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Choriocarcinoma, chorioadenoma destruens, and syncytial endometritis
Choriocarcinoma, and syncytial E.
STEWART
WILLIAM Denver,
chorioadenoma
endometritis
TAYLOR,
M.D.
DROEGEMUELLER,
M.D.
Colorado
NINETEEN patients with diagnostic and therapeutic problems of diseases of the trophoblast have been seen in our hospital and consulting practice during a period of 15 years. Study of the clinical, pathologic, and hormonal characteristics of these patients has caused us to subdivide them into 10 with choriocarcinoma, 5 with chorioadenoma, and 4 with syncytial endometritis. The histories, lesions, and treatment of each are summarized in Tables I, II, and III. Many difficult problems in diagnosis and treatment were encountered which were of interest, and instructional value. Four of the 19 patients, fortunately, were proved to have a syncytial endometritis reaction instead of choriocarcinoma. Each of these 4 was considered initially to have had a malignancy of the trophoblast. One of them had a hysterectomy, but this was not needed as part of the treatment of the syncytial endometritis. All 4 of the patients are in good health as would be expected since syncytial endometritis is self-limiting. The 5 patients with chorioadenoma destruens are alive and well. The significant form of therapy for these patients was total abdominal hysterectomy. A hydatidiform mole preceded the development of chorioadenoma destruens in each case. The diag-
From
destruens,
the Department Gynecology, University Medical Center.
of Obstetrics of Colorado
nosis of a trophoblastic malignancy was suspected in 4 of the 5 cases, either because of persistently positive chorionic gonadotropin test or a recurrently positive test after a previous negative test. The diagnosis of chorioadenoma destruens could not be established in any of our cases before the hysterectomy had been performed and the specimen had been carefully studied in the laboratory. One chorioadenoma destruens caused a spontaneous perforation of the uterus with marked internal hemorrhage. Two patients with chorioadenoma destruens had pulmonary metastases. In one case they cleared spontaneously after hystcrectomy and in the other they disappeared after hysterectomy and amethopterin treatment. Three of our 10 choriocarcinoma patients are alive at this time. One has persistently elevated chorionic gonadotropin titers suggesting continued activity of the disease process. All 3 of these patients who are now alive after a diagnosis of choriocarcinoma have had amethopterin chemotherapy. We feel that one of them (No. 7) may have had a permanent remission because of the the amcthopterin therapy. Patients 9 and 10 did not respond successfully to chemotherapy. A fourth patient (No. 6) with choriocarcinoma died from amethopterin intoxication. This patient had residual choriocarcinoma present in the lungs at postmortem examination. Eight of the 10 choriocarcinoma patients had hysterectomies as part of their treatment. In one of these, the hysterectomy possibly contributed to a cure.
and
Presented at the Seventy-second Annual Meeting, American Association of Obstetrzcians and Gynecologists, Hot Springs, Virginia, Sept. 7-9, 1961.
958
Diseases
This was Patient 10. She received chemotherapy over a period of several months in an effort to arrest the disease without hysterectomy. This was not curative and hysterectomy finally was performed. Viable choriocarcinoma was found in the surgical specimen. Comment
Choriocarcinoma. This is such a rare disease and behaves in such varied ways that it is impossible to make any dogmatic statements in regard to diagnosis, treatment, or
Fig. 1. Case the
1. Choriocarcinoma
of the
trophoblast
957
prognosis. It has become evident in the past few years that there have been cures of choriocarcinoma from hysterectomy alone. Brewer’ reported in 1961 the collected esperience of the Albert Mathieu Chorionepithelioma Registry. Among 147 patients with choriocarcinoma there were 21, or 1-l per cent, who survived 5 years or longer after a positive histologic diagnosis of choriocarcinoma. There are other reports that give similar survival rates.2, 3. ’ The reasons for performing hysterectomy are four in number: first, the procedure may be cura-
in
uterus.
Fig. 2. Case carcinoma.
5. Extrauterine
chorio.
960
Taylor
and
Table I. Summary Case NO.
April 1, 1962 9m. J. Obst. & Gvnec.
Droegemueller
of cases of choriocarcinoma
Age i
Date admitted
1
26
l/26/47
Abortion
2
25
1/
Normal
full-term
3
23
5/26/55
Hydatid Normal 1954
mole Oct., 1952 full-term Jan.,
4
25
9/
6/56
Abortion
5
32
3/
6/56
Tubal
6
30
10/25/56
7
24
10/13/59
a
35
l/
9
34
4/30/60
10
17
l/51
5/60
l/25/61
I Pregnancy
Chorionic
l/20/47
6/10/50
a/18/56
Negative
Positive
qualitative
Positive
None
obtained
Positive
None
obtained
Negative
Positive
Hydatid
mole
1 O/25/56
Normal
full-term
Hydatid
Normal 1960
mole
full-term
7/15/59
May,
Chest
qualitative
12/10/55
Normal full-term 1 i/15/58
1
Positive
ectopic
a/22/59
gonadotropins
x-ray
Positive
3/26/56
Negative qualitative 2/10/57 Positive 7/a/58 300,000 M.U.
Positive
g/3/57
Negative to 3/l/60, then positive FSH at 1,000 M.U. Now normal range
Negative
Negative l/29/60,
Negative
qualitative
qualitative to then positive
Negative qualitative for months, then positive. FSH now positive at l,OOO,OOO M.U.
Positive 5,000 M.U. Normal range terectomy
2
Positive since 3/l/60, but proves with chemotherapy
Negative after
hys---
*4-Amino-N’O methyl tLederle Laboratories,
pteroylglutamin Pearl River,
acid (Methotrexate). New York.
