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Persistence of abnormal trophoblast
Persistence of abnormal trophoblast JOH~
A. KIRK, M.D.
Eugene, Oregon
fundus then measured 24 em. A diagnosis of a coexisting fetus and mole was made based on the disparity between the size of the uterus and fetal skeleton and the high chorionic gonadotropin titer. A laparotomy was done and the uterus was found to be enlarged, consistent with the previous finding. Both ovaries were characterized by cystic enlargement thought to be lutein cysts. The uterus appeared very tense and, as the incision was made, a large amount of vesicular tissue was forcibly extruded. The incision was enlarged and an intact sac was found which contained a live male fetus measuring 12.5 em. from crown to rump and a completely separate and normal placenta. The uterus was evacuated and under direct vision the cavity was inspected and found free of any residual disease. On Sept. 2, 1952, 3 weeks after hysterotomy, it was felt that the uterine fundus showed enlargement and the patient also had scant to moderate continuous vaginal bleeding. A qualitative hyperemic rat ovary pregnancy test was positive, but the quantitative test was negative in advanced dilutions ( 1/1,000). The quantitative test was repeated on Sept. 15, 1952, and was positive in all dilutions. The fundus of the uterus appeared to be enlarging, and the patient continued to have a bloody discharge associated with short episodes of profuse bleeding. She was readmitted to the hospital on Sept. 16, 1952, with a diagnosis of malignant mole and prepared for possible hysterectomy. X-ray of the chest revealed round soft tissue densities in the second right anterior interspace about the lower right hilus and in the left second and third interspaces. Because of the definite tumor, presence of metastasis, and an increase in the gonadotropic hormone titer, a total hysterectomy was performed leaving the cystic-appearing ovaries, presumed to be lutein cysts. The pathology report read: A tumor nodule is found involving the superior and posterior portion of the fundus. The tumor nodule is orange-yellow in color and
T H I S C A S E P R 0 V I D E S an interesting addition to the literature because of the long-term follow-up and the appearance of ovarian pathology related to the tumor and the actual appearance of the tumor 11 years and 7 months after the onset of pregnancy. Case report This is the ca5e of a 19-year-old white married para i who had had one normal term pregnancy. Her last normal menses was on April 10, 1952. On June 21, 1952 she had an episode of moderately profuse bleeding from the vagina. Her physician, examining her at intervals, noted a sudden enlargement of the uterus to above the umbilicus. On admission to the hospital, a series of x-rays of the abdomen were taken and they revealed a fetal skeleton compatible with a 4 month fetus in the right upper quadrant of the enlarged utt>rus, larger than expected for a 4 month gestation. Physical examination was normal exct>pt for the abdomen which revealed a mass arising from the pelvis, typical of an enlarged uterus, which measured 20 em. No fetal parts were identified and no fetal heart tones were heard. The cervix was 3 em. long and closed. The hemoglobin was 7.9 Gm. A quantitative pregnancy test was run and the test was positive in all dilutions including 1/1,000. A test of the kidney, ureter, and bladder and a repeat x-ray t'xamination were performed, which at this time failed to show the fetal skeleton. Every effort was made to recover possible villi from the vagina and spt>cimens were sent to the laboratory hut no positive identification of villi was made. On July 30, the patient had some cramping and a short episode of profuse bleeding and the From the Women's and Children's Clinic. Presented by invitation at the Thirty-first Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Santa Barbara, California, Nov. 4-7, 1964.
