- Email: [email protected]
Management of benign trophoblastic tumors
Management of benign trophoblastic tumors DEREK LLEWELLYN-JONES, O.B.E., M.D., M.A.O., F.R.C.O.G.* Kuala Lumpur, Malaysia In a consecutive series of 250 cases of hydatidiform mole, the initial treatment was related to the mortality from subsequent malignancy. When hysterectomy was performed, either with the mole in situ (28 cases) or within 5 days of spontaneous or oxytodn-induced vaginal expulsion (46 cases) malignancy was detected in 6 cases and one patient died. When the hydatidiform mole was expelled vaginally, either spontaneously or following an oxytocin infusion and hysterectomy was not performed, 23 of 176 patients developed a malignant tumor, and 12 of them are dead. It is suggested that hysterectomy with ovarian conservation is protective against the subsequent development of malignancy and is the treatment of choice for patients, irrespective of age, who have a hydatidiform mole and who have no desire for further children.
W H I L E the incidence of trophoblastic tumor in the United States is 1 in 2,500 pregnancies, the incidence in Southeast Asia among all indigenous races is at least four times as high, and in Central Malaya it is 1 in 600 of all pregnancies occurring in the area. The cause of this disproportionate increase is not clear, but there is evidence of a disturbed immunologic response among patients presenting with benign and malignant trophoblastic tumors. 6 The present paper records the management of 250 consecutive cases of hydatidiform mole encountered in a single hospital between 1958 and 1964.
mainly syncytium, penetrates the decidua and infiltrates between myometrial fibers, but vvithout any evidence of destruction of the myometrial cells or of hemorrhage. The condition is benign and is referred to as "syncytial metritis." Malignant trophoblastic tumors. Invasive mole. This is a term applied when there is penetration of the myometrium by molar tissue with destruction of myometrial fibers or extension of molar tissue to other organs, the vascular pattern of the original mole always being maintained. Choriocarcinoma. This is a more malignant form in which syncytio- and cytotrophoblast invades the myometrium with marked tissue destruction and hemorrhage and is usually carried by the systemic bloodstream producing distant metastases. Histologically, the tumor is characterized by sheets of trophoblastic cells, with rarely any vesicle formation.
Definitions
Benign trophoblastic tumors. Hydatidiform mole. This is a neoplastic condition characterized by hydropic swelling and vesicle formation of the placental villi, paucity or absence of blood vessels within the villus, and is associated with proliferation of trophoblast which is most marked in the placental bed. Occasionally, the trophoblast,
Primary management !Table II
Vaginal expulsion. Spontaneous. One hundred and forty of the patients expelled the mole spontaneously or with the additional use of an oxytocic infusion to speed up the process. If the uterine contractions were sustained and bleeding
From the Department of Obstetrics and Gynaecology, General Hospital. *Prese,nt address: Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia.
589
590
Llewellyn-Jones
October 15, 1967 Am.]. Obst. & Gynec.
Table I. Method of treatment adopted in 250 cases of hydatidiform mole Digitally aided expulsion and curettage Digitally aided expulsion followed by hysterectomy Oxytocin-induced expulsion and curettage Oxytocin-induced expulsion followed by hysterectomy Oxytocin failure and hysterotomy Oxytocin failure and hysterectomy with mole in situ
40 68 6 2 4 6 24
slight, interference was avoided and only after the greater part of the mole had been expelled was digital evacuation carried out. In 50 cases, the uterine contractions were inadequate or bleeding increased and expulsion of the tumor was aided by the use of a dilute oxytocin infusion ( 1 in 1,000 in 5 per cent dextrose) using 10 mU. per minute initially. When the cervix was sufficiently dilated and vesicles were being expelled, evacuation of the uterus was aided digitally. Curettage was not perlormed at the time because of the excessive vascularity and thinness of the myometrium, but was performed routinely 5 days later, except in the 40 patients who were treated by hysterectomy 3 to 7 days after molar expulsion. Oxytocin-induced expulsion. Oxytocin infusion was given to induce expulsion in 80 cases and was successful in 74. The concentration used initially was 10 mU. per minute (approximately equal to 15 drops per minute of a 1 in 1,000 solution) and this was increased incrementally to obtain uterine contractions. No infusion was run for more than 10 hours. Sixty patients required a concentration of 40 mU. per minute and 14 required a concentration of 80 mU. per minute to effect the expulsion of the tumor. In 53 cases the tumor was expelled within 12 hours of setting up the infusion; 16 required a second infusion and 5 a third. In 6 cases the infusion was abandoned; in one because of deteriorating pre-eclampsia and in the 5 other cases because three infusions of oxytocin failed to induce expulsion. In these 5 cases
