomal constitution of complete mole has become increasingly complex and diverse. Complete molar pregnancy appears to be the morphologic expression of a wide variety of chromosomal patterns. The risk of developing postmolar choriocarcinoma may be related to the chromosomal pattern of the molar tissue. The present patient with a 45,X hydatidiform mole developed choriocarcinoma and required chemotherapy to achieve gonadotropin remission. Unfortunately, most cytogenetic analyses of molar pregnancies have ignored the clinical course of the examined patients. Cytogenetic studies should be continued to further understand the genesis of molar pregnancy and to determine whether molar chromosomal patterns are related to the risk of developing persistent trophoblastic disease. ACKNOWLEDGMENT The authors wish to express their appreciation to Margaret M. Powers for her technical work in performing the chromosomal studies.
REFERENCES 1. Kajii, T., and Ohama, K. Androgenetic origin of hydatidiform mole, Nature (Lo&~n) 268, 633-634 (1977). 2. Jacobs, P. A., Hassold, T. J., Matsuyama, A. M., and Newlands, I. M. Chromosome constitution of gestational trophoblastic disease, Lancer 2, 49 (1978). 3. Wake, N., Takagi, N., and Sasaki, M. Androgenesis as a cause of hydatidiform mole, J. Nat. Cancer Inst. 60, 51-53 (1978). 4. Yamashita, K., Wake, N., Araki, T., Ichinoe, K., and Makoto, K. Human lymphocyte antigen expression in hydatidiform mole: Androgenesis following fertilization by a haploid sperm, Amer. J. O&et. Gynecol. 135, 597-600 (1979).
CASE
REPORTS
283
5. Yamashita, K., Wake, N., Araki, T., Ichinoe, K., and Makoto, K. A further HLA study of hydatidiform moles, Gynecol. Oncol. 11, 23-28 (1981). 6. Surti, U., Szulman, A. E., and O’Brien, S. Complete (classic) hydatidiform mole with 46,XY karyotype of paternal origin, Hum. Genet. 51, 153-155 (1979). 7. Pattillo, R. A., Sasaki, S., Katayama, K. P., Roesler, M. and Mattingly, R. F. Genesis of 46,XY hydatidiform mole, Amer. J. Obstet. Gynecol. 141, 104-105 (1981). 8. Hertig, A. T., and Mansell, H. Atlas of tumor pathology: Tumors of the female sex organs, Part I, Hydatidiform mole and choriocarcinoma, Armed Forces Inst. of Pathol., Washington, D.C., Sect. IX, Fast. 33 (1956). 9. Goldstein, D. P., and Berkowitz, R. S. Gestational trophoblastic neoplasms-Clinical principles of diagnosis and management, Saunders, Philadelphia (1982). 10. Berkowitz, R. S., Desai, U., Goldstein, D. P., Driscoll, S. G., Marean, A. R., and Bernstein, M. R. Pretreatment curettage-A predictor of chemotherapy response in gestational trophoblastic neoplasia, Gynecol. Oncol. 10, 39-43 (1980). 11. Berkowitz, R. S., and Goldstein, D. P. Methotrexate with citrovorum factor rescue for nonmetastatic gestational trophoblastic neoplasms, Obstet. Gynecol. 54, 725-728 (1979). 12. Jacobs, P. A., Wilson, C. M., Sprenkle, J. A., Rosenshein, N. B., and Migeon, B. R. Mechanism of origin of complete hydatidiform moles, Nature (London) 286, 714-716 (1980).