667
668
Kirk
July I l'lfi:, :\m . j. Ohst . & ( ;yneL
Fig. l. Lymph node containing tumor cells. measures 6.5 x 4.5 x I em. There are 2 small villi found at the lateral margin of the nod ule. Fixed sections reveal areas of proliferating Langhans cells with the formation of papillary structures with stratification of the cells. Other areas revea l highly hyperchromatic infiltrating cells of irregular sizes and shapes with num erous mitoses. These cells are invading the myometrium and the lymphatic sinusoids. The diagnosis was chorioa denoma destruens. These slides were then sent to the Albert Mathieu C horionepithelioma Registry and the diagnosis was confirmed. The postopera tive course was uneventful and the patient was given 100 mg. stilbestrol daily which she tolerated very well. Pregnancy tests remained positive until Jan. 16, 1953 ( 4 months after hysterectomy) and remain ed negative for 2 years and then were discontinued. Chest x-rays revealed gradual diminution of her lung metastasis and on Nov. 24, 1953, there was no evidmct· of metastasis and stilbestrol was discontinued. Pulmonary metastasis in cho ri oadenoma dcstru ens usually spontaneously regress a ft er h ysterectomy. The patient then moved to Bend, Oregon, and in July, 1958, she developed sudden right lower quadrant abdominal pain and a laparotomy was don e. The abdomen contained a moderate amount of bloody fluid and a hemorrhagic mass consisting of a right ovary and tube with a twisted pedicle. The left tube and ovary werP normal to inspection. The pathology report indicated a hemorrhagic ovary 7 em. in diamt'ter with attached Fallopian tube. Multiple sections of the ova ry reveal an intense hemo rrhagic infiltration throughout. No evidence of lining mem-
brane or character of this cyst ca n 1)(' obtained. Howeve r, many sma ll follicul a r cysts were noted. The patient then moved to Pottland, Ore.gon , and in November, 1963 ( 11 yea rs and 2 months aftPr hysterec tomy for chorioadenoma destrucns ) she developed a sudden onset of excruciating severe left lower quadrant pain. Pelvic examination revealed a left adnexal mass measuring 4 to 5 ern. in diameter and exquisitely tender. A diagn osis of a twisted ovarian cyst was marie and a la paro to my was done. Manual explora tion of the abodmen was done which rev•·aled no abnorma lities and no significant hypogastric or p••riaortic lym ph nodes. An irregula1· ovary an d corpus hemorrhagicum approximately + to 5 em . were found in the pelvis. The ovarian mass was then dissected from its attachment and removed intact. Benea th the ovarian mass lay a firm I em. irregular and poorly defined mass ove rlying thP distal third of the ureter. This was dissected fr ee. The pathology report indicatrd a cystic ovary lll<'asuring 7 x 4.5 x 2 cn1. a nd tisSll(' from tlw rf'tro peritoneal a rea. Cut su rfa ces of th< ~ ovarian tissue show follicular cysts as \W I! as a co rpu s lut<~ um cyst. Sections of the ovary show the stroma to contain many spindle-shaped basophilic ce lls and an occasional small follicular cyst. Lut rinization of the stroma is present in some regions. On microscopic examination, the tissu e removf'd from the retroperitonea l area contains one lymph node--like structure and this is greatly distorted by necrosis accompa nying th e small islands of neoplastic tissue (Fig. I : . There are isla nds of tumor tissue appearing in n'mnants of the lymphoid stroma and these are quite hyperchromatic and p!Pomorphi.-. Th~:
Volume 92
Number 5
large nuclei, the presence of mitotic figures, and the general appearance leaves no doubt that a malignancy is present, although the nature of it is difficult to determine. However, it is typical of cells of the trophoblast. Chest x-rays at this time were negative and a chorionic gonadotropic hormone assay on Dec. 10, 1963, \Vas negative under 500 International Units per liter. The patient has been well and in apparently good health since her last opera! ion.
Persistence of abnormal trophoblast 669
tomy; (d) the elaboration of small amounts of chorionic gonadotropic hormone by the residual trophoblast cells and the response of the ovaries by becoming cystic and containing areas of luteinized stroma with incidental twisting of the pedicle of one ovary; and (e) the presence of malignant trophoblast cells in a pelvic lymph node 11 years and 7 months after the original tumor. Summary
Comment
This case illustrates a number of interesting variations that can occur in trophoblastic tumors: (a) the development of a hydatidiform mole at the same time a normal pregnancy is developing; (b) the subsequent transformation of this benign mole into an invasive and destructive mole ( chorioadenoma destruens) ; (c) apparent metastasis to the lungs that regressed after hysterec-
1. This is a case report of a patient who had a twin pregnancy associated with a hydatidiform mole. 2. This was foilowed by a chorioadenoma destruens and apparent large lung metastasis which eventually cleared. 3. The patient developed apparent related ovarian pathology subsequent to the discovery of trophoblastic cells in pelvic lymph node 11 years and 2 months after a hysterectomy.