each infusion lasted 10 hours, and the concentration of the solution was incrementally increased to 200 mU. per minute before the method was abandoned. Two of these 6 cases were treated by hysterotomy and 4 by hysterectomy. Of the 74 cases in which the infusion was successful, curettage was performed 5 days later in 68 and hysterectomy in 6. Vaginal expulsion, whether spontaneous or oxytocin-induced, was attended in 18 cases (10 per cent) by a marked systemic upset (tachycardia, dyspnea, and episodic cyanosis), the symptoms suggesting the intravascular spread of emboli of trophoblast. Three patients died. Abdominal operation. Hysterotomy. In the early part of the series, hysterotomy was considered an adequate treatment and was carried out as a primary procedure in 6 cases, and after the failure of an oxytocin infusion in 2 cases. With the introduction of infusions of oxytocin in high concentration, irrespective of the size of the uterus, the need for hysterotomy decreased. The operation is inadequate, as all the risk of manipulative spread of trophoblast is present without the advantage of removing the uterus. A false sense of security results if the cavity is cleared of trophoblast, for active, potentially malignant, cells may persist deep in the myometrium. Moreover, the operation inevitably leaves a vertical scar and subsequent deliveries must be by cesarean section. If, on the other hand, the patient has no desire for further children, hysterotomy is incomplete treatment. It is rarely indicated in the management of benign trophoblastic tumor. Hysterectomy. Hysterectomy with the mole in situ was performed in 24 cases; following failure of oxytocin infusion in 4 cases and within 7 days of expulsion of the mole in a further 46 cases. Aftercare
The patients remained in hospital until uterine involution was proceeding normally and blood loss per vaginam was minimal. Of the 174 patients whose uterus had not
Volume 99 Number4
Management of benign trophoblastic tumors 591
been removed, a second curettage was required in 30, a third in 8, and a fourth in one patient before it was felt that all trophoblastic tissue had been removed. In 10 of these 30 patients, a malignant trophoblastic tumor was discovered subsequently. Since the main purpose of aftercare of patients expelling a hydatidiform mole is the early detection of malignant change, several methods were routinely adopted. These were ( 1) histologic assessment of the degree of trophoblastic proliferation and "anaplasia" in the mole and in the curettings, (2) clinical determination of the rate of involution of the uterus, and ( 3) serial estimations of urinary chorionic gonadotropin. Prognosis from histologic examination of curettings. Hertig and ManselJ5 had noted that the greater the degree of "anaplasia" of the trophoblast, and the greater the amount of trophoblastic proliferation on the villi, the greater was the risk of the subsequent development of malignancy. Their criteria were applied in the histologic examination of molar tissue, particularly that obtained on curettage following molar expulsion, in 170 of the 250 cases. It was concluded from this study that ( 1) the quantity of trophoblast varied very considerably in different parts of the tumor and (2) the criteria gave no prognostic evidence regarding the subsequent development of malignancy. Clinical examination. Uterine involution was slower following expulsion of a hydatidiform mole than in cases of abortion and was not complete for between 21 and 28 days after the expulsion. Increase in the size of the uterus or increase in bleeding during this time was suggestive of residual trophoblast
in the uterus or the development of malignancy. Curettage in which no debris was evacuated favored the latter but no clear prognostic guide could be obtained. Urinary chorionic gonadotropin excretion. Gonadotropin assays were perfonned each week from the time of expulsion of the hydatidiform mole until they had been negative for 4 consecutive weeks, and thereafter monthly until a year had passed since molar expulsion. Initially the Aschheim-Zondek or Galli-Mainini test was used, but was replaced by the hemagglutination-inhibition test when it had been detennined that the latter test was more sensitive. 7 Following hysterectomy the test became negative within 14 days in 71 of the 74 cases, and was negative in all 21 days after operation. When hysterectomy was not performed the time taken for the test to become negative was variable and bore no relationship to the size of the uterus before molar expulsion. By the twenty-first day it was negative in 60.4 per cent and by the forty-second day the percentage had risen to 83.5 per cent (Table II). Of the 29 patients who had positive tests persisting for more than 42 days, in 17 ( 60 per cent) a malignant trophoblastic turnor was subsequently discovered. Effect of primary treatment on mortality and malignancy
It was evident during the course of this study that two distinct groups could be delineated; those in whom hysterectomy was performed either with the mole in situ or within 7 days of its expulsion per vaginam and those in whom hysterectomy was not performed as initial treatment of a benign trophoblastic tumor. These groups
Table II. Urinary chorionic gonadotropin in the follow-up of cases of hydatidiform mole Days after vaginal expulsion or hysterectomy
Vaginal expulsion ( 176 cases) Per cent positive cases)
7
14
153 87.0 56 75.5
127 72.1 3 4.0
I
21 65 39.6 1 1.4
I
28 43 24.4 0
I
35
35 20.0 0
I
42 29 16.5 0
I
49
56
26 14.8 0
23 13.1 0
592
L!ewe!!yn-Jones Am.
