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Metastases in benign hydatidiform mole and chorioadenoma destruens
Metastases in benign hydatidiform mole and chorioadenoma destruens CHIEN-TIEN HSU, M.D. LIOU-CHEN HUANG, M.D. TING-YAO CHEN, M.D. Taipei, Taiwan, China
adding to the knowledge of these special points.
A c A s E of hydatidiform mole associated with bloody sputum and numerous round shadows in both lungs was observed by the author in 1937. The symptoms and signs disappeared spontaneously half a year after the evacuation of the mole and the patient has survived. Inasmuch as metastasis can occur in benign hydatidiform mole, the question arises as to what is the usual cause of such a metastasis. In recent years, the possibility of pulmonary spread of trophoblastic tissue has been well established not only in choriocarcinoma but also in normal pregnancy and in the intermediate group of moles. Novak15 stated in 1954 that, whereas x-ray evidence of metastases in cases where the uterus showed benign mole need not be of grave import, the possibility of choriocarcinoma subsequently developing from primarily benign trophoblastic pulmonary metastases cannot be excluded. Spontaneous regression of the metastasis as well as the primary lesion may also occur and make difficult the interpretation of radiation effects. We are presenting in this paper a series of cases of benign hydatidiform mole and chorioadenoma destruens from a distinct ethnic and geographic area, in the hope of
Material
This series consisted of the patients who presented themselves directly or were referred by other specialists to the Department of Gynecology and Obstetrics, Provincial Taipei Hospital, during a period of 3 years, from January, 1958, to December, 1960. The cases in which metastases were present while the moles were still in the uterus or developed sometime after their evacuation were included in the category of benign hydatidiform mole, even without a pathologic examination of the uterus. On the other hand, in all cases of chorioadenoma destruens, myometrial invasion was confirmed by pathologic examination of the removed uteri. There was, therefore, no case of chorioadenoma destruens in which the diagnosis was based merely on the pathologic examination of the curettings. During the 3 year period there were observed 48 cases of hydatidiform mole and 9 cases of choriocarcinoma. In addition, the following cases of chorioadenoma destruens or hydatidiform mole were seen : 1. Two cases (Cases 4 and 6) of hydatidiform mole with metastasis simultaneously with lesions in the uterus. 2. Three cases (Cases 8, 10, and 11) of chorioadenoma destruens, with metastases also appearing concomitantly with the lesions in the uterus.
From the Department of Obstetrics and Gynecology, Provincial Taipei Hospital, and Taipei Medical Callege, and from the Institute of Pathology, College of Medicine, the National Taiwan University.
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3. Two cases (Cases 2 and 7) with metastases but with negative uterus after abortion of moles. 4. Three cases (Cases 1, 12, and 13) of hydatidiform mole in which metastases developed sometime after the evacuation of the moles. 5. One case of chorioadenoma destruens (Case 9) in which metastasis developed sometime after hysterectomy. 6. One case of chorioadenoma destruens (Case 5) in the endocervix with no history of hydatidiform mole. 7. Two cases (Cases 3 and 14) of chorioadenoma destruens showing no metastases. It should be noted that Cases 10 and 11 were included in this series although they were observed in 1954 and 1946. A summary of these cases is given in Table I and brief clinical histories and the pertinent pathologic findings of some of the particularly interesting cases follow.
Fig. 1. Case 1. Metastasis of hydatidiform mole to right inguinal node, showing several syncytial cells in the adenoid structure with coagulation
necrosis at left lower corner.