Discussion
DR. IvAN I. LANGLEY, Portland, Oregon. It would seem that the occurrence of this problt>m in a multiple pregnancy is interesting but not vital in the course of therapy. I feel almost certain that any of us, having been faced with this girl's problem, in 1964 rather than 1952, would have treated it much more vigorously. Specifically, a patient with a diagnosis of malignant trophoblastic disease substantiated by tissue from curettage with a positive x-ray diagnosis of pulmonary metastases would most certainly be treatC'd today by the majority of us with antimetabolites, probably Methotrexate, actinomycin D, or both, with or without operation, and congratulat<> ourselves 12 years hence for a m('dical cure. It is interesting that this patient of Dr. Kirk's, under similar circumstances, is alive and well 11 years and 7 months after diagnosis and without chemotherapy. She probably has living trophoblastic tissue in her body now dating from her disease nearly 12 years ago. I feel it is fair to assume that the ovarian cystomas subsequently trrated wer(' produced by gonadotropic stimulation and that the necrosis in the lymph nodes was due to malignant cells present there. At a meeting of this society in 1952, Dr. How-
ard Stearns presented 10 cases of malignant trophoblastic disease treated without the benefit of antimetabolitic drugs. Seven of these 10 patients survived their disease. It is obvious that this small series is not statistically significant. But the survival rate is about what we anticipate now can be obtained with the use of drug therapy. It is obvious that many of these cases were not truly choriocarcinomas. Many surely wen' in the so-called "gray zone" between mole and true choriocarcinomas. Since we have potent drugs which have been shown to be active against the malignant disease, it becomes increasingly important to make sure of our diagnosis before instituting therapy. A recent case report in Obstetrics and Gynecology beautifully illustrates what can happen when the anxiety to treat overcomes the responsibility to diagnose. A patient who was followed after evacuation of a potentially malignant mole suddenly developed a massive rise in gonadotropin titer out of all proportion to that sfen in any normal pregnancy. The patient was trt>ated with not one but two courses of amethopterin (Methotrexatr) with no reduction in titer. Pelvic examination showed a markedly enlarged uterus, and x-ray confirmed
670
Kirk
the presence of a twin pregnancy. The patient went on to term and was delivered of living twins in spite of, and obviously not because of, her treatment. I do not know the mortality in the use of antimetabolites, but I think it fair to state the morbidity and potential damage to a fptus makes it imperative that we be accurate in our diagnosis in case a rising gonadatropin titer reflect pregnancy rather than persistence of malignant cells in this disease. I am sure that many of us could sponsor the cause of treating Dr. Kirk's patimt now with antimetabolites. Others will argut' that the near 12 year time interval would seem to prove the benignancy of her diseast'. It is apparent that our ability to treat exceeds our accuracy in diagnosis. Dr. Kirk's case amply demonstrates this fact. DR. ERNEST \V. PAGE, San Francisco, California. A Japanese scholar, Dr. Tominaga, who is working in my laboratory, has just studied slides of trophoblastic tumors from the AlbPrt Mathieu Chorionepithelioma Registrv. WP were interested in the sex chromatin of these tumors. Of 18 cases of hyd:ltid moles, all wPrP chromatin positive. Of 30 cases of choriocarcinoma. 25 were chromatin positive. and of the S "rnak" tumors, one was from a tPsticular cancer. I have no idea why this should be so, but we must consider tht· possibility that the Y chromosome has some tissue antigens associated with it and those tumors arc more often rejected by the mother. I would likr to ask about the sex of thr fctusC's. We could have a situation hPre wherr thP mal<" has a normal placrnta and thr fpmalP trophoblast deVl'lops a mole DR. \VILL!Al\1 SLATE,* Los Ang<"les, California. \Ve at th<" Los Angc!C's County Hospital are reviewing the patirnts who havr had trophoblastic dis<"ase in thP past 13 years. \Ve haw approximately 130 molrs, approximately 10 per yrar. In addition, there were 19 patiPnts who had a diagnosis of cithrr chorioadenoma destrut"ns or choriocarcinoma. Of thcsp 130 patients who had a hydatidiform molr 3 of them had an associatPd fetus. One of these was a viable sizPd fetus just over 1,000 grams and 2 others wne Parlier pregnancies; however, the fetus was rrcognizable. Unfortunately, the particular information with respect to sex and chromatin studies is not availablt' at present. I think that this fact that 3 of tht"se had an associated fetus may support *By invitation.