OctobN 11, l%7 Ohst. & Gyn,····
J.
Table III. Incidence of malignancy and mortality in cases treated and not treated hy primary hysterectomy
Hysterectomy No hysterectomy
74 6 176 23 --250 29 --------
were matched for race, age, and parity although the numbers treated were disparate. Cases in which hysterectomy was performed as primary treatment. Mortality. Two of the 74 patients died within 72 hours of operation: one from shock and cor pulmonale, which was considered due to intravascular trophoblastic spread to the pulmonary capillaries, and one from the effects of electrolyte imbalance following paralytic ileus. One patient died from choriocarcinoma 28 days after operation: Case 11/64. The patient was Indian, aged 42, and gravida 12. The preoperative assessment showed that the disease was confined to the uterus. A total hysterectomy was performed with the tumor in situ, and histologic examination of the specimen confirmed that it was a hydatidiform mole with no evidence of invasion of the Inyonletriutn. The patient was discharged 14 days after operation, when an immunologic test for gonadotropin was negative. Two weeks later she had developed a vaginal secondary deposit, the lung contained multiple secondary deposits, and the gonadotropin test was strongly positive. Within 2 days, signs of cerebral involvement occurred and she died 3 days later. Autopsy revealed choriocarcinoma. The over-all mortality was 3 out of 74, or 4.0 per cent, and that from malignancy 1.4 per cent (Table III). Incidence of malignancy. Ali the 74 uteri were examined microscopically. In 3 cases, "syncytial metritis" was found and in 5 there was evidence of invasion of the myometrium by trophoblastic covered villi with destruction of myometrial fibers and hemorrhage. These 5 cases were classified as invasive mole,
9.0 13.0 --11.6
3 17 20
4.0 9.7
-----
so
1.4 7 (I
12 13
~-·-~---
5.2
Table IV. Detection or development of malignancy in the follow• up of benign trophoblastic tumor It
T •••o
~"v"'
I TlonA I! Tnlnl
J
~~.,.~
~
v~r..c;"
Hysterectomy as initial treatment or within 5 days of vaginal evacuation of the mole
No malignancy detected "Syncytial metritis" Invasive mole confined to the uterus Choriocarcinoma with extrauterine deposits
63
2
3 5
65 3
5
71
3
74
148
5
153 4
Vaginal evacuation of mole; no immediate hysterectomy
No malignancy detected Invasive mole confined to the uterus Invasive mole with extrauterine deposits Choriocarcinoma confined to the uterus Choriocarcinoma with extrauterine·deposits
3
1
6
5
2
10
12
!59
17
176
and in one a shadow in the left 'lung suggestive of a metastatic deposit was detected 15 days after the operation. This shadow disappeared after methotrexate therapy. As has been reported, one patient developed choriocarcinoma and is dead. The incidence of maiignancy was 6 out of 74 cases, or 9 per cent (Table IV) . Cases in which hysterectOIQ.y was not perfomred as primatyt~t. Mortality. Five of the 176 patients died within 72 hours of molar expulsion. Unfortunately, permission for autopsy is difficult
Volume 99 Number4
to obtain in Malaya, and only 2 of the 5 were so examined. Three of the patients developed pyrexia, increasing tachycardia, shock out of all proportion to the blood loss, cyanosis, and dyspnea during the course of molar expulsion. The clinical impression suggested cor pulmonale due to trophoblastic emboli in the lungs. An autopsy was obtained in one of these cases and the clinical impression was confirmed. The autopsy showed that trophoblastic covered villi had penetrated deeply into the myometrium and trophoblast was found occluding many pulmonary vessels. One of the other 2 patients died in the immediate postexpulsion period from shock follo\ving hysterotomy (autopsy perforr:ned 1 and the other from a mismatched blood transfusion. Twelve of the 171 patients surviving the immediate postexpulsion period are dead, and the cause of death in all was malignancy. The over-all mortality was therefore 17 out of 176 or 9. 7 per cent, and that from malignancy 7.0 per cent (Table III). Incidence of malignancy. Trophoblastic malignancy was subsequently detected in 23 of the 176 patients, the time interval between molar expulsion and detection varying between 14 days and 6 months. In 10 the diagnosis was invasive mole and in 13 it was choriocarcinoma. The incidence of malignancy was 13.0 per cent (Table IV). Comment
Trophoblast is unique as it is an homologous tissue which normally invades maternal structures before reaching a state of symbiosis with the host. Why trophoblastic invasion ceases at about day 80 to 85 in normal pregnancy is not understood, but this may be due to an increased oxygen tension which develops in the surrounding maternal tissues. 8 Even if intravascular spread does occur-and it may be fairly common in normal pregnancies-the trophoblastic emboli are destroyed in the lungs. 1 Under certain circumstances, the restraint on the trophoblastic invasion is reduced or the trophoblastic activity is increased, and either a partial or a complete hydatidiform
