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Metastasizing benign trophoblastic tumors
volume 84 number 11, part 1 December 1, 1962 American Journal of
Obstetrics and Gynecology
OBSTETRICS
Metastasizing benign trophoblastic tumors RAY A. THIELE, M.D. RUSSELL R.
DE
ALVAREZ, M.D.
Seattle, Washington
TROPHOBLASTIC tumors are widely recognized as possessing bizarre anQ. capricious behavioral patterns. 4 • 5 • 1, s, Is, 2s, a2 These attributes have been emphasized as the knowledge of hormonal assays, roentgenography, biopsy, and submicroscopic structural detail increases, and have often caused difficulty in delineating benign and malignant lesions. 5 • 7 • 8 • 24 • 25 • 32 In an attempt to clarify thinking in this field, Ewing, 9 in 1910, divided trophoblastic tumors into the three principal categories of hydatidiform mole, chorioadenoma destruens, and choriocarci-
noma, naming the latter two de novo. Hydatidiform mole was described as exhibiting typical gross anatomic characteristics, confined to the endometrial cavity, and microscopically showing avascular villi with little or no trophoblastic anaplasia. Chorioadenoma destruens included those tumors which were "composed of villi, syncytium, and Langhans' cells without marked metaplasia," and which "were long confined to the uterine cavity or wall, but in many instances extensions have occurred to the broad ligaments and pelvic veins." Ewing further stated: "It is true that chorioadenoma destruens produces metastases, but these are apt to be limited in extent and . . . may- undergo spontaneous regression." "It rarely, if ever, produces general metastases." The term "choriocarcinoma" was reserved for those trophoblastic tumors which showed marked trophoblastic anaplasia, lack of villi or structure, and which rapidly produced widespread metastases and an almost invariably fatal outcome. The fact that benign trophoblastic tumors
From the Department of Obstetrics and Gynecology, University of Washington School of Medicine and Affiliated Hospitals. Supported in part by Research Grant CLT-7102 from the National Institutes of Health, United States Public Health Service, and by a grant from the Pacific Northwest Obstetrical and Gynecological Society. Presented at the Thirteenth Annual Meeting of the Pacific Northwest Obstetrical and Gynecological Association, Seaside, Oregon, June 19-21, 1961.
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1396 Thiele and de Alvarez
are capable of giving rise to benign metastases was not new even in Ewing's day. In 1893 SchmorP 4 described his discovery of normal trophoblast in the lungs during uncomplicated pregnancy, and in 1905 he reported three cases of syncytial transport to the lungs in molar pregnancy. In 1897 Pick 28 described a case of hydatidiform mole with ' vaginal metastases proved at biopsy, and postulated the occurrence of other metastatic sites. Fleishman, in 1905, collected seven reports of patients who had trophobla~tic tumors with pulmonary metastases and who recovered from their disease, although the evidence of metastases was based solely on a history of cough and hemoptysis. 8 Schmauch, 32 in 1907, mentioned 13 cases of biopsy-proved vaginal metastases in patients with benign trophoblastic disease. Despite this early work, the concept that benign trophoblastic tumors are capable of giving rise to benign metastases has been slow to gain acceptance. As recently as 1947 Hertig and Sheldon 11 defined chorioadenoma destruens as "invasion of myometrium by malignant mole but without metastases." Park and Lees, 27 in their review article in 1950, made no distinction at all bet,veen chorioadenoma destruens and choriocarcinoma. Of the 23 cases of choriocarcinoma which they reported, probably 18 were chorioadenoma destruens. Yet in 1954, when Novak and Seah 25 • 26 reported the cases in the Albert Mathieu Chorionepithelioma Registry, 4 patients were listed as having chorioadenoma destruens with pulmonary metastases. According to their definition, chorioadenoma destruens included "those moles in which there is an inordinate degree of trophoblastic proliferation and/or undue penetration of the mole through the uterine wall." This definition really represents a n~statP.mt>nt or. at most. a close aooroxima~:;n of-~h~- ~re~e~tly acc~pted defidi~ion originally proposed by Ewing. Novak and Seah26 further state: "If normal trophoblastic tissue can be deported to the lungs, there certainly seems to be no reason why similar dissemination cannot occur with either chorioadenoma destruens or
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December 1, 1962 J. Obst. & Gynec.
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Fig. 1. The relation of chorionic gonadotropin titer to clinical events.
benign moles, and there is no longer any doubt as to this possibility." The concept that hydatidiform moles are capable of metastasizing is still not widely accepted; however. In 1959 Greene 10 stated that all benign moles exhibiting metastases should be included in the category of chorioadenoma destruens, and in 1961 Wilson and associates36 concurred in this viewpoint. In addition to those examples in which histologic differentiation of benign and malignant trophoblast is often extremely difficult, there are many reported instances of obviously benign uterine lesions which give nse to w1aespreaa metastases wmcn are m~tologically malignant. 5 • 7 • 18 • 25 • 32 The unique attribute of trophoblastic tumors is the ability to give rise to metastases that are biologically and histologically benign. 7 • 8 ' 17 ' 23 ' 29 ' 36 The lungs are the principal site of metastases, be they benign or malignant, due to the marked ability of trophoblast to invade vessel walls and enter the systemic circulation. 9 ' 34 In an attempt to summarize some items in the clinical course, the investigation of suspected chorioadenoma destruens, and some of the problems of diagnosis and treatment of the metastatic sites, 2 new cases of metastasizing benign trophoblastic tumors are presented. •
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Case reports
Case 1. Mrs. J. B. was a 25-year-old, white, married woman, gravida ii, para i, whose last normal menses occurred Feb. 19, 1955. In the third month of gestation she complained of intermittent, bright red vaginal bleeding of 2 rnonths~
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Metastasizing benign trophoblastic tumors 1397
duration. Examination showed the uterine fundus to extend 17 em. above the pubic symphysis. The remainder of the physical examination was normal. On pelvic examination, the vaginal walls and cervix were slightly cyanotic; the cervical os was closed. The palpable abdominal mass was found to be continuous with the cervix, was smooth in contour and rather boggy in consistency. The ovaries were not palpable. A marked anemia was present. The Aschheim-Zondek pregnancy test was positive (Fig. 1) in a 1 : 100 dilution of serum. On May 25, 1955, after multiple transfusions of whole blood, an abdominal hysterotomy was performed with removal of
1,200 grams of tissue grossly typical of hydatidiform mole. Both ovaries were enlarged with multiple cysts. Microscopy confirmed the gross diagnosis, the Langhans cells were not proliferative, and few syncytial cells were seen. On June 30, 1955, 5 weeks after the hysterotomy, the uterus was the size of a 6 weeks' gestation, and the polycystic ovaries were becoming smaller, although they were still twice normal size. The Aschheim-Zondek test was positive in a 1: 10 serum dilution. In the ensuing 4 months the patient's menstrual cycle was not re-established and the serum chorionic gonadotropin titers remained elevated in dilutions from 1 :80 to full strength serum. Curettage was performed on July 18, 1955, and was repeated on Sept. 14, 1955, but no molar tissue was obtained on either occasion. The pathology reports were "decidua, blood clot, and smooth muscle" and "myometrium only-no endometrium seen." The patient was first seen by the senior author on Oct. 12, 1955, some 4Y2 months after the hysterotomy. The general physical examination was normal except that a few discrete 1 em. firm inguinal nodes were palpated in each groin. On pelvic examination the uterine fundus was enlarged to the size of a 6 weeks' gestation with siight irreguiarity over the anterior surface. The right ovary was 4 by 6 em. in diameter, discrete, and cystic in consistency; the left ovary '\vas nor-
Fig. 2A. Case 1. Photograph of gross surgical specimen.