July l, 1~lh:'l
Am. J. Oh:-.t. &
C~yii('L
the idea hydatidiform mole is more common in the twin prPgnancy. Finally, I would just like to support th•· sug~estion that this lesion is very unprrdictabk and the mon· one is associatC'd with it the less (Jilt' i.s ablP to have an idea what is going to occur and what is going to be the prognosis. DR. ERVI:-i E. NICHOLS, Pasad<'na, California. Dr. Slate and I have had a running feud about moles and choriocarcinoma for the last year or two. Not that WP are completely opposed to ont· anothrr. I suppose that ha\·ing a ~crirs of , asc·s sornrhO\\' makt"s you somr sort l!f an authorit\' I am not surr this is tnw. In ow· practi<"' in Pasadena in thc· last 15 months \\ ,. have· had occasion to care for 7 patients who havc· had either mole or malignant changes- -trophoblasti< changes. one of these ha\·ing lwcn a clwriocarcinoma. I would like to mPntion some clini,·al problems. On" of thr problf'rns of a clinician, I think, is basically the nt•t·d fnr an accuralt' mPthocl of nwasuring gonadotropins. \Vhat ahnut thr new precipitation tests:' \\'hat abnm tlw various tt·sts that wt· arc usin,g· tnda) as a nH·a..;un·
of gonadotropinS:' I feel that ''" baw been traditionalh' IJotnlCI to do hyst<·rotnmie.s on patit•nts with moles and I hav<· rlf'Vl'r hc'cn ablr to subscribc to this particular approach. I think this is a traditional attitudt' rath<"r than a practical attitude. For th<' last I fl yrars in any of thesr cascs that f ha1 ,. had anything to do with. lw thn at th<' White Mt·rnorial Hospital, at thf' County Hospital. or in my own practicr, I han' always Pmptied the uterus \'aginally and I still fe,·l that this i:.; pn•ferablr· to subjecting the patit·nt to a laparotomy. I know that thP argunlC'nt will he that you _gr·t a hrtter look at the inside of tlw utnu:.;; I am not sun• that this is actually true lwcattS<' I am not sun• that rn•n if you do a hystt·rotomy you look in tht· nooks and crannies, and I think that 11 ,. were talking about a microscopH· pinur<'. prefer dilatation and curettage tn hvstt'rectornv. DR. KIRK (Closing). My real ,·onn·m at the momrnt is, what do thrse n·lls look likr in th<' lymph node? Do they look like trapped cells that art" not ,going to havr any more actil'itv or do they look likr n·lls that arr artiv<'iy growing:' Is thr arra of Iwcrosis in a lymph nod<' a significant finding? ThPse, I think, arc prrtinPnt questions l)f'causp of the fact that vnu want some decision as to the basis of furthPr therapy. Should we give this patient Methotrexate or should we not?
Volume 92 Number 5
In looking at the senes of chorioadenoma destruens cases that have been reported, oddly Pnough there have been no reports of delayed activity, and the delayed feature of the tumor is always confined to choriocarcinoma. This, I think, is a question for us to answer in this case. I would find it somewhat difficult to do a
Persistence of abnormal trophoblast 671
dilatation and curettage on a uterus approximately 6 months pregnant, and I would think that it would be easier to do a hysterotomy, although I would certainly agree that whenever we can do a dilatation and curettage, this would be a safer and better approach.