Management of benign trophoblastic 1umors
593
mole develops. The former is a not uncommon finding in cases of abortion/' but the latter is relatively rare. Partial hydatidiform mole rarely becomes malignant but could explain the cases of malignant trophoblastic tumor which follow abortion or term pregnancy. Complete hydatidiform mole, on the other hand, has a significant chance of becoming malignant, and there appears to be a continuum ranging from the relatively benign hydatidiform mole to the highly malignant choriocarcinoma. Although the incidence of hydatidiform mole in Southeast Asia is fivefold that found in the United States, approxirnate!y the sarne percentage undergoes ma .. lignant change or is malignant ab initio. Of the 250 cases studied, 15 (6.0 per cent) were finally diagnosed as invasive moles and 14 ( 5.6 per cent) as choriocarcinoma. This compares with an incidence of malignancy following hydatidiform mole of 7 to 18 per cent in the United States. 2 • 4 The differentiation be: ween invasive mole and choriocarcinoma can be extremely difficult both on clinical and on histologic grounds, and since both metastasize, the two forms should be considered malignant trophoblastic tumors. Malignant tumors ran be further subdivided into ( 1) those cases in which the tumor is apparently confined to the uterus and (2) those cases in which the tumor has spread beyond the uterus. The suggested classification is shown in Table V. The majority of cases in which the tumor was confined to the uterus were invasive moles, but a significant proportion of cases (39 per cent in this series) in which extrauterine spread occurred were thought to be invasive mol<> and not choriocarcinoma. In this study it was apparent that the treatment adopted to deal with the mole had a significant bearing upon the subsequent
Table V. Classification of trophoblastic tumors Benign Malignant
(hydatidiform mole) (a) apparently confined to the uterus (b) with extrauterine spread
594 llewellyn-Jones
development or detection of malignancy. When hysterectomy was performed with the mole in situ, or within 5 days of its expulsion, invasive mole was found unexpectedly in 5 cases; in all the malignancy was confined to the uterus and all the patients survived without recurrence. One patient, whose excised uterus showed no evidence of malignancy, was readmitted to hospital 26 days after operation with multiple metastatic deposits of choriocarcinoma and died soon after admission. The incidence of malignancy among patients treated by hysterectomy was 9.0 per cent and the mortality from malignancy 1.4 per cent. When expulsion per vaginam was not followed by immediate hysterectomy, malignancy was subsequently detected in 23 of the 176 cases, an incidence of 13.0 per cent, and 12 of these patients died, a mortality from malignancy of 7.0 per cent. The type of malignancy was invasive mole in 10 cases (with 2 deaths) and choriocarcinoma in 13 cases (with 10 deaths). These findings, as well as our inability to obtain any correlation between trophoblastic proliferation, as shown by histology, and subsequent malignancy suggest that hysterectomy with ovarian conservation should be increasingly employed as a method of treatment of benign trophoblas-
Am.
October 15. 1967 Obst. & Gynec.
J.
tic tumors. This should be adopted irrespective of the patient's age provided she has no desire for further children. When the patient desires further children, expulsion should be induced with a dilute oxytocin infusion and curettage performed 5 days later. If uterine involution is not complete within 28 days, or if further enlargement of the uterus occurs before this time or if increased bleeding occurs, a further curettage is essentiaL The persistence of a positive gonadotropin test for 42 days, particularly if curettage fails to reveal chorionic villi, indicates that active trophoblast persists deep in the myometrium or that extrauterine spread has occurred. These patients should receive methotrexate therapy as the risk of development of malignancy is at least 60 per cent. Following hysterectomy, the chorionic gonadotropin test became negative within 14 days in over 90 per cent of cases and persistence of a positive test beyond the twentyfirst day may be an indication for methotrexate therapy as a prophylactic measure. This is at present under study, and information from Singapore9 suggests that prophylactic use of methotrexate is of value in reducing the incidence of malignant trophoblastic tumors.
REFERENCES
1. Attwood, H. D., and Park, W. W.: J. Obst. & Gynaec. Brit. Comm. 68: 611, 1961. 2. Delfs, E.: Ann. New York Acad. Sc. 80: 125, 1959. 3. Edmonds, H. W.: Ann. New York Acad. Sc. 80: 86, 1959. 4. Hertig, A. T., and Sheldon, W. H.: AM. J. 0BsT. & GYNEC. 53: 1, 1947. 5. Hertig, A. T., and Mansell, H.: Atlas of Tumor Pathology, Washington, D. C., 1956, Armed
6. 7. 8. 9.