Fig. 2B. Case 1. Photomicrograph of section from tumor nodule in wall of uterine fundus. (x72; reduced Y3.)
mal. A chest film on this date showed no significant abnormality. Papanicolaou smears of the
1398 Thiele and de Alvarez
cervix and vaginal pool were interpreted as being Class II. The Friedman test on a 24 hour urine specimen was positive in a 1 ; 10 dilution, representing a chorionic gonadotropin titer of 6,200 rat units. Subsequent Friedman determinations remained positive in 1: 10 to 1 : 30 dilutions of serum despite gradual return of the right ovary to normal size. In view of the duration of the persistent gonadotropin elevation, the absence of trophoblast on repeated curettage, the enlarged uterine fundus, and, thus a tentative diagnosis of chorioadenoma destruens or choriocarcinoma, laparotomy was performed on Dec. 30, 1955. The uterus was the size of an 8 weeks' gestation and was congested, with a 3 by 4 by 2 em. smooth protrusion of the left anterior uterine surface. With a tentative diagnosis of choriocarcinoma, total hysterectomy and bilateral salpingo-oophorectomy were performed. When the surgical specimen was openC'd, a 2.5 by 1 em. raised white nodulP contammg a hemorrhagic center was found within the myometrium under the anterior wall protrusion (Fig. 2. 4). . Microscopic examination of this nodule revealed chorioadenoma destruens, in which diagnosis the Albert Mathieu Chorionepithelioma Registry concurred (Fig. 2B). In the ensuing 2 months multiple Friedman tests were obtained; each was positive when undiluted serum was used. A repeat chest roentgenogram obtained on Feb. 24, 1956, showed a 1.5 em. nodular density in the left costophrenic angle. This was not present on previous films and was thought to represent metastatic trophoblast. One month later the pulmonary lesion was unchanged. However, on physical examination a 2.5 em. round firm nodule was noted in the subcutaneous tissue underlying the lower pole of the abdominal scar. At the same time pelvic examination demonstrated a 1 em. nodule palpable in the right vaginal fornix. No therapy was instituted at this time. These nodules gradually regressed during the following 2 months. On June 12, 1956, at the end of the fifth postoperative month, no abnormalities could be detected on physical examination. The Friedman test had reverted to negative at this time, but a 6 mm. nodular density persisted in the left costophrenic angle on x-ray examination. In mid-September of 1956; 8 months after the hysterectomy, chest film showed complete resolution of the nodule. Subsequent physical examinations, radiologic and laboratory studies, up to the present time, all have failed to demonstrate residual trophoblastic
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December I, 1962 Obst, & Gynec.
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Fig. 3. The relation of chorionic gonadotropin titer to clinical events. activity, and the patient has remained in good health to the time of this writing. Case 2. Mrs. P. G. was an 18-year-old, white, married woman, gravida ii, para 0, whose last normal menses occurred May 25, 1960. This pregnancy was complicated by hyperemesis and by a brown serous vaginal discharge which started early in the second month. In the third month of gestation the boggy uterus was the size of a 5 months' pregnancy. X-ray films of the pelvis failed to demonstrate fetal parts. On Aug. 23, 1960, the patient had increased vaginal bleeding of bright red blood and cramping lower abdominal pain. Shortly thereafter a large amount of tissue typical of hydatidiform mole was spontaneously expelled. The following morning a uterine curettage was performed with recovery of similar tissue. Microscopic examination confirmed the gross impression of benign hydatidiform mole. During the ensuing 2 months, the uterus and ovaries ren1ained somewhat enlarged, and the Aschheim-Zondek pregnancy test remained positive at 1:1,000 dilution of serum (Fig. 3). Vaginal spotting of brown serous fluid continued intermittently. Because of these findings, a second curettage was performed on Oct. 25, 1960. Tissue obtained was typical of benign hydatidiform mole. Following this procedure the ovaries returned to normal size but the uterus remained the size of a 3 months' gestation. The AschheimZondek test was positive at 1: 1,000 serum dilution. A chest film was normal. With a preoperative diagnosis of chorioadenoma destruens, the patient was scheduled for laparotomy. On the day prior to the scheduled surgery, Nov. 28, 1960, the patient collapsed. She was hospitalized in shock and showed signs and symptoms of an acute abdominal crisis. Laparotomy was performed as an emergency. A large tumor
Volume 84 Number 11 , Part I
mass was found in the right broad ligament invading the ovarian vessels. A briskly bleeding 1 em. perforation of the uterosacral ligament was apparent. Subtotal hysterectomy, right salpingooophorectomy, and resection of the broad ligament mass were accomplished. The surgical specimen revealed chorioadenoma destruens in the uterus, myometrium, and right broad ligament (Figs. 4A and 4B) . Tumor cell invasion of the ovarian vessels was apparent. On the tenth postoperative day the patient noted the onset of
Metastasizing benign trophoblastic tumors 1399
dyspnea and mild chest pain. A chest film showed diffuse pulmonary infiltrates compatible with widespread metastatic disease. A second film one week later showed questionable slight clearing of these lesions, but no symptomatic improvement was evident. On Dec. 20, 1960, the patient developed hemoptysis, pleuritic chest pain, and increasing dyspnea. A repeat chest film showed progression of the metastatic process. The patient was then first seen at the King County Hospital on Dec. 27, 1960, 4 months
Fig. 4A. Case 2. Photomicrograph of surgical specimen. Section of right parametrial mass from region of ovarian hilum. (x54; reduced jt3.)
Fig. 48. Case 2. Section of small ovarian vein coursing through right parametrial mass. (X84; reduced l-'3.)
1400 Thiele and de Alvarez
after passage of the mole and one month following the hysterectomy. Examination on admission revealed a thin, pale, somewhat cachectic white female with a frequent productive cough. The vital signs included a temperature of 99° F. orally, respirations of 22 per minute, pulse of 80 per minute, and blood pressure of 108j60 mm. Hg. No physical abnormalities of the head, neck,
Fig. 5A. Case 2. Chest x-ray taken Jan. 13, 1961.
Am.
heart, or extremities were found. A distinct pleural friction rub was audible over the lung bases posteriorly, in the absence of percussion findings. No rales were audible. No abdominal organs or masses were palpable. On pelvic examination the cervix was slightly congested with a closed nulliparous external os. The fundus and right ovary were absent, but a firm 2 by 3 em. slightly movable mass was palpable in the right adnexal area adjacent to the cervix. The left ovary was normal in size and consistency. A I em. firm nodule was palpable within the vaginal mucosa of the anterior fornix. A Friedman test (blood) was positive in a 1: 100 dilution of the serum. The chest film taken when the patient was admitted showed numerous small densities in each lung field, resembling bronchopneumonia (Fig. 5A). While in the hospital the patient had a chronic cough productive of brown-red sputum, associated with a pleuritic pain in the right side of the chest. Two weeks after admittance definite radiologic evidence of progression of the pulmonary infiltrates was apparent. Meanwhile, on Jan. 9, 1961, the vaginal nodule was excised, and the specimen was reported as chorioadenoma destruens on the basis of a large "ghost" villus found in an area of syntrophoblast. Serum chorionic gonadotropin determinations remained positive in dilutions of 1 :50 to 1 : 100. Because of the multiple foci of chorionic tissue and progression of the pulmonary lesions, therapy with amethopterin was started Jan. 13, 1961. Ten • milligrams of the drug were given orally twice daily for 4 days. At the completion of this first course of therapy the chest x-ray showed faint clearing. The serum chorionic gonadotropin determination remained positive in a dilution of 1 : 200. A second course of amethopterin was started on Jan. 31, 1961, in the same dosage for 4 days. The pulmonary nodules continued to regress, and after 160 mg. of amethopt<'rin in the
Fig. 5B. Case 2. Chest x-ray taken March 27, 1961.