Lederle
Laboratories,
Pearl
River,
New
York.
im-
Volume Number
83 7
Diseases
Treatment Hysterectomy,
Result
2/l/47
Stilbestrol
Craniotomy
6/l/55
Vaginal metastasis laparotomy .wcy perforated uterus Nitrogen mustard Hysterectomy
excised. 1 l/1/56
Emerfor
3/6/56
Hysterectomy 3/l 7/57 X-ray and radioactive gold Lung resection 9/l l/57 Amethopterin,* 5 courses
Excision, vaginal metastasis Hysterectomy 10/20/59 Amethopterin, 3 courses
10/8/59
of the
trophoblast
961
Remarks
Died
a/24/47
Autopsy showed generalized metastases to lungs, brain, and liver (Fig. 1) . Uterus free of choriocarcinoma at hysterectomy
Died
2/2/5
Died
6/Z/55
No
Died
12/l/56
Autopsy showed widespread throughout the body
Died
4/7/56
Autopsy large
Died
1 l/15/58
Microscopic sections from uterus, Figs. 3 and 4. Lung resection, g/11/57, for pulmonary metastasis. Fresh pulmonary lesions appeared 6/30/58. On 7/8/58, patient referred to National Institutes of Health for 5 courses of amethopterin therapy. Died of amethopterin intoxication. Autopsy showed residual choriocarcinema in lungs
Autopsy brain, vagina
1
Alive and free cific disease
of spe-
autopsy volved
performed,
but
lungs
and
and (Fig.
a 2)
gonadotropin tests negative until when patient had cerebral hemorrhage. 3 courses of amethopterin which FSH levels to normal. Patient has some neurological defect. Appears to be
Died
Hysterectomy Amethopterin, Nitrogen-mustard Vinblastinelz
Alive with probable choriocarcinoma
No
Alive and free ease
Hysterectomy finally required. Nidus of choriocarcinoma found in uterus. Now has gonadotropin levels in normal range and appears to be free of disease. Treated at National Institutes of Health
Amethopterin, Actinomycin-Dt Chlorambucil Hysterectomy
3 courses
Aug.,
1961
Patient fell orrhage. that time showed malignant pancreas
in-
choriocarcinoma
showed generalized metastases pelvic mass of choriocarcinoma
Qualitative 3/l/60 Received brought residual cured
brain
Hysterectomy 1 l/10/59 Emergency operation for liver hemorrhages l/17/60, l/25/60, 2/l 5/60
5/5/60 5 courses
2/18/60
showed generalized metastases to lungs, liver, and peritoneum, but uterus and uninvolved
of dis-
on ice 12/29/59, initiating liver hemQualitative gonadotropins negative at so amethopterin not started. Autopsy liver necrosis and hemorrhage. Few trophoblast cells found in liver and (Figs. 5 and 6)
choriocarcinoma found in uterus after hysterectomy. Clinical improvement and regression of pulmonary lesions with chemotherapy, but FSH titer remains high. General condition of patient is good
962
Taylor
and
.4pril 1, 1962 Am. J. Obst. & Ggncc.
Droegemueller
Table II. Summary
of cases of chorioadenoma -.~~~ _
Case NO. 11
Age 39
12
/
1
Date admitted
Pregnancy
Chorionic gonadotropins
I
..~~.-~-...Chest
I
10/25/53
Hydatid
mole
7/23/53
Negative Positive
19
g/26/54
Hydatid
mole
g/15/54
Positive qualitative months
for
6
Positive
13
21
6/
Hydatid
mole
6/l/56
Positive weeks
qualitative
for
6
Negative
14
21
12/16/56
Hydatid
mole
12/l
Positive qualitative 1.!15/57
to
15
30
10/16/60
Hydatid
mole
6/14/60
Table III. Summary
No. Case 16
Age 40
17
II
l/56
of cases of syncytial Date admitted
7/56
at 6 weeks 10/19/53
.~~
x-,cry
Negative
FSH 1.000 M.U. 10/16/60 FSH normal range 1 l/20/60
for 6 months
Negative Positive
to 5//17/61
endometritis
I
ChO&XliC gonadotropins
Pregnancy
I Chest
x-raj
1 l/12/47
Incomplete
abortion
1 l/5/47
Negative
Negative
35
7/23/49
Incomplete
abortion
7/15/49
Negative
Negative
18
30
8/l
Hydatid
mole
Negative
Negative
19
25
Ectopic
pregnancy
Negative
Negative
7/49
12/26/49
tive; second, it is often necessary in order to make an accurate diagnosis; third, the incidence of spontaneous uterine perforation from choriocarcinoma is as high as 25 per cent:; fourth, there is at least the hope that removal of the primary lesion will be followed by spontaneous regression of the secondary lesions. Dilatation and curettage of the uterus often proves to be an unrewarding diagnostic procedure in this disease.
7/2/49
12/26/49
The accumulating experience by Hert/ and others6z7 in the treatment of metastatic choriocarcinoma by amethopterin is the most hopeful news that has yet appeared in the field of chemotherapy for malignant disease. In choriocarcinoma Cases 7 and 8 the quantities of chorionic gonadotropin in the urine were very low the first few months after the diagnosis of choriocarcinoma was made. Because of the negative to Meal&-
Volume Number
Diseases of the trophoblast
83 7
Treatment
Hysterectomy
Emergency uterine
Result
10/26/53
hysterectomy perforation 12/l
for 3/54
spontaneous
963
Remarks
Well
Pathologist’s diagnosis choriocarcinoma originally. Review of histology caused reclassification to chorioadenoma. Myometrium contained chorioadenoma (Fig. 7)
Well
Pulmonary metastasis disappeared spontaneously, 6 months after emergency hysterectomy. Myometrium perforated by chorioadenoma that had spread to broad ligament
Hysterectomy
7/16/56
Well
Original diagnosis cinema. After to chorioadenoma. ometrium
Hysterectomy
4/15/57
Well
Chorioadenoma
Hysterectomy Amethopterin,
7/28/60 2 courses
Well
FSH levels normal after first course of amethopterin. Lung metastasis disappeared on 5/l 7/61. Fig. 9 shows histology
Treatment
from curettings was choriocarhysterectomy, diagnosis changed Chorioadenoma found in myfound
Result
in
myometrium
(Fig.
81
Remarks
Curettage
1 l/13/47
Well
Pathologist’s original diagnosis choriocarcinoma. Material sent to Chorionepithelioma Registry where opinions varied between choriocarcinoma, syncytial endometritis, and normal pregnancy tissue (Fig. 10). Final diagnosis was syncytial endometrits
Curettage Hysterectomy
7/24/49 8/27/49
Well
Histologic diagnosis choriocarcinoma
Curetta,ge
8/20/49
Well. Has had pregnancies
subsequent
Patient referred to hospital with a pathologic diagnosis of choriocarcinoma. With review of sections, diagnosis changed to syncytial endometritis (Fig. 12)
Well. Has had pregnancies
subsequent
Pathologists made diagnosis of choriocarcinoma. Consultation with gynecologic pathologist sought, who changed diagnosis to normal pregnancy reaction in tube (Fig. 13)
Salpingectomy
12/26/49
_~__--
positive chorionic gonadotropin tests, amethopterin was not started in either case as soon as the diagnosis of choriocarcinoma was made. In Patient 7, the chorionic gonadotropin test was not detected as positive until a serious cerebral hemorrhage complicated the disease. Then vigorous chemotherapy was initiated. It might have been prudent to have started chemotherapy before this point. Patient 8 died of liver metastases and severe liver hemorrhage with
was syncytial was considered
endometritis, (Fig. 11)
but
necrosis. This patient might better have been treated with chemotherapy soon after hysterectomy, even though her quantitative urine test for chorionic gonadotropin was negative at that time. It appears that only a scant number of malignant cells killed this patient, or the malignancy was of such a destructive nature that it destroyed itself as it destroyed the host. The treatment of Patient 10 represents an interesting departure from tradition in
964
Fig.