Forces Institute of Pathology, Part 1, Fascicle 33, Section XI. Llewellyn-Jones, D.: J. Obst. & Gynaec. Brit. Comm. 72: 242, 1965. Maitland, H. B., and Llewellyn-Jones, D.: M. J. Malaya 19: 273, 1965. Reynolds, S. R. M.: AM. J. 0BsT. & GYNEC. 94: 425, 1966. Tow, W. S. H.: J. Obst. & Gynaec. Brit. Comm. 73: 544, 1966.
W H I L E the incidence of trophoblastic tumor in the United States is 1 in 2,500 pregnancies, the incidence in Southeast Asia among all indigenous races is at least four times as high, and in Central Malaya it is 1 in 600 of all pregnancies occurring in the area. The cause of this disproportionate increase is not clear, but there is evidence of a disturbed immunologic response among patients presenting with benign and malignant trophoblastic tumors. 6 The present paper records the management of 250 consecutive cases of hydatidiform mole encountered in a single hospital between 1958 and 1964.
mainly syncytium, penetrates the decidua and infiltrates between myometrial fibers, but vvithout any evidence of destruction of the myometrial cells or of hemorrhage. The condition is benign and is referred to as "syncytial metritis." Malignant trophoblastic tumors. Invasive mole. This is a term applied when there is penetration of the myometrium by molar tissue with destruction of myometrial fibers or extension of molar tissue to other organs, the vascular pattern of the original mole always being maintained. Choriocarcinoma. This is a more malignant form in which syncytio- and cytotrophoblast invades the myometrium with marked tissue destruction and hemorrhage and is usually carried by the systemic bloodstream producing distant metastases. Histologically, the tumor is characterized by sheets of trophoblastic cells, with rarely any vesicle formation.
Definitions
Benign trophoblastic tumors. Hydatidiform mole. This is a neoplastic condition characterized by hydropic swelling and vesicle formation of the placental villi, paucity or absence of blood vessels within the villus, and is associated with proliferation of trophoblast which is most marked in the placental bed. Occasionally, the trophoblast,
Primary management !Table II
Vaginal expulsion. Spontaneous. One hundred and forty of the patients expelled the mole spontaneously or with the additional use of an oxytocic infusion to speed up the process. If the uterine contractions were sustained and bleeding
From the Department of Obstetrics and Gynaecology, General Hospital. *Prese,nt address: Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia.
589
590
Llewellyn-Jones
October 15, 1967 Am.]. Obst. & Gynec.
Table I. Method of treatment adopted in 250 cases of hydatidiform mole Digitally aided expulsion and curettage Digitally aided expulsion followed by hysterectomy Oxytocin-induced expulsion and curettage Oxytocin-induced expulsion followed by hysterectomy Oxytocin failure and hysterotomy Oxytocin failure and hysterectomy with mole in situ
40 68 6 2 4 6 24
slight, interference was avoided and only after the greater part of the mole had been expelled was digital evacuation carried out. In 50 cases, the uterine contractions were inadequate or bleeding increased and expulsion of the tumor was aided by the use of a dilute oxytocin infusion ( 1 in 1,000 in 5 per cent dextrose) using 10 mU. per minute initially. When the cervix was sufficiently dilated and vesicles were being expelled, evacuation of the uterus was aided digitally. Curettage was not perlormed at the time because of the excessive vascularity and thinness of the myometrium, but was performed routinely 5 days later, except in the 40 patients who were treated by hysterectomy 3 to 7 days after molar expulsion. Oxytocin-induced expulsion. Oxytocin infusion was given to induce expulsion in 80 cases and was successful in 74. The concentration used initially was 10 mU. per minute (approximately equal to 15 drops per minute of a 1 in 1,000 solution) and this was increased incrementally to obtain uterine contractions. No infusion was run for more than 10 hours. Sixty patients required a concentration of 40 mU. per minute and 14 required a concentration of 80 mU. per minute to effect the expulsion of the tumor. In 53 cases the tumor was expelled within 12 hours of setting up the infusion; 16 required a second infusion and 5 a third. In 6 cases the infusion was abandoned; in one because of deteriorating pre-eclampsia and in the 5 other cases because three infusions of oxytocin failed to induce expulsion. In these 5 cases