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separate courses of therapy, the serurn
and urine Friedman assays of chorionic gonadotropin were negative. However, the more sensitive assay of chorionic gonadotropin with the use of immature female rat uterine and ovarian weight showed a residuai titer of one International unit per cubic centimeter of serum. Then'fore a third course of amethopterin was started on Feb. 25, 1961, following which the chest film showed virtually complete clearing (Fig. 5B) with the serum chorionic gonadotropin titer positive at 0.125 International unit per cubic centi-
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Metastasizing benign trophoblastic tumors 1401
meter. Pelvic examination disclosed minimal right parametrial thickening without evidence of nodularity, and the vaginal biopsy site was healed. On March 27, 1961, physical examination findings were normal except for minimal right parametrial scarring. The chorionic gonadotropin titer was positive at 2 International units per cubic centimeter. A fourth course of amethopterin was started April 17 because of the persistent slight elevation in chorionic gonadotropin titer. The patient remained asymptomatic except for an infrequent cough productive of yellow mucoid material and an associated slight pleuritic chest pain. The chorionic gonadotropin titer was negative on June 1, 1961, and has remained so. A chest film taken July 24, 1961, showed minimal scarring at the metastatic sites. At that time the patient's cough had cleared and she had returned to her pregravid weight. She has remained in good heaith to this writing.
tastases in patients with benign trophoblastic ttL'llors. Prior to 1950 only a fe\'l scattered case reports may be found in the literature, and large series of benign tumors fail to mention metastases.11• 28 • 31 • 33 Most reports even during the past 10 years still draw the majority of their cases from older hospital records, with quite low incidences of metastatic disease21 • 35 (Tables I and II). Even so, there seems to be a very definite trend toward reporting higher percentages of patients showing metastases as diagnostic techniques improve. That the percentage of chorioadenoma destruens exhibiting metastases exceeds that of hydatidiform moles probably reflects the higher degree of trophoblastic proliferation, anaplasia, and vessel invasion in the former. The treatment employed in patients with
benign trophoblastic tumors (benign moles and chorioadenoma destruens) and metastases has varied widely in the past. This probably reflects the fact that no one person nor any single clinic sees the disease with great enough frequency to become proficient in all aspects of management. Spontaneous resolution of the metastases in both conditions has
Comment
The many variations in definition expressed earlier, plus the relatively recent emphasis on x-ray and chorionic gonadotropin determinations, contribute to the difficulty in ascertaining the frequency of me-
Table I. Incidence of metastases in hydatidiform mole No. of patients Year
Author
Total
1947 1953 1954 1955
Hertig and Sheldonll Hunt et al.16 Novak and Seah26 Alter and Cosgrove3 Deifs 7 Shelpert35 Logan and Motyloff21 Acosta-Sison 1 Reiner and Doughertyao
195 38 120 90
i95i 1958 1958 1959 1960
I With
metastases
0 0 6 0
81
1
64 65 155 62
0 1 1 1
Percentage
0 0
5.0 0 0.8 0
1.5 0.7 1.6
Table II. Incidence of metastases in chorioadenoma destruens No. of patients
Year
Author
Total
IWithmetastases pulmonary
1947 1954 1959 1960 1961
Hertig and Sheldon 11 Novak and Seah25 Greenelo Acosta-Sison 2 Wilson et aJ.36
32 36 42 41 20
0 4 6 5 8
With other metastases
0 1
5 5 1
Percentage
0 13.8 26.2 24.3 45.0
D(•C('Uibt•J' 1. lYt>:.! \m. J, ()IJ;t. & Gyn<'C.
1402 Thiele and de Alvarez
Table III. Treatment and results in reported cases of hydatidiform mole with metastases Treatment
i I
Author
Sites of metastases
I
Of
l
I 0/ hydatidiform mole I metastases
Results
Savagc31
Lung
Curettage
None
2 year follov:~up, no recurrence
Bardawil et aJ.4
Lung
Curettage, hysterectomy, None bilateral salpingooophorectomy
3 year follow-ufJ, no recurrence
Logan and Motyloff21
Lung
Curettage, hysterectomy, None bilateral salpingooophorectomy
3 year follow-up,
Curettage, hysterotomy
3 ~ year follow-up,
Jacobson and Enzer 17
Lung
Resection
no recurrence
no recurrence Novak and Seah25 (CR 31)*
Lung
Novak and Seah25 (CR 65)*
Lung
Curettage, hysterectomy Radiation
8 year follow-up, no recurrence
Curettage
None
8 year follow-up, no recurrence
Novak and Seah25 (CR 154)
Lung, vagina, Curettage, hysterectomy, None and femur trachelectomy
4 year follow-up, no recurrence
Greene 10 (CR 372)
Vagina
2 year follow-up,
Hysterectomy
Excision
no recurrence Acosta-Sison~
Lung
Hysterectomy
Radiation
Unknown
Acosta-Sison2
Lung
Hysterectomy
Radiation
Unknown
Shultz 4 t
Lung
Hysterectomy
None
14 month followup, no recurrence
Hou Pau Chiang4t
Lungs
Hysterectomy
None
Hertz et al.H
Lungs
Curettage
Amethopterin 16 month followup, marginal eievation of chorionic gonadotropin titer
Hreshchyshyn et aJ.15
Lungs
Curettage
Amethopterin 19 month followup, no recurrence
Vagina
Curettage
~Jone
Dinh-De and
~vfinh 8
Died 1 year later, no evidence of recurrence at autopsy
20 month follow·up, no recurrence
*May be chorioadenoma destruens. tQuoted in Bardawil's article.
occurred following treatment of the pelvic lesion alone by curettage, hysterectomy, hysterectomy and roentgen therapy, and biopsy and local excision with roentgen therapy.
The metastatic lesions themselves have been successfully treated by radiation, surgical resection, and chemotherapeutic agents (Tables III and IV).
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Metastasizing benign trophoblastic tumors
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Table IV. Treatment and results in reported cases of chorioadenoma destruens with metastases
Author
Sites of metastases
Treatment Of pelvic lesion
Of metastases
Results
Schultze33
Lung
Curettage, hysterectomy with Radiation bilateral sal pingo-oophorecto my
5 year follow-up, no recurrence
Hunt et al_i6
Lung
Curettage, hysterectomy, x-ray Radiation
25 month followup, no recurrence
Hunt et aJ,l6
Lung and vagina
Curettage, biopsy, x-ray
Radiation
25 month followup, no recurrence
Nolan et aJ.23
Lungs
Hysterectomy, bilateral salpingo-oophorectomy
Radiation
2 year follow-up, no recurrence
De!fs 7
Lung, extradural space
Curettage, hysterectomy, Resection bilateral salpingo-oophorectomy
Died in 3 Y2 years of metastases
Logan and Motyloff21
Lung
Curettage
None
4 year follow-up, no recurrence
Logan and Motyloff21
Lung
Hysterectomy, bilateral salpingo-oophorectomy
Radiation
12 year follow-up, no recurrence
Greene 10 (CR 263)
Lung
Curettage, ? hysterectomy
None
3 year follow-up, no recurrence
Greene 10 (CR 410)
Lung
Hysterectomy
?
Died 11 months postoperatively
Greene 10 (CR 70)
Lung, vulva, and vagina
Curettage, local excision, x-ray
Radiation
9 year follow-up, no recurrence
Greene 10 (CR 80)
Vagina
Hysterectomy
Excision
5 year follow-up, no recurrence
Greene 10 (CR 180)
Vagina
Hysterectomy, bilateral salpingo-oophorectomy
Radiation
6Y2 year follow-up, no recurrence
Greene 10 (CR 450)
Vagina
Hysterectomy
Excision
6 month follow-up. no recurrence
Acosta-Sison2
Vagina and labia
Local excision, x-ray
Radiation
Unknown
Acosta-Sison2
Lung and para- Local excision metrium
None
Died during surgery
Acosta-Sison 2
Vaginal
Resection Radiation
4 year follow-up, no recurrence
Acosta-Sison2
? Hysterectomy, excision of Radiation Lungs and parametrium parametrial masses
Unknown
Wilson et ai,S6
Lung
Curettage, hysterectomy
None
13 year follow-up, no recurrence
Wilson et al,s6
Lung
Curettage, hysterectomy, None bilateral salpingo-oophorectomy
9 year follow-up, no recurrence
Wilson et al,36
Lung and vagina
Hysterectomy
None
4 year follow-up, no recurrence
Subtotal hysterectomy
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December 1, !962 Am. J, Obst. & Gyncc.