Taylor
and
Droegemueller
3. Case. 6. Choriocarcinoma
April 1, 1962 :Am. J. Ohst. & Gynrc.
in
the
uterus.
that chemotherapy was chosen to precede operation. This was not successful. Hysterectomy had to he performed. The patient is now well. Choriocarcinoma metastases are at times so rapid and virulent that primary surgical therapy is impossible. Cases 2 and 4 illustrate this problem. In other instances, the disease process may extend over a period of years before lethal metastases occur. All of our choriocarcinoma cases followed normal term pregnancy, hydatidiform mole, spontaneous abortion or ectopic pregnancy. Park and Lee? in their general review of 516 cases of choriocarcinoma found that 20 per cent of choriocarcinomas followed a normal pregnancy, 30 per cent followed abortion, and 50 per cent a hydatidiform mole. The ordinary hospital Rana pipiens test or Aschheim-Zondek test for chorionic
Fig.
lung.
4. Case
6. Choriocarcinoma
metastatic
to the
gonadotropin hormone is not sensitive or reliable enough to detect an early rising titer of chorionic gonadotropin hormone. In 3 of our choriocarcinoma patients (Nos. 7, 8, and lo), the qualitative chorionic gonadotropin hormone tests were either negative or only weakly positive. A reliable method for quantitative gonadotropin testing is necessary in following patients with suspected malignancies of the trophoblast. The Delfs” or Klinefelterl” quantitative chorionic gonadotropin tests are recommended by Hertz.’ Chorioadenoma destruens. It is important to separate chorioadenoma destruens from choriocarcinoma because of the superior
Fig. 5. Cast liver.
8. Choriocarcinoma
mctastatic
to the
prognosis of chorioadenoma. We had only 5 chorioadenoma patients and all have survived. Wilsonll reported upon 20 patients with chorioadenoma destruens who survived. The main form of therapy followed in his series was hysterectomy with irradiation of pulmonary metastases in some cases. It is known that distant metastases from chorioadenoma destruens will often undergo spontaneous regression when the primary lesion is removed frqm the uterus. Case 12 from our series is an example. Case 14 suggests that amethopterin may hasten resolution of pulmonary metastases. Hertz has reported several excellent results from the chemotherapy of distant metastases of chorioadenoma destruens.
Volume Number
83 7
Fig. 6. Case 8. Choriocarcinoma pancreas.
Diseases of the trophoblast
metastatic to the
Fig. 8. Case 14. Chorioadenoma uterus.
965
destruens in the
One may question the advisability of using a toxic drug such as amethopterin for treatment of chorioadenoma destruens metastases when the results from operation alone or operation combined with x-ray have been so excellent. This, however, must he balanced against the knowledge that chorioadenoma may be lethal if a large vesWI or an organ like the brain is involved. Syncytial endometritis. Syncytial endometritis is a self-limiting condition and needs but to be recognized. The absence of chorionic gonadotropin in the urine is helpful in making the correct diagnosis. The entity deserves some discussion because the histologic findings (Figs. 10 to 13) often are enough to startle the pathologist and alarm the clinician. Probably one who sees many choriocarcinomas under the microscope \vnuld discount svncvtial endometritis as a
legitimate consideration in the differential diagnosis. The 4 patients with syncytial endometritis in our series did cause some temporary diagnostic consternation, however.
Fig. 7. Case 11. Chorioadenoma uterus.
Fig. 9. Case 15. Chorioadenoma uterus.
destruens in the
Summary
and
conclusions
Nineteen patients with actual or suspected malignancies of the trophoblast have been seen by us in a period of 15 years. Ten had choriocarcinomas, 5 chorioadenoma destruens, and 4 syncytial endometritis. Three of the patients with choriocarcinema are alive at this time. Four patients with choriocarcinoma and one with chorioadenoma were treated with amethopterin. All of the patients with chorioadenoma and syncytial endometritis have survived. Distant metastases from chorioadenoma should be treated with amethopterin even
destruens in the
966
Taylor
Fig.
10. Casr
16. Syncytial
Fig.
12.
18.
Case
and
Droegemueller
Syncytial
endometritis.
endometritis.
though such distant metastases may disappear after excision of the primary lesion. Quantitative chorionic gonadotropin tests performed on rats or mice are necessary for early detection of rising chorionic gonadotropin levels from anaplastic choriocarcinomas, for the ordinary qualitative chorionic gonadotropin tests are not sufficiently sensitive. Amethopterin should be used as an adjunct to hysterectomy in the treatment of a11 patients with proved choriocarcinoma.
Fig. 13. Case reaction.
19. Tubal
pregnancy
with
atypical
‘The reasons are that a lethal hemorrhage may occur from a very few malignant cells that have a correspondingly low hormone production and the risk to the patient from an initial course of amethopterin is not yreat. We wish to thank Drs. Charles R. Freed and Raymond C. Chatfield for Case 5; Dr. George M. Horner for Case 6; and Colonel John S. Zelenik, Fitzsimons Army Hospital, for details concerning Cases 2, 3, 1, 10, and 12.
REFERENCES
1. Brewer, J. I., Rinehart, J. J., and Dunbar, R. W.: AM. J. OBST. & GYNEC. 81: 574, 1961. 2. Report of the Joint Project for Study of Choriocarcinoma and Hydatidiform Mole in Asia: Ann. New York Acad. SC. 80: 178, 1959.
3. 4.
5.
Brews, A.: J. Obst. & Gynaec. Brit. Emp. 46: 813, 1939. Smalbraak, J.: Trophoblastic Growths, Amsterdam, 1957, Elsevier Publishing Co., p. 309. Acosta-Sison, H.: AM. J. OBST. & GYNFC. 42: 878, 1941.
Volume 83 Number
Diseases
of the
trophoblast
967
7
6. Hertz, R., Bergenstal, D. M., Lipsett, M. B., Price. E. B.. and Hilbish, T. F.: J. A. M. A. 168:
-845,
1958.
7. Hertz, Price, York 8. Park.
R., Bergenstal, D. M., Lipsett, M. B., E. B., and Hilbish, T. F.: Ann. New Acad. SC. 80: 262, 1959. W. W.. and Lees., _1. C.: Arch. Path. 49: $3, 1950.’ 9. Delfs, E.: Obst. & Gynec. 9: 1, 1957.