each infusion lasted 10 hours, and the concentration of the solution was incrementally increased to 200 mU. per minute before the method was abandoned. Two of these 6 cases were treated by hysterotomy and 4 by hysterectomy. Of the 74 cases in which the infusion was successful, curettage was performed 5 days later in 68 and hysterectomy in 6. Vaginal expulsion, whether spontaneous or oxytocin-induced, was attended in 18 cases (10 per cent) by a marked systemic upset (tachycardia, dyspnea, and episodic cyanosis), the symptoms suggesting the intravascular spread of emboli of trophoblast. Three patients died. Abdominal operation. Hysterotomy. In the early part of the series, hysterotomy was considered an adequate treatment and was carried out as a primary procedure in 6 cases, and after the failure of an oxytocin infusion in 2 cases. With the introduction of infusions of oxytocin in high concentration, irrespective of the size of the uterus, the need for hysterotomy decreased. The operation is inadequate, as all the risk of manipulative spread of trophoblast is present without the advantage of removing the uterus. A false sense of security results if the cavity is cleared of trophoblast, for active, potentially malignant, cells may persist deep in the myometrium. Moreover, the operation inevitably leaves a vertical scar and subsequent deliveries must be by cesarean section. If, on the other hand, the patient has no desire for further children, hysterotomy is incomplete treatment. It is rarely indicated in the management of benign trophoblastic tumor. Hysterectomy. Hysterectomy with the mole in situ was performed in 24 cases; following failure of oxytocin infusion in 4 cases and within 7 days of expulsion of the mole in a further 46 cases. Aftercare
The patients remained in hospital until uterine involution was proceeding normally and blood loss per vaginam was minimal. Of the 174 patients whose uterus had not
Volume 99 Number4
Management of benign trophoblastic tumors 591
been removed, a second curettage was required in 30, a third in 8, and a fourth in one patient before it was felt that all trophoblastic tissue had been removed. In 10 of these 30 patients, a malignant trophoblastic tumor was discovered subsequently. Since the main purpose of aftercare of patients expelling a hydatidiform mole is the early detection of malignant change, several methods were routinely adopted. These were ( 1) histologic assessment of the degree of trophoblastic proliferation and "anaplasia" in the mole and in the curettings, (2) clinical determination of the rate of involution of the uterus, and ( 3) serial estimations of urinary chorionic gonadotropin. Prognosis from histologic examination of curettings. Hertig and ManselJ5 had noted that the greater the degree of "anaplasia" of the trophoblast, and the greater the amount of trophoblastic proliferation on the villi, the greater was the risk of the subsequent development of malignancy. Their criteria were applied in the histologic examination of molar tissue, particularly that obtained on curettage following molar expulsion, in 170 of the 250 cases. It was concluded from this study that ( 1) the quantity of trophoblast varied very considerably in different parts of the tumor and (2) the criteria gave no prognostic evidence regarding the subsequent development of malignancy. Clinical examination. Uterine involution was slower following expulsion of a hydatidiform mole than in cases of abortion and was not complete for between 21 and 28 days after the expulsion. Increase in the size of the uterus or increase in bleeding during this time was suggestive of residual trophoblast
in the uterus or the development of malignancy. Curettage in which no debris was evacuated favored the latter but no clear prognostic guide could be obtained. Urinary chorionic gonadotropin excretion. Gonadotropin assays were perfonned each week from the time of expulsion of the hydatidiform mole until they had been negative for 4 consecutive weeks, and thereafter monthly until a year had passed since molar expulsion. Initially the Aschheim-Zondek or Galli-Mainini test was used, but was replaced by the hemagglutination-inhibition test when it had been detennined that the latter test was more sensitive. 7 Following hysterectomy the test became negative within 14 days in 71 of the 74 cases, and was negative in all 21 days after operation. When hysterectomy was not performed the time taken for the test to become negative was variable and bore no relationship to the size of the uterus before molar expulsion. By the twenty-first day it was negative in 60.4 per cent and by the forty-second day the percentage had risen to 83.5 per cent (Table II). Of the 29 patients who had positive tests persisting for more than 42 days, in 17 ( 60 per cent) a malignant trophoblastic turnor was subsequently discovered. Effect of primary treatment on mortality and malignancy
It was evident during the course of this study that two distinct groups could be delineated; those in whom hysterectomy was performed either with the mole in situ or within 7 days of its expulsion per vaginam and those in whom hysterectomy was not performed as initial treatment of a benign trophoblastic tumor. These groups
Table II. Urinary chorionic gonadotropin in the follow-up of cases of hydatidiform mole Days after vaginal expulsion or hysterectomy
Vaginal expulsion ( 176 cases) Per cent positive cases)
7
14
153 87.0 56 75.5
127 72.1 3 4.0
I
21 65 39.6 1 1.4
I
28 43 24.4 0
I
35
35 20.0 0
I
42 29 16.5 0
I
49
56
26 14.8 0
23 13.1 0
592
L!ewe!!yn-Jones Am.
OctobN 11, l%7 Ohst. & Gyn,····
J.