Thiele and de Alvarez
Table IV-Cont'd
Author
Wilson et al. 36
Sites of metastases
Treatment Of pelvic lesion
Of metastases
Results
Curettage, hysterectomy, Radiation bilateral salpingo-oophorectomy, x-ray
14 year follow-up,
Lung and vagina
Curettage, hysterectomy, x-ray Radiation
11 year follow-up,
Wilson et aJ.3 6
Lung
Curettage, hysterectomy, xray, radium
Radiation
5 year follow-up, no recurrence
Wilson et a1. 36
Lung and vagina
Curettage, local excision, xray
Radiation
11 year follow-up,
Lung
Hysterectomy, right salpingo- Resection oophorectomy
Lungs
Wilson et al. 36
Reed et al.29 Hertz et aJ. 12, 13
Lung
no recurrence
no recurrence
Hysterectomy, ? bilateral salpingo-oophorectomy
no recurrence
3 Y2 year follow-up, no recurrence
Amethopterin 29 month followup, no recurrence
13
Lung
Hysterectomy, ? bilateral salpingo-oophorectomy
Amethopterin 7 month follow-up, marginal elevation of chorionic gonadotropin titer
Li et al. 19
Lungs
Hysterectomy, ? bilateral salpingo-oophorectomy
Amethopterin 2
Li et aJ.19
Lung
Hysterectomy, bilateral saipingo-oophorectomy
Amethopterin 23 month followup, no recurrence
Li et al.20
Lung
I-Iysterecton1y, bilateral
Arnethopterin
Hertz et
1
al. ~•
salpingo-oophorectomy
month followup, no recurrence
month foliowup, marginal elevation of chorionic gonadotropin titer
Amethopterin 2 year follow-up, no recurrence
Manahan et aJ.2 2
Vagina
Biopsy of vaginal lesion
Manahan et aJ.2"
Parametrium
Hysterectomy, biopsy of pelvic Amethopterin 2 year follow-up, mass no recurrence
Manahan et al.2 2
Lungs
Thiele and de Alvarez Lung and vagina
Hysterectomy Hysterotomy, curettage, hysterectomy, bilateral salpingo-oophorectomy
Amethopterin 2 year follow-up, no recurrence None
6 year follow-up, no recurrence
Thiele and de Alvarez Lungs, paraCurettage, hysterectomy, right Amethopterin 13 month followsalpingo-oophorectomy up, no recurmetrium, and vagina renee
Successful treatment of patients with benign trophoblastic lesions and metastases must be varied since no one method of approach is ideal for all patients, but from the
cases reported the following broad principles of management emerge: 1. The initial evaluation of patients with trophoblastic disease should include painstak-
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Metastasizing benign trophoblastic tumors 1405
ingly detailed history and physical examination, careful pelvic examination with attention to uterine contour and ovarian size, chest x-ray, and chorionic gonadotropin titer. 2. Evacuation of the uterus should be carried out promptly in all patients as soon as the diagnosis is established. If the uterus is less than the size of a 10 to 12 weeks' gestation, prim~,.,! curettage should be atte:r.npted. If the uterus is larger than the size of a 3 months' pregnancy, oxytocin stimulation should be initiated. This may result in partial uterine emptying, thus increasing the ease and safety of evacuation. In many instances, partial evacuation of the uterus may be accomplished with ovum forceps, followed by immediate and definitive curettage. In rare cases, especially if oxytocin stimulation fails and the uterus is large, hysterotomy may prove the most expeditious procedure. 3. Postoperatively, all patients with hydatidiform mole or chorioadenoma destru.ens should be followed closely with chorionic gonadotropin assays. Even though Delfs7 recommends further study if any titer exceeds 20,000 International units per liter after 30 days, we feel that, if the titer persists, in any amount, longer than 6 weeks following evacuation, residual trophoblast should be considered present in the pelvis or lungs, and further investigation is required. 6 4. If metasta.tic foci of trophoblast are found in the presence of a deciining chorionic gonadotropin titer, continued close observation is probably justified. 5. If the chorionic gonadotropin level persists or its concentration rises, with or without metastatic lesions, total hysterectomy should be performed to eliminate the possibility of chorioadenoma destruens or choriocarcinoma. REFERENCES
1. Acosta-Sison, H.: AM.
J.
OnsT. & GvNEC.
78: 876, 1959. 2. Acosta-Sison, H.: AM. J. OnsT. & GvNEC. 80: 176, 1960. 3. Alter, N. M., and Cosgrove, S. A.: Obst. & Gynec. 5: 755, 1955. 4. Bardawil, W. A., Hertig, A. T., and Velardo, J. T.: Obst. & Gynec. 10: 614, 1957.
6. Chorioadenoma destruens may invade the uterine fundus locally, spread locally into contiguous and neighboring pelvic viscera, or metastasize remotely to any viscus of the body. The sites of predilection of metastases are the lungs or other organs along the inferior vena cava system. 7. Surgery for pulmonary metastases is probably not indicated. The effect of radiotherapy on pulmonary lesions is dubious. If metastatic tumor persists or progresses after hysterectomy, amethopterin appears to offer a satisfactory therapeutic approach to cure or palliation. If drug resistance occurs, vincaleukoblastine may be used. 14 8. All patients with trophoblastic tumors should be followed for a minimum period of 5 years with physical examinations, chest films, and chorionic gonadotropin titers. Appropriate chemotherapy should be instituted in inoperable cases. Summary
Two patients with chorioadenoma destruens and pulmonary and local metastases successfully treated by removal of the pelvic organs in one instance and by removal of the pelvic organs and the use of amethopterin in the other are reported. A review of the reported cases of hydatidiform moles and chorioadenoma destruens with metastases is presented. Principles of management are suggested.
We wish to acknowledge with appreciation the kindness of Dr. R. H. Welding, Ellensburg, Washington, for providing a detailed sequence of preoperative data and of posttherapy follow-up of the patient in Case 2.
5. Bardawii, W. A., and Toy, B. L.: Ann. New York Acad. Sc. 80: 197, 1959. 6. de Alvarez, R. R.: AM. J. OnsT. & GvNEC. 43: 59, 1942. 7. Delfs, E.: Obst. & Gynec. 9: 1, 1957. 8. Dinh-De, T., and Minh, H. N.: AM. J. OnsT. & GYNEC. 82: 660, 1961. 9. Ewing, J.: Surg. Gynec. & Obst. 10: 366, 1910.
1406 Thiele and de Alvarez
10. Greene, R. R.: Ann. New York Acad. Sc. 80: 143, 1959. 11. Hertig, A. T., and Sheldon, W. H.: AM. J. 0BST. & GYNEC. 53: 1, 1947. 12. Hertz, R., Bergenstal, D. M., Lipsett, M. B., Price, E. B., and Hilbish, T. F.: i\nn. Ne"v York Acad. Sc. 80: 262, 1959. 13. Hertz, R., Bergenstal, D. M .. Lipsett, M. B., Price, E. B., and Hilbish, T. F.: J. A. M. A. 168: 845, 1958. 14. Hertz, R., Lewis, J., Jr., and Lipsett, M. B.: AM. J. 0BST. & GYNEC. 82: 631, 1961. 15. Hreshchyshyn, M. M., Graham, J. B., and Holland, ]. F.: AM. ]. 0BST. & GYNEC. 81: 688, 1961. 16. Hunt, W., Dockerty, M. B., and Randall, L. M.: Obst. & Gynec. 1: 593, 1953. 17. Jacobson, F. ]., and Enzer, N.: AM. J. 0BST. & GYNEC. 78: 868, 1959. 18. Kistner, R. W.: AM. J. 0BsT. & GYNEC. 63: 888, 1952. 19. Li, M. C., Hertz, R., and Bergenstal, D. M.: New England J. Med. 259: 66, 1958. 20. Li, M. C., Hertz, R., and Spencer, D. B.: Proc. Soc. Exper. Bioi. & Med. 93: 361, 1956. 21. Logan, B.]., and Motyloff, L.: AM. J. 0BST. & GYNEC. 75: 1134, 1958. 22. Manahan, C. P., Benitez, 1., and Estrella, F.: AM. J. 0BST. & GYNEC. 82: 641, 1961.
Am.
Dt'c\_ tnbt'' 1. l9tl~ Oh>t. & c;ym:c.
J.
2::1. Nolan, J. F., Cook, E. M., Jr., and Dallke, W. E.: West. J. Surg. 63: 101, 1955. 2+. Novak. E.: AM. J. 0BsT. & GYNEC. 59: 1355, 1950. 25. Novak, E., and Seah, C. S.: AM. J. 0BST. & C!v""''' 1Q~4. . ._.. ............... ~7 ...,. ..• Q\l·
Obstetrics and Gynecology
OBSTETRICS
Metastasizing benign trophoblastic tumors RAY A. THIELE, M.D. RUSSELL R.