10. Klinefelter, J. F., Jr., Albright, F., and Griswold, G. C.: J. Clin. Endocrinol. 3: 529, 1943. 11. Wilson, R. B., Hunter, J. S., and Dockerty, M. B.: AM. J. OBST. & GYNEC. 81: 546, 1961. 12. Hertz, R., Lipsett, M. B., and Moy, R. H.: Cancer Res. 20% 1050, 1960.
Discussion ROY HERTZ,* Bethesda, Maryland. Inasmuch as we have recently published our studies on 63 cases of choriocarcinoma and related trophoblastic disease (AM. J. OBST. & GYNEC. 82: 631, 1961), I shall not repeat our findings in any- detail here. In that paper we have also set forth our concept of the relationship between the several varieties of trophoblastic disease which we regard as a continuous spectrum of disease proccsscs. Since this article will provide a detailed account of our point of view and experience as they relate to Dr. Taylor’s fine study, I shall not reiterate these statements at this juncture. Suffice it to say that our personal gratification in seeing many of these patients improve is equaled only by the gratification which has come to us from the cooperation and helpfulness of the members of your branch of the profession in so selflessly referring these patients for study. I want especially to thank Dr. Taylor and the many others in the audience who have participated with us in this study. Without this type of moral as well as clinical support, we could not have accomplished our work. DR.
DR. ROBERT B. WILSON, Rochester, Minnesota. Since most pathologists, who are our authorities on the subject, have repeatedly written that it is seldom possible to make a firm diagnosis on curettings alone, I would like to ask Dr. Taylor whether or not he feels that examination of the curettings alone is sufficient. In the pathologic differentiation between choriocarcinoma and chorioadenoma destruens, it is usually considered necessary to cut many thin serial blocks of tissue because of the smallness and infrequency of diagnostic villi in chorioadenoma destruens. If the diagnosis is difficult with actual myometrial tissue, it would seem well nigh impossible with crlrettings alone. Time has proved, of course, *By
invitation
the correctness of the diagnosis in most instances. A similar comment may be made on the matter of making a firm diagnosis of choriocarcinoma on the basis of the microscopic appearance of an isolated metastatic growth. As Dr. Arthur Hertig has written, with whom our Dr. Dockerty agrees, it is possible to have a metastatic lesion composed of trophoblast without villi which is not a choriocarcinoma, provided villi are found in the primary lesion. These comments are made in view of the fact that, of the 3 patients who had diagnoses of choriocarcinoma and are still alive, in one (Case 7) the diagnosis was made on the appearance of a vaginal lesion, a persistent excretion of chorionic gonadotropin, and the occurrence of a cerebrovascular accident; in another (Case 9) there has been no histologic diagnosis but the x-ray appearance of the chest continues to show tumor and chorionic gonadotropin continues to be excreted; and in the third (Case 10) the diagnosis was established by the examination of curettings and the continued excretion of chorionic gonadotropin. As we have had patients with x-ray and other evidence of metastatic disease such as vaginal lesions and with persistent excretion of chorionic gonadotropin who had destruens rather than choriocarcinoma, I would ask Dr. Taylor whether he is completely confident that the persistent excretion of chorionic gonadotropin with or without other evidence of metastatic disease is actually diagnostic of this particular entity. As to treatment, there can be little question as to the desirability of treating true choriocarcinema with a chemotherapeutic agent. However, I have become alarmed at the frequency with which such a toxic agent as amethopterin is being used. During my participation in a recent exhibit on this subject, many physcians related their experiences with patients who had had a molar pregnancy and subsequently had been treated with amethopterin because a diag-
968
Taylor
and
April 1, 1962 Am. J. Obst. & Gynec.
Droegemueller
nosis of choriocarcinoma had been made on the examination of curettings alone, with or without associated evidence of persistent excretion of chorionic gonadotropin. I wonder whether Dr. Taylor would not agree that this very toxic drug should be reserved almost exclusively for the treatment of proved choriocarcinoma. I do not wish to leave the impression that any patient with or without evidence of a metastatic lesion and with persistent excretion of chorionic gonadotropin should not be treated. In patients with suspected choriocarcinoma or chorioadenoma destruens, I agree with Dr. Taylor that in most instances operation should be performed in order to establish a diagnosis conclusively. If a patient is found to have a choriocarcinoma, the uterus, tubes, and ovaries should be removed and this followed by the administration of amethopterin with or without other chemotherapeutic agents. If a patient is found to have a chorioadenoma destruens and conservation of the childbearing function is not necessary, then again the uterus and tubes and, if necessary, the ovaries should be removed if technically possible. In some instances of chorioadenoma destruens it is not possible to remove all of the diseased tissue and there may be metatastic lesions. In these, again if the childbearing function is not important and if there is a continuing excretion of chorionic gonadotropin, x-ray therapy has been effective in our hands and we thus avoid the administration of a toxic drug. At the time of exploratory operation there is a good chance that patients with chorioadenoma destruens may have an isolated lesion which can be locally excised. In our series of 20 patients, examination of the hysindicated that excision terectomy specimen could have been done in 6 instances-only cently have we realized the feasibility procedure and have done it successfully
of in
rethis one
instance. Therefore, it seems to me that chemotherapy should be used in the treatment of patients with chorioadenoma destruens only when local excision is not possible and when the childbearing function is to be conserved. Last, a word of caution in evaluating the effectiveness of any therapy for these entities is in order. We must always remember the builtin regressive property of trophoblastic tissue and recognize that we are on treacherous ground, particularly in patients with chorioadenoma destruens, if we attribute our cures to anything other than surgical removal and this regressive property. DR. TAYLOR (Closing). Dr. Wilson and I differ on the approach to this problem. Perhaps I! years ago I would have agreed with him but I do not agree now that one can wait for a proved histologic diagnosis of choriocarcinoma. There are some situations when it is impossible to make a histologic diagnosis of choriocarcinema. You have the history of a patient with a mole. A hysterectomy is done after persistence of titer for several months and the uterus is found free of any tumor tissue after serial study. You have then nothing on which to base your diagnosis except the shadows in the lungs and a highly positive gonadotrophic titer. What do you want to call that? Do you want to wait until you do an autopsy and get the choriocarcinema tissue from the lung? One of our patients even had a lung biopsy and nothing but blood clots was found for the pathologist to examine. One of the points of our paper is to emphasize that one must know the natural history of the disease and know the possibilities and not be dependent upon pathologic findings alone. This is a combined clinical, pathologic, and hormonal diagnosis that one has to make.