Table III. Incidence of malignancy and mortality in cases treated and not treated hy primary hysterectomy
Hysterectomy No hysterectomy
74 6 176 23 --250 29 --------
were matched for race, age, and parity although the numbers treated were disparate. Cases in which hysterectomy was performed as primary treatment. Mortality. Two of the 74 patients died within 72 hours of operation: one from shock and cor pulmonale, which was considered due to intravascular trophoblastic spread to the pulmonary capillaries, and one from the effects of electrolyte imbalance following paralytic ileus. One patient died from choriocarcinoma 28 days after operation: Case 11/64. The patient was Indian, aged 42, and gravida 12. The preoperative assessment showed that the disease was confined to the uterus. A total hysterectomy was performed with the tumor in situ, and histologic examination of the specimen confirmed that it was a hydatidiform mole with no evidence of invasion of the Inyonletriutn. The patient was discharged 14 days after operation, when an immunologic test for gonadotropin was negative. Two weeks later she had developed a vaginal secondary deposit, the lung contained multiple secondary deposits, and the gonadotropin test was strongly positive. Within 2 days, signs of cerebral involvement occurred and she died 3 days later. Autopsy revealed choriocarcinoma. The over-all mortality was 3 out of 74, or 4.0 per cent, and that from malignancy 1.4 per cent (Table III). Incidence of malignancy. Ali the 74 uteri were examined microscopically. In 3 cases, "syncytial metritis" was found and in 5 there was evidence of invasion of the myometrium by trophoblastic covered villi with destruction of myometrial fibers and hemorrhage. These 5 cases were classified as invasive mole,
9.0 13.0 --11.6
3 17 20
4.0 9.7
-----
so
1.4 7 (I
12 13
~-·-~---
5.2
Table IV. Detection or development of malignancy in the follow• up of benign trophoblastic tumor It
T •••o
~"v"'
I TlonA I! Tnlnl
J
~~.,.~
~
v~r..c;"
Hysterectomy as initial treatment or within 5 days of vaginal evacuation of the mole
No malignancy detected "Syncytial metritis" Invasive mole confined to the uterus Choriocarcinoma with extrauterine deposits
63
2
3 5
65 3
5
71
3
74
148
5
153 4
Vaginal evacuation of mole; no immediate hysterectomy
No malignancy detected Invasive mole confined to the uterus Invasive mole with extrauterine deposits Choriocarcinoma confined to the uterus Choriocarcinoma with extrauterine·deposits
3
1
6
5
2
10
12
!59
17
176
and in one a shadow in the left 'lung suggestive of a metastatic deposit was detected 15 days after the operation. This shadow disappeared after methotrexate therapy. As has been reported, one patient developed choriocarcinoma and is dead. The incidence of maiignancy was 6 out of 74 cases, or 9 per cent (Table IV) . Cases in which hysterectOIQ.y was not perfomred as primatyt~t. Mortality. Five of the 176 patients died within 72 hours of molar expulsion. Unfortunately, permission for autopsy is difficult
Volume 99 Number4
to obtain in Malaya, and only 2 of the 5 were so examined. Three of the patients developed pyrexia, increasing tachycardia, shock out of all proportion to the blood loss, cyanosis, and dyspnea during the course of molar expulsion. The clinical impression suggested cor pulmonale due to trophoblastic emboli in the lungs. An autopsy was obtained in one of these cases and the clinical impression was confirmed. The autopsy showed that trophoblastic covered villi had penetrated deeply into the myometrium and trophoblast was found occluding many pulmonary vessels. One of the other 2 patients died in the immediate postexpulsion period from shock follo\ving hysterotomy (autopsy perforr:ned 1 and the other from a mismatched blood transfusion. Twelve of the 171 patients surviving the immediate postexpulsion period are dead, and the cause of death in all was malignancy. The over-all mortality was therefore 17 out of 176 or 9. 7 per cent, and that from malignancy 7.0 per cent (Table III). Incidence of malignancy. Trophoblastic malignancy was subsequently detected in 23 of the 176 patients, the time interval between molar expulsion and detection varying between 14 days and 6 months. In 10 the diagnosis was invasive mole and in 13 it was choriocarcinoma. The incidence of malignancy was 13.0 per cent (Table IV). Comment
Trophoblast is unique as it is an homologous tissue which normally invades maternal structures before reaching a state of symbiosis with the host. Why trophoblastic invasion ceases at about day 80 to 85 in normal pregnancy is not understood, but this may be due to an increased oxygen tension which develops in the surrounding maternal tissues. 8 Even if intravascular spread does occur-and it may be fairly common in normal pregnancies-the trophoblastic emboli are destroyed in the lungs. 1 Under certain circumstances, the restraint on the trophoblastic invasion is reduced or the trophoblastic activity is increased, and either a partial or a complete hydatidiform
Management of benign trophoblastic 1umors
593