A. KIRK, M.D.
Eugene, Oregon
fundus then measured 24 em. A diagnosis of a coexisting fetus and mole was made based on the disparity between the size of the uterus and fetal skeleton and the high chorionic gonadotropin titer. A laparotomy was done and the uterus was found to be enlarged, consistent with the previous finding. Both ovaries were characterized by cystic enlargement thought to be lutein cysts. The uterus appeared very tense and, as the incision was made, a large amount of vesicular tissue was forcibly extruded. The incision was enlarged and an intact sac was found which contained a live male fetus measuring 12.5 em. from crown to rump and a completely separate and normal placenta. The uterus was evacuated and under direct vision the cavity was inspected and found free of any residual disease. On Sept. 2, 1952, 3 weeks after hysterotomy, it was felt that the uterine fundus showed enlargement and the patient also had scant to moderate continuous vaginal bleeding. A qualitative hyperemic rat ovary pregnancy test was positive, but the quantitative test was negative in advanced dilutions ( 1/1,000). The quantitative test was repeated on Sept. 15, 1952, and was positive in all dilutions. The fundus of the uterus appeared to be enlarging, and the patient continued to have a bloody discharge associated with short episodes of profuse bleeding. She was readmitted to the hospital on Sept. 16, 1952, with a diagnosis of malignant mole and prepared for possible hysterectomy. X-ray of the chest revealed round soft tissue densities in the second right anterior interspace about the lower right hilus and in the left second and third interspaces. Because of the definite tumor, presence of metastasis, and an increase in the gonadotropic hormone titer, a total hysterectomy was performed leaving the cystic-appearing ovaries, presumed to be lutein cysts. The pathology report read: A tumor nodule is found involving the superior and posterior portion of the fundus. The tumor nodule is orange-yellow in color and
T H I S C A S E P R 0 V I D E S an interesting addition to the literature because of the long-term follow-up and the appearance of ovarian pathology related to the tumor and the actual appearance of the tumor 11 years and 7 months after the onset of pregnancy. Case report This is the ca5e of a 19-year-old white married para i who had had one normal term pregnancy. Her last normal menses was on April 10, 1952. On June 21, 1952 she had an episode of moderately profuse bleeding from the vagina. Her physician, examining her at intervals, noted a sudden enlargement of the uterus to above the umbilicus. On admission to the hospital, a series of x-rays of the abdomen were taken and they revealed a fetal skeleton compatible with a 4 month fetus in the right upper quadrant of the enlarged utt>rus, larger than expected for a 4 month gestation. Physical examination was normal exct>pt for the abdomen which revealed a mass arising from the pelvis, typical of an enlarged uterus, which measured 20 em. No fetal parts were identified and no fetal heart tones were heard. The cervix was 3 em. long and closed. The hemoglobin was 7.9 Gm. A quantitative pregnancy test was run and the test was positive in all dilutions including 1/1,000. A test of the kidney, ureter, and bladder and a repeat x-ray t'xamination were performed, which at this time failed to show the fetal skeleton. Every effort was made to recover possible villi from the vagina and spt>cimens were sent to the laboratory hut no positive identification of villi was made. On July 30, the patient had some cramping and a short episode of profuse bleeding and the From the Women's and Children's Clinic. Presented by invitation at the Thirty-first Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Santa Barbara, California, Nov. 4-7, 1964.