STEWART
WILLIAM Denver,
chorioadenoma
endometritis
TAYLOR,
M.D.
DROEGEMUELLER,
M.D.
Colorado
NINETEEN patients with diagnostic and therapeutic problems of diseases of the trophoblast have been seen in our hospital and consulting practice during a period of 15 years. Study of the clinical, pathologic, and hormonal characteristics of these patients has caused us to subdivide them into 10 with choriocarcinoma, 5 with chorioadenoma, and 4 with syncytial endometritis. The histories, lesions, and treatment of each are summarized in Tables I, II, and III. Many difficult problems in diagnosis and treatment were encountered which were of interest, and instructional value. Four of the 19 patients, fortunately, were proved to have a syncytial endometritis reaction instead of choriocarcinoma. Each of these 4 was considered initially to have had a malignancy of the trophoblast. One of them had a hysterectomy, but this was not needed as part of the treatment of the syncytial endometritis. All 4 of the patients are in good health as would be expected since syncytial endometritis is self-limiting. The 5 patients with chorioadenoma destruens are alive and well. The significant form of therapy for these patients was total abdominal hysterectomy. A hydatidiform mole preceded the development of chorioadenoma destruens in each case. The diag-
From
destruens,
the Department Gynecology, University Medical Center.
of Obstetrics of Colorado
nosis of a trophoblastic malignancy was suspected in 4 of the 5 cases, either because of persistently positive chorionic gonadotropin test or a recurrently positive test after a previous negative test. The diagnosis of chorioadenoma destruens could not be established in any of our cases before the hysterectomy had been performed and the specimen had been carefully studied in the laboratory. One chorioadenoma destruens caused a spontaneous perforation of the uterus with marked internal hemorrhage. Two patients with chorioadenoma destruens had pulmonary metastases. In one case they cleared spontaneously after hystcrectomy and in the other they disappeared after hysterectomy and amethopterin treatment. Three of our 10 choriocarcinoma patients are alive at this time. One has persistently elevated chorionic gonadotropin titers suggesting continued activity of the disease process. All 3 of these patients who are now alive after a diagnosis of choriocarcinoma have had amethopterin chemotherapy. We feel that one of them (No. 7) may have had a permanent remission because of the the amcthopterin therapy. Patients 9 and 10 did not respond successfully to chemotherapy. A fourth patient (No. 6) with choriocarcinoma died from amethopterin intoxication. This patient had residual choriocarcinoma present in the lungs at postmortem examination. Eight of the 10 choriocarcinoma patients had hysterectomies as part of their treatment. In one of these, the hysterectomy possibly contributed to a cure.
and
Presented at the Seventy-second Annual Meeting, American Association of Obstetrzcians and Gynecologists, Hot Springs, Virginia, Sept. 7-9, 1961.
958
Diseases
This was Patient 10. She received chemotherapy over a period of several months in an effort to arrest the disease without hysterectomy. This was not curative and hysterectomy finally was performed. Viable choriocarcinoma was found in the surgical specimen. Comment
Choriocarcinoma. This is such a rare disease and behaves in such varied ways that it is impossible to make any dogmatic statements in regard to diagnosis, treatment, or
Fig. 1. Case the
1. Choriocarcinoma
of the
trophoblast
957
prognosis. It has become evident in the past few years that there have been cures of choriocarcinoma from hysterectomy alone. Brewer’ reported in 1961 the collected esperience of the Albert Mathieu Chorionepithelioma Registry. Among 147 patients with choriocarcinoma there were 21, or 1-l per cent, who survived 5 years or longer after a positive histologic diagnosis of choriocarcinoma. There are other reports that give similar survival rates.2, 3. ’ The reasons for performing hysterectomy are four in number: first, the procedure may be cura-
in
uterus.
Fig. 2. Case carcinoma.
5. Extrauterine
chorio.
960
Taylor
and
Table I. Summary Case NO.
April 1, 1962 9m. J. Obst. & Gvnec.
Droegemueller
of cases of choriocarcinoma
Age i
Date admitted
1
26
l/26/47
Abortion
2
25
1/
Normal
full-term
3
23
5/26/55
Hydatid Normal 1954
mole Oct., 1952 full-term Jan.,
4
25
9/
6/56
Abortion
5
32
3/
6/56
Tubal
6
30
10/25/56
7
24
10/13/59
a
35
l/
9
34
4/30/60
10
17
l/51
5/60
l/25/61
I Pregnancy
Chorionic
l/20/47
6/10/50
a/18/56
Negative
Positive
qualitative
Positive
None
obtained
Positive
None
obtained
Negative
Positive
Hydatid
mole
1 O/25/56
Normal
full-term
Hydatid
Normal 1960
mole
full-term
7/15/59
May,
Chest
qualitative
12/10/55
Normal full-term 1 i/15/58
1
Positive
ectopic
a/22/59
gonadotropins
x-ray
Positive
3/26/56
Negative qualitative 2/10/57 Positive 7/a/58 300,000 M.U.
Positive
g/3/57
Negative to 3/l/60, then positive FSH at 1,000 M.U. Now normal range
Negative
Negative l/29/60,
Negative
qualitative
qualitative to then positive
Negative qualitative for months, then positive. FSH now positive at l,OOO,OOO M.U.
Positive 5,000 M.U. Normal range terectomy
2
Positive since 3/l/60, but proves with chemotherapy
Negative after
hys---
*4-Amino-N’O methyl tLederle Laboratories,
pteroylglutamin Pearl River,
acid (Methotrexate). New York.
Lederle
Laboratories,
Pearl
River,
New
York.
im-
Volume Number
83 7
Diseases
Treatment Hysterectomy,
Result
2/l/47
Stilbestrol
Craniotomy
6/l/55
Vaginal metastasis laparotomy .wcy perforated uterus Nitrogen mustard Hysterectomy
excised. 1 l/1/56
Emerfor
3/6/56
Hysterectomy 3/l 7/57 X-ray and radioactive gold Lung resection 9/l l/57 Amethopterin,* 5 courses
Excision, vaginal metastasis Hysterectomy 10/20/59 Amethopterin, 3 courses
10/8/59
of the
trophoblast
961
Remarks
Died
a/24/47
Autopsy showed generalized metastases to lungs, brain, and liver (Fig. 1) . Uterus free of choriocarcinoma at hysterectomy
Died
2/2/5
Died
6/Z/55
No
Died
12/l/56
Autopsy showed widespread throughout the body
Died
4/7/56
Autopsy large
Died
1 l/15/58
Microscopic sections from uterus, Figs. 3 and 4. Lung resection, g/11/57, for pulmonary metastasis. Fresh pulmonary lesions appeared 6/30/58. On 7/8/58, patient referred to National Institutes of Health for 5 courses of amethopterin therapy. Died of amethopterin intoxication. Autopsy showed residual choriocarcinema in lungs
Autopsy brain, vagina
1
Alive and free cific disease
of spe-
autopsy volved
performed,
but
lungs
and
and (Fig.