DE
ALVAREZ, M.D.
Seattle, Washington
TROPHOBLASTIC tumors are widely recognized as possessing bizarre anQ. capricious behavioral patterns. 4 • 5 • 1, s, Is, 2s, a2 These attributes have been emphasized as the knowledge of hormonal assays, roentgenography, biopsy, and submicroscopic structural detail increases, and have often caused difficulty in delineating benign and malignant lesions. 5 • 7 • 8 • 24 • 25 • 32 In an attempt to clarify thinking in this field, Ewing, 9 in 1910, divided trophoblastic tumors into the three principal categories of hydatidiform mole, chorioadenoma destruens, and choriocarci-
noma, naming the latter two de novo. Hydatidiform mole was described as exhibiting typical gross anatomic characteristics, confined to the endometrial cavity, and microscopically showing avascular villi with little or no trophoblastic anaplasia. Chorioadenoma destruens included those tumors which were "composed of villi, syncytium, and Langhans' cells without marked metaplasia," and which "were long confined to the uterine cavity or wall, but in many instances extensions have occurred to the broad ligaments and pelvic veins." Ewing further stated: "It is true that chorioadenoma destruens produces metastases, but these are apt to be limited in extent and . . . may- undergo spontaneous regression." "It rarely, if ever, produces general metastases." The term "choriocarcinoma" was reserved for those trophoblastic tumors which showed marked trophoblastic anaplasia, lack of villi or structure, and which rapidly produced widespread metastases and an almost invariably fatal outcome. The fact that benign trophoblastic tumors
From the Department of Obstetrics and Gynecology, University of Washington School of Medicine and Affiliated Hospitals. Supported in part by Research Grant CLT-7102 from the National Institutes of Health, United States Public Health Service, and by a grant from the Pacific Northwest Obstetrical and Gynecological Society. Presented at the Thirteenth Annual Meeting of the Pacific Northwest Obstetrical and Gynecological Association, Seaside, Oregon, June 19-21, 1961.
1395
1396 Thiele and de Alvarez
are capable of giving rise to benign metastases was not new even in Ewing's day. In 1893 SchmorP 4 described his discovery of normal trophoblast in the lungs during uncomplicated pregnancy, and in 1905 he reported three cases of syncytial transport to the lungs in molar pregnancy. In 1897 Pick 28 described a case of hydatidiform mole with ' vaginal metastases proved at biopsy, and postulated the occurrence of other metastatic sites. Fleishman, in 1905, collected seven reports of patients who had trophobla~tic tumors with pulmonary metastases and who recovered from their disease, although the evidence of metastases was based solely on a history of cough and hemoptysis. 8 Schmauch, 32 in 1907, mentioned 13 cases of biopsy-proved vaginal metastases in patients with benign trophoblastic disease. Despite this early work, the concept that benign trophoblastic tumors are capable of giving rise to benign metastases has been slow to gain acceptance. As recently as 1947 Hertig and Sheldon 11 defined chorioadenoma destruens as "invasion of myometrium by malignant mole but without metastases." Park and Lees, 27 in their review article in 1950, made no distinction at all bet,veen chorioadenoma destruens and choriocarcinoma. Of the 23 cases of choriocarcinoma which they reported, probably 18 were chorioadenoma destruens. Yet in 1954, when Novak and Seah 25 • 26 reported the cases in the Albert Mathieu Chorionepithelioma Registry, 4 patients were listed as having chorioadenoma destruens with pulmonary metastases. According to their definition, chorioadenoma destruens included "those moles in which there is an inordinate degree of trophoblastic proliferation and/or undue penetration of the mole through the uterine wall." This definition really represents a n~statP.mt>nt or. at most. a close aooroxima~:;n of-~h~- ~re~e~tly acc~pted defidi~ion originally proposed by Ewing. Novak and Seah26 further state: "If normal trophoblastic tissue can be deported to the lungs, there certainly seems to be no reason why similar dissemination cannot occur with either chorioadenoma destruens or
Am.
December 1, 1962 J. Obst. & Gynec.
f
,.~
~
l
1
'
~
c
~
c ~
Fig. 1. The relation of chorionic gonadotropin titer to clinical events.
benign moles, and there is no longer any doubt as to this possibility." The concept that hydatidiform moles are capable of metastasizing is still not widely accepted; however. In 1959 Greene 10 stated that all benign moles exhibiting metastases should be included in the category of chorioadenoma destruens, and in 1961 Wilson and associates36 concurred in this viewpoint. In addition to those examples in which histologic differentiation of benign and malignant trophoblast is often extremely difficult, there are many reported instances of obviously benign uterine lesions which give nse to w1aespreaa metastases wmcn are m~tologically malignant. 5 • 7 • 18 • 25 • 32 The unique attribute of trophoblastic tumors is the ability to give rise to metastases that are biologically and histologically benign. 7 • 8 ' 17 ' 23 ' 29 ' 36 The lungs are the principal site of metastases, be they benign or malignant, due to the marked ability of trophoblast to invade vessel walls and enter the systemic circulation. 9 ' 34 In an attempt to summarize some items in the clinical course, the investigation of suspected chorioadenoma destruens, and some of the problems of diagnosis and treatment of the metastatic sites, 2 new cases of metastasizing benign trophoblastic tumors are presented. •
~
1
'I
.
•
1
• - 1
--
1
.. _.,
Case reports
Case 1. Mrs. J. B. was a 25-year-old, white, married woman, gravida ii, para i, whose last normal menses occurred Feb. 19, 1955. In the third month of gestation she complained of intermittent, bright red vaginal bleeding of 2 rnonths~
Volume 84 Number 11, Part 1
Metastasizing benign trophoblastic tumors 1397
duration. Examination showed the uterine fundus to extend 17 em. above the pubic symphysis. The remainder of the physical examination was normal. On pelvic examination, the vaginal walls and cervix were slightly cyanotic; the cervical os was closed. The palpable abdominal mass was found to be continuous with the cervix, was smooth in contour and rather boggy in consistency. The ovaries were not palpable. A marked anemia was present. The Aschheim-Zondek pregnancy test was positive (Fig. 1) in a 1 : 100 dilution of serum. On May 25, 1955, after multiple transfusions of whole blood, an abdominal hysterotomy was performed with removal of
1,200 grams of tissue grossly typical of hydatidiform mole. Both ovaries were enlarged with multiple cysts. Microscopy confirmed the gross diagnosis, the Langhans cells were not proliferative, and few syncytial cells were seen. On June 30, 1955, 5 weeks after the hysterotomy, the uterus was the size of a 6 weeks' gestation, and the polycystic ovaries were becoming smaller, although they were still twice normal size. The Aschheim-Zondek test was positive in a 1: 10 serum dilution. In the ensuing 4 months the patient's menstrual cycle was not re-established and the serum chorionic gonadotropin titers remained elevated in dilutions from 1 :80 to full strength serum. Curettage was performed on July 18, 1955, and was repeated on Sept. 14, 1955, but no molar tissue was obtained on either occasion. The pathology reports were "decidua, blood clot, and smooth muscle" and "myometrium only-no endometrium seen." The patient was first seen by the senior author on Oct. 12, 1955, some 4Y2 months after the hysterotomy. The general physical examination was normal except that a few discrete 1 em. firm inguinal nodes were palpated in each groin. On pelvic examination the uterine fundus was enlarged to the size of a 6 weeks' gestation with siight irreguiarity over the anterior surface. The right ovary was 4 by 6 em. in diameter, discrete, and cystic in consistency; the left ovary '\vas nor-
Fig. 2A. Case 1. Photograph of gross surgical specimen.