667
668
Kirk
July I l'lfi:, :\m . j. Ohst . & ( ;yneL
Fig. l. Lymph node containing tumor cells. measures 6.5 x 4.5 x I em. There are 2 small villi found at the lateral margin of the nod ule. Fixed sections reveal areas of proliferating Langhans cells with the formation of papillary structures with stratification of the cells. Other areas revea l highly hyperchromatic infiltrating cells of irregular sizes and shapes with num erous mitoses. These cells are invading the myometrium and the lymphatic sinusoids. The diagnosis was chorioa denoma destruens. These slides were then sent to the Albert Mathieu C horionepithelioma Registry and the diagnosis was confirmed. The postopera tive course was uneventful and the patient was given 100 mg. stilbestrol daily which she tolerated very well. Pregnancy tests remained positive until Jan. 16, 1953 ( 4 months after hysterectomy) and remain ed negative for 2 years and then were discontinued. Chest x-rays revealed gradual diminution of her lung metastasis and on Nov. 24, 1953, there was no evidmct· of metastasis and stilbestrol was discontinued. Pulmonary metastasis in cho ri oadenoma dcstru ens usually spontaneously regress a ft er h ysterectomy. The patient then moved to Bend, Oregon, and in July, 1958, she developed sudden right lower quadrant abdominal pain and a laparotomy was don e. The abdomen contained a moderate amount of bloody fluid and a hemorrhagic mass consisting of a right ovary and tube with a twisted pedicle. The left tube and ovary werP normal to inspection. The pathology report indicated a hemorrhagic ovary 7 em. in diamt'ter with attached Fallopian tube. Multiple sections of the ova ry reveal an intense hemo rrhagic infiltration throughout. No evidence of lining mem-
brane or character of this cyst ca n 1)(' obtained. Howeve r, many sma ll follicul a r cysts were noted. The patient then moved to Pottland, Ore.gon , and in November, 1963 ( 11 yea rs and 2 months aftPr hysterec tomy for chorioadenoma destrucns ) she developed a sudden onset of excruciating severe left lower quadrant pain. Pelvic examination revealed a left adnexal mass measuring 4 to 5 ern. in diameter and exquisitely tender. A diagn osis of a twisted ovarian cyst was marie and a la paro to my was done. Manual explora tion of the abodmen was done which rev•·aled no abnorma lities and no significant hypogastric or p••riaortic lym ph nodes. An irregula1· ovary an d corpus hemorrhagicum approximately + to 5 em . were found in the pelvis. The ovarian mass was then dissected from its attachment and removed intact. Benea th the ovarian mass lay a firm I em. irregular and poorly defined mass ove rlying thP distal third of the ureter. This was dissected fr ee. The pathology report indicatrd a cystic ovary lll<'asuring 7 x 4.5 x 2 cn1. a nd tisSll(' from tlw rf'tro peritoneal a rea. Cut su rfa ces of th< ~ ovarian tissue show follicular cysts as \W I! as a co rpu s lut<~ um cyst. Sections of the ovary show the stroma to contain many spindle-shaped basophilic ce lls and an occasional small follicular cyst. Lut rinization of the stroma is present in some regions. On microscopic examination, the tissu e removf'd from the retroperitonea l area contains one lymph node--like structure and this is greatly distorted by necrosis accompa nying th e small islands of neoplastic tissue (Fig. I : . There are isla nds of tumor tissue appearing in n'mnants of the lymphoid stroma and these are quite hyperchromatic and p!Pomorphi.-. Th~:
Volume 92
Number 5
large nuclei, the presence of mitotic figures, and the general appearance leaves no doubt that a malignancy is present, although the nature of it is difficult to determine. However, it is typical of cells of the trophoblast. Chest x-rays at this time were negative and a chorionic gonadotropic hormone assay on Dec. 10, 1963, \Vas negative under 500 International Units per liter. The patient has been well and in apparently good health since her last opera! ion.
Persistence of abnormal trophoblast 669
tomy; (d) the elaboration of small amounts of chorionic gonadotropic hormone by the residual trophoblast cells and the response of the ovaries by becoming cystic and containing areas of luteinized stroma with incidental twisting of the pedicle of one ovary; and (e) the presence of malignant trophoblast cells in a pelvic lymph node 11 years and 7 months after the original tumor. Summary
Comment
This case illustrates a number of interesting variations that can occur in trophoblastic tumors: (a) the development of a hydatidiform mole at the same time a normal pregnancy is developing; (b) the subsequent transformation of this benign mole into an invasive and destructive mole ( chorioadenoma destruens) ; (c) apparent metastasis to the lungs that regressed after hysterec-
1. This is a case report of a patient who had a twin pregnancy associated with a hydatidiform mole. 2. This was foilowed by a chorioadenoma destruens and apparent large lung metastasis which eventually cleared. 3. The patient developed apparent related ovarian pathology subsequent to the discovery of trophoblastic cells in pelvic lymph node 11 years and 2 months after a hysterectomy.