a 2)
gonadotropin tests negative until when patient had cerebral hemorrhage. 3 courses of amethopterin which FSH levels to normal. Patient has some neurological defect. Appears to be
Died
Hysterectomy Amethopterin, Nitrogen-mustard Vinblastinelz
Alive with probable choriocarcinoma
No
Alive and free ease
Hysterectomy finally required. Nidus of choriocarcinoma found in uterus. Now has gonadotropin levels in normal range and appears to be free of disease. Treated at National Institutes of Health
Amethopterin, Actinomycin-Dt Chlorambucil Hysterectomy
3 courses
Aug.,
1961
Patient fell orrhage. that time showed malignant pancreas
in-
choriocarcinoma
showed generalized metastases pelvic mass of choriocarcinoma
Qualitative 3/l/60 Received brought residual cured
brain
Hysterectomy 1 l/10/59 Emergency operation for liver hemorrhages l/17/60, l/25/60, 2/l 5/60
5/5/60 5 courses
2/18/60
showed generalized metastases to lungs, liver, and peritoneum, but uterus and uninvolved
of dis-
on ice 12/29/59, initiating liver hemQualitative gonadotropins negative at so amethopterin not started. Autopsy liver necrosis and hemorrhage. Few trophoblast cells found in liver and (Figs. 5 and 6)
choriocarcinoma found in uterus after hysterectomy. Clinical improvement and regression of pulmonary lesions with chemotherapy, but FSH titer remains high. General condition of patient is good
962
Taylor
and
.4pril 1, 1962 Am. J. Obst. & Ggncc.
Droegemueller
Table II. Summary
of cases of chorioadenoma -.~~~ _
Case NO. 11
Age 39
12
/
1
Date admitted
Pregnancy
Chorionic gonadotropins
I
..~~.-~-...Chest
I
10/25/53
Hydatid
mole
7/23/53
Negative Positive
19
g/26/54
Hydatid
mole
g/15/54
Positive qualitative months
for
6
Positive
13
21
6/
Hydatid
mole
6/l/56
Positive weeks
qualitative
for
6
Negative
14
21
12/16/56
Hydatid
mole
12/l
Positive qualitative 1.!15/57
to
15
30
10/16/60
Hydatid
mole
6/14/60
Table III. Summary
No. Case 16
Age 40
17
II
l/56
of cases of syncytial Date admitted
7/56
at 6 weeks 10/19/53
.~~
x-,cry
Negative
FSH 1.000 M.U. 10/16/60 FSH normal range 1 l/20/60
for 6 months
Negative Positive
to 5//17/61
endometritis
I
ChO&XliC gonadotropins
Pregnancy
I Chest
x-raj
1 l/12/47
Incomplete
abortion
1 l/5/47
Negative
Negative
35
7/23/49
Incomplete
abortion
7/15/49
Negative
Negative
18
30
8/l
Hydatid
mole
Negative
Negative
19
25
Ectopic
pregnancy
Negative
Negative
7/49
12/26/49
tive; second, it is often necessary in order to make an accurate diagnosis; third, the incidence of spontaneous uterine perforation from choriocarcinoma is as high as 25 per cent:; fourth, there is at least the hope that removal of the primary lesion will be followed by spontaneous regression of the secondary lesions. Dilatation and curettage of the uterus often proves to be an unrewarding diagnostic procedure in this disease.
7/2/49
12/26/49
The accumulating experience by Hert/ and others6z7 in the treatment of metastatic choriocarcinoma by amethopterin is the most hopeful news that has yet appeared in the field of chemotherapy for malignant disease. In choriocarcinoma Cases 7 and 8 the quantities of chorionic gonadotropin in the urine were very low the first few months after the diagnosis of choriocarcinoma was made. Because of the negative to Meal&-
Volume Number
Diseases of the trophoblast
83 7
Treatment
Hysterectomy
Emergency uterine
Result
10/26/53
hysterectomy perforation 12/l
for 3/54
spontaneous
963
Remarks
Well
Pathologist’s diagnosis choriocarcinoma originally. Review of histology caused reclassification to chorioadenoma. Myometrium contained chorioadenoma (Fig. 7)
Well
Pulmonary metastasis disappeared spontaneously, 6 months after emergency hysterectomy. Myometrium perforated by chorioadenoma that had spread to broad ligament
Hysterectomy
7/16/56
Well
Original diagnosis cinema. After to chorioadenoma. ometrium
Hysterectomy
4/15/57
Well
Chorioadenoma
Hysterectomy Amethopterin,
7/28/60 2 courses
Well
FSH levels normal after first course of amethopterin. Lung metastasis disappeared on 5/l 7/61. Fig. 9 shows histology
Treatment
from curettings was choriocarhysterectomy, diagnosis changed Chorioadenoma found in myfound
Result
in
myometrium
(Fig.
81
Remarks
Curettage
1 l/13/47
Well
Pathologist’s original diagnosis choriocarcinoma. Material sent to Chorionepithelioma Registry where opinions varied between choriocarcinoma, syncytial endometritis, and normal pregnancy tissue (Fig. 10). Final diagnosis was syncytial endometrits
Curettage Hysterectomy
7/24/49 8/27/49
Well
Histologic diagnosis choriocarcinoma
Curetta,ge
8/20/49
Well. Has had pregnancies
subsequent
Patient referred to hospital with a pathologic diagnosis of choriocarcinoma. With review of sections, diagnosis changed to syncytial endometritis (Fig. 12)
Well. Has had pregnancies
subsequent
Pathologists made diagnosis of choriocarcinoma. Consultation with gynecologic pathologist sought, who changed diagnosis to normal pregnancy reaction in tube (Fig. 13)
Salpingectomy
12/26/49
_~__--
positive chorionic gonadotropin tests, amethopterin was not started in either case as soon as the diagnosis of choriocarcinoma was made. In Patient 7, the chorionic gonadotropin test was not detected as positive until a serious cerebral hemorrhage complicated the disease. Then vigorous chemotherapy was initiated. It might have been prudent to have started chemotherapy before this point. Patient 8 died of liver metastases and severe liver hemorrhage with
was syncytial was considered
endometritis, (Fig. 11)
but
necrosis. This patient might better have been treated with chemotherapy soon after hysterectomy, even though her quantitative urine test for chorionic gonadotropin was negative at that time. It appears that only a scant number of malignant cells killed this patient, or the malignancy was of such a destructive nature that it destroyed itself as it destroyed the host. The treatment of Patient 10 represents an interesting departure from tradition in
964
Fig.