Fig. 2B. Case 1. Photomicrograph of section from tumor nodule in wall of uterine fundus. (x72; reduced Y3.)
mal. A chest film on this date showed no significant abnormality. Papanicolaou smears of the
1398 Thiele and de Alvarez
cervix and vaginal pool were interpreted as being Class II. The Friedman test on a 24 hour urine specimen was positive in a 1 ; 10 dilution, representing a chorionic gonadotropin titer of 6,200 rat units. Subsequent Friedman determinations remained positive in 1: 10 to 1 : 30 dilutions of serum despite gradual return of the right ovary to normal size. In view of the duration of the persistent gonadotropin elevation, the absence of trophoblast on repeated curettage, the enlarged uterine fundus, and, thus a tentative diagnosis of chorioadenoma destruens or choriocarcinoma, laparotomy was performed on Dec. 30, 1955. The uterus was the size of an 8 weeks' gestation and was congested, with a 3 by 4 by 2 em. smooth protrusion of the left anterior uterine surface. With a tentative diagnosis of choriocarcinoma, total hysterectomy and bilateral salpingo-oophorectomy were performed. When the surgical specimen was openC'd, a 2.5 by 1 em. raised white nodulP contammg a hemorrhagic center was found within the myometrium under the anterior wall protrusion (Fig. 2. 4). . Microscopic examination of this nodule revealed chorioadenoma destruens, in which diagnosis the Albert Mathieu Chorionepithelioma Registry concurred (Fig. 2B). In the ensuing 2 months multiple Friedman tests were obtained; each was positive when undiluted serum was used. A repeat chest roentgenogram obtained on Feb. 24, 1956, showed a 1.5 em. nodular density in the left costophrenic angle. This was not present on previous films and was thought to represent metastatic trophoblast. One month later the pulmonary lesion was unchanged. However, on physical examination a 2.5 em. round firm nodule was noted in the subcutaneous tissue underlying the lower pole of the abdominal scar. At the same time pelvic examination demonstrated a 1 em. nodule palpable in the right vaginal fornix. No therapy was instituted at this time. These nodules gradually regressed during the following 2 months. On June 12, 1956, at the end of the fifth postoperative month, no abnormalities could be detected on physical examination. The Friedman test had reverted to negative at this time, but a 6 mm. nodular density persisted in the left costophrenic angle on x-ray examination. In mid-September of 1956; 8 months after the hysterectomy, chest film showed complete resolution of the nodule. Subsequent physical examinations, radiologic and laboratory studies, up to the present time, all have failed to demonstrate residual trophoblastic
Am.
December I, 1962 Obst, & Gynec.
J.
Fig. 3. The relation of chorionic gonadotropin titer to clinical events. activity, and the patient has remained in good health to the time of this writing. Case 2. Mrs. P. G. was an 18-year-old, white, married woman, gravida ii, para 0, whose last normal menses occurred May 25, 1960. This pregnancy was complicated by hyperemesis and by a brown serous vaginal discharge which started early in the second month. In the third month of gestation the boggy uterus was the size of a 5 months' pregnancy. X-ray films of the pelvis failed to demonstrate fetal parts. On Aug. 23, 1960, the patient had increased vaginal bleeding of bright red blood and cramping lower abdominal pain. Shortly thereafter a large amount of tissue typical of hydatidiform mole was spontaneously expelled. The following morning a uterine curettage was performed with recovery of similar tissue. Microscopic examination confirmed the gross impression of benign hydatidiform mole. During the ensuing 2 months, the uterus and ovaries ren1ained somewhat enlarged, and the Aschheim-Zondek pregnancy test remained positive at 1:1,000 dilution of serum (Fig. 3). Vaginal spotting of brown serous fluid continued intermittently. Because of these findings, a second curettage was performed on Oct. 25, 1960. Tissue obtained was typical of benign hydatidiform mole. Following this procedure the ovaries returned to normal size but the uterus remained the size of a 3 months' gestation. The AschheimZondek test was positive at 1: 1,000 serum dilution. A chest film was normal. With a preoperative diagnosis of chorioadenoma destruens, the patient was scheduled for laparotomy. On the day prior to the scheduled surgery, Nov. 28, 1960, the patient collapsed. She was hospitalized in shock and showed signs and symptoms of an acute abdominal crisis. Laparotomy was performed as an emergency. A large tumor
Volume 84 Number 11 , Part I
mass was found in the right broad ligament invading the ovarian vessels. A briskly bleeding 1 em. perforation of the uterosacral ligament was apparent. Subtotal hysterectomy, right salpingooophorectomy, and resection of the broad ligament mass were accomplished. The surgical specimen revealed chorioadenoma destruens in the uterus, myometrium, and right broad ligament (Figs. 4A and 4B) . Tumor cell invasion of the ovarian vessels was apparent. On the tenth postoperative day the patient noted the onset of
Metastasizing benign trophoblastic tumors 1399
dyspnea and mild chest pain. A chest film showed diffuse pulmonary infiltrates compatible with widespread metastatic disease. A second film one week later showed questionable slight clearing of these lesions, but no symptomatic improvement was evident. On Dec. 20, 1960, the patient developed hemoptysis, pleuritic chest pain, and increasing dyspnea. A repeat chest film showed progression of the metastatic process. The patient was then first seen at the King County Hospital on Dec. 27, 1960, 4 months
Fig. 4A. Case 2. Photomicrograph of surgical specimen. Section of right parametrial mass from region of ovarian hilum. (x54; reduced jt3.)
Fig. 48. Case 2. Section of small ovarian vein coursing through right parametrial mass. (X84; reduced l-'3.)
1400 Thiele and de Alvarez
after passage of the mole and one month following the hysterectomy. Examination on admission revealed a thin, pale, somewhat cachectic white female with a frequent productive cough. The vital signs included a temperature of 99° F. orally, respirations of 22 per minute, pulse of 80 per minute, and blood pressure of 108j60 mm. Hg. No physical abnormalities of the head, neck,
Fig. 5A. Case 2. Chest x-ray taken Jan. 13, 1961.
Am.
heart, or extremities were found. A distinct pleural friction rub was audible over the lung bases posteriorly, in the absence of percussion findings. No rales were audible. No abdominal organs or masses were palpable. On pelvic examination the cervix was slightly congested with a closed nulliparous external os. The fundus and right ovary were absent, but a firm 2 by 3 em. slightly movable mass was palpable in the right adnexal area adjacent to the cervix. The left ovary was normal in size and consistency. A I em. firm nodule was palpable within the vaginal mucosa of the anterior fornix. A Friedman test (blood) was positive in a 1: 100 dilution of the serum. The chest film taken when the patient was admitted showed numerous small densities in each lung field, resembling bronchopneumonia (Fig. 5A). While in the hospital the patient had a chronic cough productive of brown-red sputum, associated with a pleuritic pain in the right side of the chest. Two weeks after admittance definite radiologic evidence of progression of the pulmonary infiltrates was apparent. Meanwhile, on Jan. 9, 1961, the vaginal nodule was excised, and the specimen was reported as chorioadenoma destruens on the basis of a large "ghost" villus found in an area of syntrophoblast. Serum chorionic gonadotropin determinations remained positive in dilutions of 1 :50 to 1 : 100. Because of the multiple foci of chorionic tissue and progression of the pulmonary lesions, therapy with amethopterin was started Jan. 13, 1961. Ten • milligrams of the drug were given orally twice daily for 4 days. At the completion of this first course of therapy the chest x-ray showed faint clearing. The serum chorionic gonadotropin determination remained positive in a dilution of 1 : 200. A second course of amethopterin was started on Jan. 31, 1961, in the same dosage for 4 days. The pulmonary nodules continued to regress, and after 160 mg. of amethopt<'rin in the
Fig. 5B. Case 2. Chest x-ray taken March 27, 1961.
December 1. 1962 Obst. & Gyncc.