Discussion
DR. IvAN I. LANGLEY, Portland, Oregon. It would seem that the occurrence of this problt>m in a multiple pregnancy is interesting but not vital in the course of therapy. I feel almost certain that any of us, having been faced with this girl's problem, in 1964 rather than 1952, would have treated it much more vigorously. Specifically, a patient with a diagnosis of malignant trophoblastic disease substantiated by tissue from curettage with a positive x-ray diagnosis of pulmonary metastases would most certainly be treatC'd today by the majority of us with antimetabolites, probably Methotrexate, actinomycin D, or both, with or without operation, and congratulat<> ourselves 12 years hence for a m('dical cure. It is interesting that this patient of Dr. Kirk's, under similar circumstances, is alive and well 11 years and 7 months after diagnosis and without chemotherapy. She probably has living trophoblastic tissue in her body now dating from her disease nearly 12 years ago. I feel it is fair to assume that the ovarian cystomas subsequently trrated wer(' produced by gonadotropic stimulation and that the necrosis in the lymph nodes was due to malignant cells present there. At a meeting of this society in 1952, Dr. How-
ard Stearns presented 10 cases of malignant trophoblastic disease treated without the benefit of antimetabolitic drugs. Seven of these 10 patients survived their disease. It is obvious that this small series is not statistically significant. But the survival rate is about what we anticipate now can be obtained with the use of drug therapy. It is obvious that many of these cases were not truly choriocarcinomas. Many surely wen' in the so-called "gray zone" between mole and true choriocarcinomas. Since we have potent drugs which have been shown to be active against the malignant disease, it becomes increasingly important to make sure of our diagnosis before instituting therapy. A recent case report in Obstetrics and Gynecology beautifully illustrates what can happen when the anxiety to treat overcomes the responsibility to diagnose. A patient who was followed after evacuation of a potentially malignant mole suddenly developed a massive rise in gonadotropin titer out of all proportion to that sfen in any normal pregnancy. The patient was trt>ated with not one but two courses of amethopterin (Methotrexatr) with no reduction in titer. Pelvic examination showed a markedly enlarged uterus, and x-ray confirmed
670
Kirk
the presence of a twin pregnancy. The patient went on to term and was delivered of living twins in spite of, and obviously not because of, her treatment. I do not know the mortality in the use of antimetabolites, but I think it fair to state the morbidity and potential damage to a fptus makes it imperative that we be accurate in our diagnosis in case a rising gonadatropin titer reflect pregnancy rather than persistence of malignant cells in this disease. I am sure that many of us could sponsor the cause of treating Dr. Kirk's patimt now with antimetabolites. Others will argut' that the near 12 year time interval would seem to prove the benignancy of her diseast'. It is apparent that our ability to treat exceeds our accuracy in diagnosis. Dr. Kirk's case amply demonstrates this fact. DR. ERNEST \V. PAGE, San Francisco, California. A Japanese scholar, Dr. Tominaga, who is working in my laboratory, has just studied slides of trophoblastic tumors from the AlbPrt Mathieu Chorionepithelioma Registrv. WP were interested in the sex chromatin of these tumors. Of 18 cases of hyd:ltid moles, all wPrP chromatin positive. Of 30 cases of choriocarcinoma. 25 were chromatin positive. and of the S "rnak" tumors, one was from a tPsticular cancer. I have no idea why this should be so, but we must consider tht· possibility that the Y chromosome has some tissue antigens associated with it and those tumors arc more often rejected by the mother. I would likr to ask about the sex of thr fctusC's. We could have a situation hPre wherr thP mal<" has a normal placrnta and thr fpmalP trophoblast deVl'lops a mole DR. \VILL!Al\1 SLATE,* Los Ang<"les, California. \Ve at th<" Los Angc!C's County Hospital are reviewing the patirnts who havr had trophoblastic dis<"ase in thP past 13 years. \Ve haw approximately 130 molrs, approximately 10 per yrar. In addition, there were 19 patiPnts who had a diagnosis of cithrr chorioadenoma destrut"ns or choriocarcinoma. Of thcsp 130 patients who had a hydatidiform molr 3 of them had an associatPd fetus. One of these was a viable sizPd fetus just over 1,000 grams and 2 others wne Parlier pregnancies; however, the fetus was rrcognizable. Unfortunately, the particular information with respect to sex and chromatin studies is not availablt' at present. I think that this fact that 3 of tht"se had an associated fetus may support *By invitation.