Taylor
and
Droegemueller
3. Case. 6. Choriocarcinoma
April 1, 1962 :Am. J. Ohst. & Gynrc.
in
the
uterus.
that chemotherapy was chosen to precede operation. This was not successful. Hysterectomy had to he performed. The patient is now well. Choriocarcinoma metastases are at times so rapid and virulent that primary surgical therapy is impossible. Cases 2 and 4 illustrate this problem. In other instances, the disease process may extend over a period of years before lethal metastases occur. All of our choriocarcinoma cases followed normal term pregnancy, hydatidiform mole, spontaneous abortion or ectopic pregnancy. Park and Lee? in their general review of 516 cases of choriocarcinoma found that 20 per cent of choriocarcinomas followed a normal pregnancy, 30 per cent followed abortion, and 50 per cent a hydatidiform mole. The ordinary hospital Rana pipiens test or Aschheim-Zondek test for chorionic
Fig.
lung.
4. Case
6. Choriocarcinoma
metastatic
to the
gonadotropin hormone is not sensitive or reliable enough to detect an early rising titer of chorionic gonadotropin hormone. In 3 of our choriocarcinoma patients (Nos. 7, 8, and lo), the qualitative chorionic gonadotropin hormone tests were either negative or only weakly positive. A reliable method for quantitative gonadotropin testing is necessary in following patients with suspected malignancies of the trophoblast. The Delfs” or Klinefelterl” quantitative chorionic gonadotropin tests are recommended by Hertz.’ Chorioadenoma destruens. It is important to separate chorioadenoma destruens from choriocarcinoma because of the superior
Fig. 5. Cast liver.
8. Choriocarcinoma
mctastatic
to the
prognosis of chorioadenoma. We had only 5 chorioadenoma patients and all have survived. Wilsonll reported upon 20 patients with chorioadenoma destruens who survived. The main form of therapy followed in his series was hysterectomy with irradiation of pulmonary metastases in some cases. It is known that distant metastases from chorioadenoma destruens will often undergo spontaneous regression when the primary lesion is removed frqm the uterus. Case 12 from our series is an example. Case 14 suggests that amethopterin may hasten resolution of pulmonary metastases. Hertz has reported several excellent results from the chemotherapy of distant metastases of chorioadenoma destruens.
Volume Number
83 7
Fig. 6. Case 8. Choriocarcinoma pancreas.
Diseases of the trophoblast
metastatic to the
Fig. 8. Case 14. Chorioadenoma uterus.
965
destruens in the
One may question the advisability of using a toxic drug such as amethopterin for treatment of chorioadenoma destruens metastases when the results from operation alone or operation combined with x-ray have been so excellent. This, however, must he balanced against the knowledge that chorioadenoma may be lethal if a large vesWI or an organ like the brain is involved. Syncytial endometritis. Syncytial endometritis is a self-limiting condition and needs but to be recognized. The absence of chorionic gonadotropin in the urine is helpful in making the correct diagnosis. The entity deserves some discussion because the histologic findings (Figs. 10 to 13) often are enough to startle the pathologist and alarm the clinician. Probably one who sees many choriocarcinomas under the microscope \vnuld discount svncvtial endometritis as a
legitimate consideration in the differential diagnosis. The 4 patients with syncytial endometritis in our series did cause some temporary diagnostic consternation, however.
Fig. 7. Case 11. Chorioadenoma uterus.
Fig. 9. Case 15. Chorioadenoma uterus.
destruens in the
Summary
and
conclusions
Nineteen patients with actual or suspected malignancies of the trophoblast have been seen by us in a period of 15 years. Ten had choriocarcinomas, 5 chorioadenoma destruens, and 4 syncytial endometritis. Three of the patients with choriocarcinema are alive at this time. Four patients with choriocarcinoma and one with chorioadenoma were treated with amethopterin. All of the patients with chorioadenoma and syncytial endometritis have survived. Distant metastases from chorioadenoma should be treated with amethopterin even
destruens in the
966
Taylor
Fig.
10. Casr
16. Syncytial
Fig.
12.
18.
Case
and
Droegemueller
Syncytial
endometritis.
endometritis.
though such distant metastases may disappear after excision of the primary lesion. Quantitative chorionic gonadotropin tests performed on rats or mice are necessary for early detection of rising chorionic gonadotropin levels from anaplastic choriocarcinomas, for the ordinary qualitative chorionic gonadotropin tests are not sufficiently sensitive. Amethopterin should be used as an adjunct to hysterectomy in the treatment of a11 patients with proved choriocarcinoma.
Fig. 13. Case reaction.
19. Tubal
pregnancy
with
atypical
‘The reasons are that a lethal hemorrhage may occur from a very few malignant cells that have a correspondingly low hormone production and the risk to the patient from an initial course of amethopterin is not yreat. We wish to thank Drs. Charles R. Freed and Raymond C. Chatfield for Case 5; Dr. George M. Horner for Case 6; and Colonel John S. Zelenik, Fitzsimons Army Hospital, for details concerning Cases 2, 3, 1, 10, and 12.
REFERENCES
1. Brewer, J. I., Rinehart, J. J., and Dunbar, R. W.: AM. J. OBST. & GYNEC. 81: 574, 1961. 2. Report of the Joint Project for Study of Choriocarcinoma and Hydatidiform Mole in Asia: Ann. New York Acad. SC. 80: 178, 1959.
3. 4.
5.
Brews, A.: J. Obst. & Gynaec. Brit. Emp. 46: 813, 1939. Smalbraak, J.: Trophoblastic Growths, Amsterdam, 1957, Elsevier Publishing Co., p. 309. Acosta-Sison, H.: AM. J. OBST. & GYNFC. 42: 878, 1941.
Volume 83 Number
Diseases
of the
trophoblast
967
7
6. Hertz, R., Bergenstal, D. M., Lipsett, M. B., Price. E. B.. and Hilbish, T. F.: J. A. M. A. 168:
-845,
1958.
7. Hertz, Price, York 8. Park.
R., Bergenstal, D. M., Lipsett, M. B., E. B., and Hilbish, T. F.: Ann. New Acad. SC. 80: 262, 1959. W. W.. and Lees., _1. C.: Arch. Path. 49: $3, 1950.’ 9. Delfs, E.: Obst. & Gynec. 9: 1, 1957.