mole develops. The former is a not uncommon finding in cases of abortion/' but the latter is relatively rare. Partial hydatidiform mole rarely becomes malignant but could explain the cases of malignant trophoblastic tumor which follow abortion or term pregnancy. Complete hydatidiform mole, on the other hand, has a significant chance of becoming malignant, and there appears to be a continuum ranging from the relatively benign hydatidiform mole to the highly malignant choriocarcinoma. Although the incidence of hydatidiform mole in Southeast Asia is fivefold that found in the United States, approxirnate!y the sarne percentage undergoes ma .. lignant change or is malignant ab initio. Of the 250 cases studied, 15 (6.0 per cent) were finally diagnosed as invasive moles and 14 ( 5.6 per cent) as choriocarcinoma. This compares with an incidence of malignancy following hydatidiform mole of 7 to 18 per cent in the United States. 2 • 4 The differentiation be: ween invasive mole and choriocarcinoma can be extremely difficult both on clinical and on histologic grounds, and since both metastasize, the two forms should be considered malignant trophoblastic tumors. Malignant tumors ran be further subdivided into ( 1) those cases in which the tumor is apparently confined to the uterus and (2) those cases in which the tumor has spread beyond the uterus. The suggested classification is shown in Table V. The majority of cases in which the tumor was confined to the uterus were invasive moles, but a significant proportion of cases (39 per cent in this series) in which extrauterine spread occurred were thought to be invasive mol<> and not choriocarcinoma. In this study it was apparent that the treatment adopted to deal with the mole had a significant bearing upon the subsequent
Table V. Classification of trophoblastic tumors Benign Malignant
(hydatidiform mole) (a) apparently confined to the uterus (b) with extrauterine spread
594 llewellyn-Jones
development or detection of malignancy. When hysterectomy was performed with the mole in situ, or within 5 days of its expulsion, invasive mole was found unexpectedly in 5 cases; in all the malignancy was confined to the uterus and all the patients survived without recurrence. One patient, whose excised uterus showed no evidence of malignancy, was readmitted to hospital 26 days after operation with multiple metastatic deposits of choriocarcinoma and died soon after admission. The incidence of malignancy among patients treated by hysterectomy was 9.0 per cent and the mortality from malignancy 1.4 per cent. When expulsion per vaginam was not followed by immediate hysterectomy, malignancy was subsequently detected in 23 of the 176 cases, an incidence of 13.0 per cent, and 12 of these patients died, a mortality from malignancy of 7.0 per cent. The type of malignancy was invasive mole in 10 cases (with 2 deaths) and choriocarcinoma in 13 cases (with 10 deaths). These findings, as well as our inability to obtain any correlation between trophoblastic proliferation, as shown by histology, and subsequent malignancy suggest that hysterectomy with ovarian conservation should be increasingly employed as a method of treatment of benign trophoblas-
Am.
October 15. 1967 Obst. & Gynec.
J.
tic tumors. This should be adopted irrespective of the patient's age provided she has no desire for further children. When the patient desires further children, expulsion should be induced with a dilute oxytocin infusion and curettage performed 5 days later. If uterine involution is not complete within 28 days, or if further enlargement of the uterus occurs before this time or if increased bleeding occurs, a further curettage is essentiaL The persistence of a positive gonadotropin test for 42 days, particularly if curettage fails to reveal chorionic villi, indicates that active trophoblast persists deep in the myometrium or that extrauterine spread has occurred. These patients should receive methotrexate therapy as the risk of development of malignancy is at least 60 per cent. Following hysterectomy, the chorionic gonadotropin test became negative within 14 days in over 90 per cent of cases and persistence of a positive test beyond the twentyfirst day may be an indication for methotrexate therapy as a prophylactic measure. This is at present under study, and information from Singapore9 suggests that prophylactic use of methotrexate is of value in reducing the incidence of malignant trophoblastic tumors.
REFERENCES
1. Attwood, H. D., and Park, W. W.: J. Obst. & Gynaec. Brit. Comm. 68: 611, 1961. 2. Delfs, E.: Ann. New York Acad. Sc. 80: 125, 1959. 3. Edmonds, H. W.: Ann. New York Acad. Sc. 80: 86, 1959. 4. Hertig, A. T., and Sheldon, W. H.: AM. J. 0BsT. & GYNEC. 53: 1, 1947. 5. Hertig, A. T., and Mansell, H.: Atlas of Tumor Pathology, Washington, D. C., 1956, Armed
6. 7. 8. 9.
Forces Institute of Pathology, Part 1, Fascicle 33, Section XI. Llewellyn-Jones, D.: J. Obst. & Gynaec. Brit. Comm. 72: 242, 1965. Maitland, H. B., and Llewellyn-Jones, D.: M. J. Malaya 19: 273, 1965. Reynolds, S. R. M.: AM. J. 0BsT. & GYNEC. 94: 425, 1966. Tow, W. S. H.: J. Obst. & Gynaec. Brit. Comm. 73: 544, 1966.