July l, 1~lh:'l
Am. J. Oh:-.t. &
C~yii('L
the idea hydatidiform mole is more common in the twin prPgnancy. Finally, I would just like to support th•· sug~estion that this lesion is very unprrdictabk and the mon· one is associatC'd with it the less (Jilt' i.s ablP to have an idea what is going to occur and what is going to be the prognosis. DR. ERVI:-i E. NICHOLS, Pasad<'na, California. Dr. Slate and I have had a running feud about moles and choriocarcinoma for the last year or two. Not that WP are completely opposed to ont· anothrr. I suppose that ha\·ing a ~crirs of , asc·s sornrhO\\' makt"s you somr sort l!f an authorit\' I am not surr this is tnw. In ow· practi<"' in Pasadena in thc· last 15 months \\ ,. have· had occasion to care for 7 patients who havc· had either mole or malignant changes- -trophoblasti< changes. one of these ha\·ing lwcn a clwriocarcinoma. I would like to mPntion some clini,·al problems. On" of thr problf'rns of a clinician, I think, is basically the nt•t·d fnr an accuralt' mPthocl of nwasuring gonadotropins. \Vhat ahnut thr new precipitation tests:' \\'hat abnm tlw various tt·sts that wt· arc usin,g· tnda) as a nH·a..;un·
of gonadotropinS:' I feel that ''" baw been traditionalh' IJotnlCI to do hyst<·rotnmie.s on patit•nts with moles and I hav<· rlf'Vl'r hc'cn ablr to subscribc to this particular approach. I think this is a traditional attitudt' rath<"r than a practical attitude. For th<' last I fl yrars in any of thesr cascs that f ha1 ,. had anything to do with. lw thn at th<' White Mt·rnorial Hospital, at thf' County Hospital. or in my own practicr, I han' always Pmptied the uterus \'aginally and I still fe,·l that this i:.; pn•ferablr· to subjecting the patit·nt to a laparotomy. I know that thP argunlC'nt will he that you _gr·t a hrtter look at the inside of tlw utnu:.;; I am not sun• that this is actually true lwcattS<' I am not sun• that rn•n if you do a hystt·rotomy you look in tht· nooks and crannies, and I think that 11 ,. were talking about a microscopH· pinur<'. prefer dilatation and curettage tn hvstt'rectornv. DR. KIRK (Closing). My real ,·onn·m at the momrnt is, what do thrse n·lls look likr in th<' lymph node? Do they look like trapped cells that art" not ,going to havr any more actil'itv or do they look likr n·lls that arr artiv<'iy growing:' Is thr arra of Iwcrosis in a lymph nod<' a significant finding? ThPse, I think, arc prrtinPnt questions l)f'causp of the fact that vnu want some decision as to the basis of furthPr therapy. Should we give this patient Methotrexate or should we not?
Volume 92 Number 5
In looking at the senes of chorioadenoma destruens cases that have been reported, oddly Pnough there have been no reports of delayed activity, and the delayed feature of the tumor is always confined to choriocarcinoma. This, I think, is a question for us to answer in this case. I would find it somewhat difficult to do a
Persistence of abnormal trophoblast 671
dilatation and curettage on a uterus approximately 6 months pregnant, and I would think that it would be easier to do a hysterotomy, although I would certainly agree that whenever we can do a dilatation and curettage, this would be a safer and better approach.