J.
tV\I'O
separate courses of therapy, the serurn
and urine Friedman assays of chorionic gonadotropin were negative. However, the more sensitive assay of chorionic gonadotropin with the use of immature female rat uterine and ovarian weight showed a residuai titer of one International unit per cubic centimeter of serum. Then'fore a third course of amethopterin was started on Feb. 25, 1961, following which the chest film showed virtually complete clearing (Fig. 5B) with the serum chorionic gonadotropin titer positive at 0.125 International unit per cubic centi-
Volume 84 Number 11, Part 1
Metastasizing benign trophoblastic tumors 1401
meter. Pelvic examination disclosed minimal right parametrial thickening without evidence of nodularity, and the vaginal biopsy site was healed. On March 27, 1961, physical examination findings were normal except for minimal right parametrial scarring. The chorionic gonadotropin titer was positive at 2 International units per cubic centimeter. A fourth course of amethopterin was started April 17 because of the persistent slight elevation in chorionic gonadotropin titer. The patient remained asymptomatic except for an infrequent cough productive of yellow mucoid material and an associated slight pleuritic chest pain. The chorionic gonadotropin titer was negative on June 1, 1961, and has remained so. A chest film taken July 24, 1961, showed minimal scarring at the metastatic sites. At that time the patient's cough had cleared and she had returned to her pregravid weight. She has remained in good heaith to this writing.
tastases in patients with benign trophoblastic ttL'llors. Prior to 1950 only a fe\'l scattered case reports may be found in the literature, and large series of benign tumors fail to mention metastases.11• 28 • 31 • 33 Most reports even during the past 10 years still draw the majority of their cases from older hospital records, with quite low incidences of metastatic disease21 • 35 (Tables I and II). Even so, there seems to be a very definite trend toward reporting higher percentages of patients showing metastases as diagnostic techniques improve. That the percentage of chorioadenoma destruens exhibiting metastases exceeds that of hydatidiform moles probably reflects the higher degree of trophoblastic proliferation, anaplasia, and vessel invasion in the former. The treatment employed in patients with
benign trophoblastic tumors (benign moles and chorioadenoma destruens) and metastases has varied widely in the past. This probably reflects the fact that no one person nor any single clinic sees the disease with great enough frequency to become proficient in all aspects of management. Spontaneous resolution of the metastases in both conditions has
Comment
The many variations in definition expressed earlier, plus the relatively recent emphasis on x-ray and chorionic gonadotropin determinations, contribute to the difficulty in ascertaining the frequency of me-
Table I. Incidence of metastases in hydatidiform mole No. of patients Year
Author
Total
1947 1953 1954 1955
Hertig and Sheldonll Hunt et al.16 Novak and Seah26 Alter and Cosgrove3 Deifs 7 Shelpert35 Logan and Motyloff21 Acosta-Sison 1 Reiner and Doughertyao
195 38 120 90
i95i 1958 1958 1959 1960
I With
metastases
0 0 6 0
81
1
64 65 155 62
0 1 1 1
Percentage
0 0
5.0 0 0.8 0
1.5 0.7 1.6
Table II. Incidence of metastases in chorioadenoma destruens No. of patients
Year
Author
Total
IWithmetastases pulmonary
1947 1954 1959 1960 1961
Hertig and Sheldon 11 Novak and Seah25 Greenelo Acosta-Sison 2 Wilson et aJ.36
32 36 42 41 20
0 4 6 5 8
With other metastases
0 1
5 5 1
Percentage
0 13.8 26.2 24.3 45.0
D(•C('Uibt•J' 1. lYt>:.! \m. J, ()IJ;t. & Gyn<'C.
1402 Thiele and de Alvarez
Table III. Treatment and results in reported cases of hydatidiform mole with metastases Treatment
i I
Author
Sites of metastases
I
Of
l
I 0/ hydatidiform mole I metastases
Results
Savagc31
Lung
Curettage
None
2 year follov:~up, no recurrence
Bardawil et aJ.4
Lung
Curettage, hysterectomy, None bilateral salpingooophorectomy
3 year follow-ufJ, no recurrence
Logan and Motyloff21
Lung
Curettage, hysterectomy, None bilateral salpingooophorectomy
3 year follow-up,
Curettage, hysterotomy
3 ~ year follow-up,
Jacobson and Enzer 17
Lung
Resection
no recurrence
no recurrence Novak and Seah25 (CR 31)*
Lung
Novak and Seah25 (CR 65)*
Lung
Curettage, hysterectomy Radiation
8 year follow-up, no recurrence
Curettage
None
8 year follow-up, no recurrence
Novak and Seah25 (CR 154)
Lung, vagina, Curettage, hysterectomy, None and femur trachelectomy
4 year follow-up, no recurrence
Greene 10 (CR 372)
Vagina
2 year follow-up,
Hysterectomy
Excision
no recurrence Acosta-Sison~
Lung
Hysterectomy
Radiation
Unknown
Acosta-Sison2
Lung
Hysterectomy
Radiation
Unknown
Shultz 4 t
Lung
Hysterectomy
None
14 month followup, no recurrence
Hou Pau Chiang4t
Lungs
Hysterectomy
None
Hertz et al.H
Lungs
Curettage
Amethopterin 16 month followup, marginal eievation of chorionic gonadotropin titer
Hreshchyshyn et aJ.15
Lungs
Curettage
Amethopterin 19 month followup, no recurrence
Vagina
Curettage
~Jone
Dinh-De and
~vfinh 8
Died 1 year later, no evidence of recurrence at autopsy
20 month follow·up, no recurrence
*May be chorioadenoma destruens. tQuoted in Bardawil's article.
occurred following treatment of the pelvic lesion alone by curettage, hysterectomy, hysterectomy and roentgen therapy, and biopsy and local excision with roentgen therapy.
The metastatic lesions themselves have been successfully treated by radiation, surgical resection, and chemotherapeutic agents (Tables III and IV).
Volume 84 Number 11, Part 1
Metastasizing benign trophoblastic tumors
1403
Table IV. Treatment and results in reported cases of chorioadenoma destruens with metastases
Author
Sites of metastases
Treatment Of pelvic lesion
Of metastases
Results
Schultze33
Lung
Curettage, hysterectomy with Radiation bilateral sal pingo-oophorecto my
5 year follow-up, no recurrence
Hunt et al_i6
Lung
Curettage, hysterectomy, x-ray Radiation
25 month followup, no recurrence
Hunt et aJ,l6
Lung and vagina
Curettage, biopsy, x-ray
Radiation
25 month followup, no recurrence
Nolan et aJ.23
Lungs
Hysterectomy, bilateral salpingo-oophorectomy
Radiation
2 year follow-up, no recurrence
De!fs 7
Lung, extradural space
Curettage, hysterectomy, Resection bilateral salpingo-oophorectomy
Died in 3 Y2 years of metastases
Logan and Motyloff21
Lung
Curettage
None
4 year follow-up, no recurrence
Logan and Motyloff21
Lung
Hysterectomy, bilateral salpingo-oophorectomy
Radiation
12 year follow-up, no recurrence
Greene 10 (CR 263)
Lung
Curettage, ? hysterectomy
None
3 year follow-up, no recurrence
Greene 10 (CR 410)
Lung
Hysterectomy
?
Died 11 months postoperatively
Greene 10 (CR 70)
Lung, vulva, and vagina
Curettage, local excision, x-ray
Radiation
9 year follow-up, no recurrence
Greene 10 (CR 80)
Vagina
Hysterectomy
Excision
5 year follow-up, no recurrence
Greene 10 (CR 180)
Vagina
Hysterectomy, bilateral salpingo-oophorectomy
Radiation
6Y2 year follow-up, no recurrence
Greene 10 (CR 450)
Vagina
Hysterectomy
Excision
6 month follow-up. no recurrence
Acosta-Sison2
Vagina and labia
Local excision, x-ray
Radiation
Unknown
Acosta-Sison2
Lung and para- Local excision metrium
None
Died during surgery
Acosta-Sison 2
Vaginal
Resection Radiation
4 year follow-up, no recurrence
Acosta-Sison2
? Hysterectomy, excision of Radiation Lungs and parametrium parametrial masses
Unknown
Wilson et ai,S6
Lung
Curettage, hysterectomy
None
13 year follow-up, no recurrence
Wilson et al,s6
Lung
Curettage, hysterectomy, None bilateral salpingo-oophorectomy
9 year follow-up, no recurrence
Wilson et al,36
Lung and vagina
Hysterectomy
None
4 year follow-up, no recurrence
Subtotal hysterectomy
1404
December 1, !962 Am. J, Obst. & Gyncc.