10. Klinefelter, J. F., Jr., Albright, F., and Griswold, G. C.: J. Clin. Endocrinol. 3: 529, 1943. 11. Wilson, R. B., Hunter, J. S., and Dockerty, M. B.: AM. J. OBST. & GYNEC. 81: 546, 1961. 12. Hertz, R., Lipsett, M. B., and Moy, R. H.: Cancer Res. 20% 1050, 1960.
Discussion ROY HERTZ,* Bethesda, Maryland. Inasmuch as we have recently published our studies on 63 cases of choriocarcinoma and related trophoblastic disease (AM. J. OBST. & GYNEC. 82: 631, 1961), I shall not repeat our findings in any- detail here. In that paper we have also set forth our concept of the relationship between the several varieties of trophoblastic disease which we regard as a continuous spectrum of disease proccsscs. Since this article will provide a detailed account of our point of view and experience as they relate to Dr. Taylor’s fine study, I shall not reiterate these statements at this juncture. Suffice it to say that our personal gratification in seeing many of these patients improve is equaled only by the gratification which has come to us from the cooperation and helpfulness of the members of your branch of the profession in so selflessly referring these patients for study. I want especially to thank Dr. Taylor and the many others in the audience who have participated with us in this study. Without this type of moral as well as clinical support, we could not have accomplished our work. DR.
DR. ROBERT B. WILSON, Rochester, Minnesota. Since most pathologists, who are our authorities on the subject, have repeatedly written that it is seldom possible to make a firm diagnosis on curettings alone, I would like to ask Dr. Taylor whether or not he feels that examination of the curettings alone is sufficient. In the pathologic differentiation between choriocarcinoma and chorioadenoma destruens, it is usually considered necessary to cut many thin serial blocks of tissue because of the smallness and infrequency of diagnostic villi in chorioadenoma destruens. If the diagnosis is difficult with actual myometrial tissue, it would seem well nigh impossible with crlrettings alone. Time has proved, of course, *By
invitation
the correctness of the diagnosis in most instances. A similar comment may be made on the matter of making a firm diagnosis of choriocarcinoma on the basis of the microscopic appearance of an isolated metastatic growth. As Dr. Arthur Hertig has written, with whom our Dr. Dockerty agrees, it is possible to have a metastatic lesion composed of trophoblast without villi which is not a choriocarcinoma, provided villi are found in the primary lesion. These comments are made in view of the fact that, of the 3 patients who had diagnoses of choriocarcinoma and are still alive, in one (Case 7) the diagnosis was made on the appearance of a vaginal lesion, a persistent excretion of chorionic gonadotropin, and the occurrence of a cerebrovascular accident; in another (Case 9) there has been no histologic diagnosis but the x-ray appearance of the chest continues to show tumor and chorionic gonadotropin continues to be excreted; and in the third (Case 10) the diagnosis was established by the examination of curettings and the continued excretion of chorionic gonadotropin. As we have had patients with x-ray and other evidence of metastatic disease such as vaginal lesions and with persistent excretion of chorionic gonadotropin who had destruens rather than choriocarcinoma, I would ask Dr. Taylor whether he is completely confident that the persistent excretion of chorionic gonadotropin with or without other evidence of metastatic disease is actually diagnostic of this particular entity. As to treatment, there can be little question as to the desirability of treating true choriocarcinema with a chemotherapeutic agent. However, I have become alarmed at the frequency with which such a toxic agent as amethopterin is being used. During my participation in a recent exhibit on this subject, many physcians related their experiences with patients who had had a molar pregnancy and subsequently had been treated with amethopterin because a diag-
968
Taylor
and
April 1, 1962 Am. J. Obst. & Gynec.
Droegemueller
nosis of choriocarcinoma had been made on the examination of curettings alone, with or without associated evidence of persistent excretion of chorionic gonadotropin. I wonder whether Dr. Taylor would not agree that this very toxic drug should be reserved almost exclusively for the treatment of proved choriocarcinoma. I do not wish to leave the impression that any patient with or without evidence of a metastatic lesion and with persistent excretion of chorionic gonadotropin should not be treated. In patients with suspected choriocarcinoma or chorioadenoma destruens, I agree with Dr. Taylor that in most instances operation should be performed in order to establish a diagnosis conclusively. If a patient is found to have a choriocarcinoma, the uterus, tubes, and ovaries should be removed and this followed by the administration of amethopterin with or without other chemotherapeutic agents. If a patient is found to have a chorioadenoma destruens and conservation of the childbearing function is not necessary, then again the uterus and tubes and, if necessary, the ovaries should be removed if technically possible. In some instances of chorioadenoma destruens it is not possible to remove all of the diseased tissue and there may be metatastic lesions. In these, again if the childbearing function is not important and if there is a continuing excretion of chorionic gonadotropin, x-ray therapy has been effective in our hands and we thus avoid the administration of a toxic drug. At the time of exploratory operation there is a good chance that patients with chorioadenoma destruens may have an isolated lesion which can be locally excised. In our series of 20 patients, examination of the hysindicated that excision terectomy specimen could have been done in 6 instances-only cently have we realized the feasibility procedure and have done it successfully
of in
rethis one
instance. Therefore, it seems to me that chemotherapy should be used in the treatment of patients with chorioadenoma destruens only when local excision is not possible and when the childbearing function is to be conserved. Last, a word of caution in evaluating the effectiveness of any therapy for these entities is in order. We must always remember the builtin regressive property of trophoblastic tissue and recognize that we are on treacherous ground, particularly in patients with chorioadenoma destruens, if we attribute our cures to anything other than surgical removal and this regressive property. DR. TAYLOR (Closing). Dr. Wilson and I differ on the approach to this problem. Perhaps I! years ago I would have agreed with him but I do not agree now that one can wait for a proved histologic diagnosis of choriocarcinoma. There are some situations when it is impossible to make a histologic diagnosis of choriocarcinema. You have the history of a patient with a mole. A hysterectomy is done after persistence of titer for several months and the uterus is found free of any tumor tissue after serial study. You have then nothing on which to base your diagnosis except the shadows in the lungs and a highly positive gonadotrophic titer. What do you want to call that? Do you want to wait until you do an autopsy and get the choriocarcinema tissue from the lung? One of our patients even had a lung biopsy and nothing but blood clots was found for the pathologist to examine. One of the points of our paper is to emphasize that one must know the natural history of the disease and know the possibilities and not be dependent upon pathologic findings alone. This is a combined clinical, pathologic, and hormonal diagnosis that one has to make.