Thiele and de Alvarez
Table IV-Cont'd
Author
Wilson et al. 36
Sites of metastases
Treatment Of pelvic lesion
Of metastases
Results
Curettage, hysterectomy, Radiation bilateral salpingo-oophorectomy, x-ray
14 year follow-up,
Lung and vagina
Curettage, hysterectomy, x-ray Radiation
11 year follow-up,
Wilson et aJ.3 6
Lung
Curettage, hysterectomy, xray, radium
Radiation
5 year follow-up, no recurrence
Wilson et a1. 36
Lung and vagina
Curettage, local excision, xray
Radiation
11 year follow-up,
Lung
Hysterectomy, right salpingo- Resection oophorectomy
Lungs
Wilson et al. 36
Reed et al.29 Hertz et aJ. 12, 13
Lung
no recurrence
no recurrence
Hysterectomy, ? bilateral salpingo-oophorectomy
no recurrence
3 Y2 year follow-up, no recurrence
Amethopterin 29 month followup, no recurrence
13
Lung
Hysterectomy, ? bilateral salpingo-oophorectomy
Amethopterin 7 month follow-up, marginal elevation of chorionic gonadotropin titer
Li et al. 19
Lungs
Hysterectomy, ? bilateral salpingo-oophorectomy
Amethopterin 2
Li et aJ.19
Lung
Hysterectomy, bilateral saipingo-oophorectomy
Amethopterin 23 month followup, no recurrence
Li et al.20
Lung
I-Iysterecton1y, bilateral
Arnethopterin
Hertz et
1
al. ~•
salpingo-oophorectomy
month followup, no recurrence
month foliowup, marginal elevation of chorionic gonadotropin titer
Amethopterin 2 year follow-up, no recurrence
Manahan et aJ.2 2
Vagina
Biopsy of vaginal lesion
Manahan et aJ.2"
Parametrium
Hysterectomy, biopsy of pelvic Amethopterin 2 year follow-up, mass no recurrence
Manahan et al.2 2
Lungs
Thiele and de Alvarez Lung and vagina
Hysterectomy Hysterotomy, curettage, hysterectomy, bilateral salpingo-oophorectomy
Amethopterin 2 year follow-up, no recurrence None
6 year follow-up, no recurrence
Thiele and de Alvarez Lungs, paraCurettage, hysterectomy, right Amethopterin 13 month followsalpingo-oophorectomy up, no recurmetrium, and vagina renee
Successful treatment of patients with benign trophoblastic lesions and metastases must be varied since no one method of approach is ideal for all patients, but from the
cases reported the following broad principles of management emerge: 1. The initial evaluation of patients with trophoblastic disease should include painstak-
Volume 114 Number 11, Part 1
Metastasizing benign trophoblastic tumors 1405
ingly detailed history and physical examination, careful pelvic examination with attention to uterine contour and ovarian size, chest x-ray, and chorionic gonadotropin titer. 2. Evacuation of the uterus should be carried out promptly in all patients as soon as the diagnosis is established. If the uterus is less than the size of a 10 to 12 weeks' gestation, prim~,.,! curettage should be atte:r.npted. If the uterus is larger than the size of a 3 months' pregnancy, oxytocin stimulation should be initiated. This may result in partial uterine emptying, thus increasing the ease and safety of evacuation. In many instances, partial evacuation of the uterus may be accomplished with ovum forceps, followed by immediate and definitive curettage. In rare cases, especially if oxytocin stimulation fails and the uterus is large, hysterotomy may prove the most expeditious procedure. 3. Postoperatively, all patients with hydatidiform mole or chorioadenoma destru.ens should be followed closely with chorionic gonadotropin assays. Even though Delfs7 recommends further study if any titer exceeds 20,000 International units per liter after 30 days, we feel that, if the titer persists, in any amount, longer than 6 weeks following evacuation, residual trophoblast should be considered present in the pelvis or lungs, and further investigation is required. 6 4. If metasta.tic foci of trophoblast are found in the presence of a deciining chorionic gonadotropin titer, continued close observation is probably justified. 5. If the chorionic gonadotropin level persists or its concentration rises, with or without metastatic lesions, total hysterectomy should be performed to eliminate the possibility of chorioadenoma destruens or choriocarcinoma. REFERENCES
1. Acosta-Sison, H.: AM.
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OnsT. & GvNEC.
78: 876, 1959. 2. Acosta-Sison, H.: AM. J. OnsT. & GvNEC. 80: 176, 1960. 3. Alter, N. M., and Cosgrove, S. A.: Obst. & Gynec. 5: 755, 1955. 4. Bardawil, W. A., Hertig, A. T., and Velardo, J. T.: Obst. & Gynec. 10: 614, 1957.
6. Chorioadenoma destruens may invade the uterine fundus locally, spread locally into contiguous and neighboring pelvic viscera, or metastasize remotely to any viscus of the body. The sites of predilection of metastases are the lungs or other organs along the inferior vena cava system. 7. Surgery for pulmonary metastases is probably not indicated. The effect of radiotherapy on pulmonary lesions is dubious. If metastatic tumor persists or progresses after hysterectomy, amethopterin appears to offer a satisfactory therapeutic approach to cure or palliation. If drug resistance occurs, vincaleukoblastine may be used. 14 8. All patients with trophoblastic tumors should be followed for a minimum period of 5 years with physical examinations, chest films, and chorionic gonadotropin titers. Appropriate chemotherapy should be instituted in inoperable cases. Summary
Two patients with chorioadenoma destruens and pulmonary and local metastases successfully treated by removal of the pelvic organs in one instance and by removal of the pelvic organs and the use of amethopterin in the other are reported. A review of the reported cases of hydatidiform moles and chorioadenoma destruens with metastases is presented. Principles of management are suggested.
We wish to acknowledge with appreciation the kindness of Dr. R. H. Welding, Ellensburg, Washington, for providing a detailed sequence of preoperative data and of posttherapy follow-up of the patient in Case 2.
5. Bardawii, W. A., and Toy, B. L.: Ann. New York Acad. Sc. 80: 197, 1959. 6. de Alvarez, R. R.: AM. J. OnsT. & GvNEC. 43: 59, 1942. 7. Delfs, E.: Obst. & Gynec. 9: 1, 1957. 8. Dinh-De, T., and Minh, H. N.: AM. J. OnsT. & GYNEC. 82: 660, 1961. 9. Ewing, J.: Surg. Gynec. & Obst. 10: 366, 1910.
1406 Thiele and de Alvarez
10. Greene, R. R.: Ann. New York Acad. Sc. 80: 143, 1959. 11. Hertig, A. T., and Sheldon, W. H.: AM. J. 0BST. & GYNEC. 53: 1, 1947. 12. Hertz, R., Bergenstal, D. M., Lipsett, M. B., Price, E. B., and Hilbish, T. F.: i\nn. Ne"v York Acad. Sc. 80: 262, 1959. 13. Hertz, R., Bergenstal, D. M .. Lipsett, M. B., Price, E. B., and Hilbish, T. F.: J. A. M. A. 168: 845, 1958. 14. Hertz, R., Lewis, J., Jr., and Lipsett, M. B.: AM. J. 0BST. & GYNEC. 82: 631, 1961. 15. Hreshchyshyn, M. M., Graham, J. B., and Holland, ]. F.: AM. ]. 0BST. & GYNEC. 81: 688, 1961. 16. Hunt, W., Dockerty, M. B., and Randall, L. M.: Obst. & Gynec. 1: 593, 1953. 17. Jacobson, F. ]., and Enzer, N.: AM. J. 0BST. & GYNEC. 78: 868, 1959. 18. Kistner, R. W.: AM. J. 0BsT. & GYNEC. 63: 888, 1952. 19. Li, M. C., Hertz, R., and Bergenstal, D. M.: New England J. Med. 259: 66, 1958. 20. Li, M. C., Hertz, R., and Spencer, D. B.: Proc. Soc. Exper. Bioi. & Med. 93: 361, 1956. 21. Logan, B.]., and Motyloff, L.: AM. J. 0BST. & GYNEC. 75: 1134, 1958. 22. Manahan, C. P., Benitez, 1., and Estrella, F.: AM. J. 0BST. & GYNEC. 82: 641, 1961.
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2::1. Nolan, J. F., Cook, E. M., Jr., and Dallke, W. E.: West. J. Surg. 63: 101, 1955. 2+. Novak. E.: AM. J. 0BsT. & GYNEC. 59: 1355, 1950. 25. Novak, E., and Seah, C. S.: AM. J. 0BST. & C!v""''' 1Q~4. . ._.. ............... ~7 ...,. ..• Q\l·