Case reports
Case 1. C. T., a Formosan housewife, aged 33, para iv, gave a history of a hydatidiform mole evacuated by dilatation and curettage at her second pregnancy, and a normal pregnancy 2 years before admission. The last menstruation was Sept. 19, 1958, lasting one week, and vaginal bleeding started 10 days prior to admission on Dec. 8, 1958. Pelvic examination disclosed a uterus the size of a newborn infant's head and a fist-sized mass probably emanating from the right ovary. The frog test was positive with 0.01 c.c. of urine. Curettings grossly showed hydatidiform mole, which was confirmed pathologically. The tumor in the right adnexal region gradually diminished in size and disappeared 2 weeks later. Frog tests on follow-up examination were all negative. About 4 months after the curettage, the patient noted a growing mass, the size of a thumb, in the right inguinal region, while frog tests still remained negative. Excisional biopsy revealed tissue interpreted as chorioadenoma destruens with hemorrhage and with young trophoblasts infiltrating the inguinal lymph node, but no villi (Fig. 1). A chest film showed no metastasis. She is living and well after a normal pregnancy which terminated in February, 1960. Comment. This case is of particular interest
Fig. 2. Case 2. Molar villi in left ovarian vein. The villi on the top and at left corner are of quite benign appearance, showing distinct central cystic degeneration with little trophoblastic proliferation. The other two villi are slightly fibrotic in appearance without cystic degeneration. Mild trophoblastic proliferation is seen around the smallest villus in the center. because of the metastasis to the inguinal node, occurring either primarily in the gland itself or extending thither from the periadenoidal vascular structure. Conservative excision of the metastatic lesion was followed by a subsequent pregnancy a.t1d survival of the patient. Case 2. C. M., a Formosan housewife, aged 49, gravida x, para vii, was referred to us on Oct. 7, 1958, because of vaginal bleeding and a positive frog test which had persisted even after repeated curettage for hydatidiform mole in March and May of the same year. Pelvic examination on admission revealed a retro-
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Table I. Summary of clinical history and pertinent findings in 14 cases of hydatidiform mole wit j
Pre- ' I vious I molar
preg- Parnancy ity
Case
Lesion in the uterus when metastases were seen
Interval between the
I
Interval between
Tre~
d:!~~~~:~oof / d::::::;o;n;t noma and 'I
I f
metastases
33
6
4
? Postmolar uterus 4 months
2
49
11
7
Negative (postmolar uterus)
3
35
5
3
Chorioadenoma destruens
4
34
5
4
Nfole
5
"t5
11
10
............. .,,_,...,.,.,...,-
metastasis
Operation
Curettage
5 months
Sim ul tan eous
Chorioadenoma
10,000
Simple panhysterectomy
1,000
Simple panhysterectomy
1,000
Subtotal hysterectomy
1,000
Simple panhysterectomy
destruens 6
19
7
24
3
8
36
5
3
Chorioadenoma destruens
Simultaneous
50,000
Subtotal hysterectomy
9
52
13
10
No uterus (re-
2 months
30,000
Simple panhysterectomy
2,000
Simple panhysterectomy
0
Mole
Simultaneous
1,000
Curettage
Negative (postmolar uterus)
1 week
1,000
Simple panhysterectomy
moved for chorioadenoma) 10
34
11
11
25
2
12
35
7
13
22
14
26
3
10
Chorioadenoma destruens
6 months
Chorioadenoma destruens
Simultaneous
6
No uterus (re2 Y2 months moved for mole)
0
? Postmo!ar uterus
2
Chorioadenoma destruens
verted, enlarged uterus with negative adnexa. The frog test was positive with 0.1 c.c. of urine. Simple total hysterectomy with bilateral salpingo-oophorectomy was carried out on Oct. 10, 1958. The pathologic examination revealed no abnormality in the uterus or the adnexa, but an
Simultaneous
3 months
( 20,000)
Simple panhysterectomy
1,000
Simple panhysterectomy
1,000
Curettage
1,000
pan·
isolated tumor about 2 em. in diameter was found in the left mesosalpinx. This proved to be chorioadenoma destruens invading the left ovarian vein (Fig. 2). According to a report received recently from her family, the patient was living and apparently well until last November,
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metastases or of chorioadenoma destruens
ment
Site of metastasis
Excision llrr?di- Chemo- Endobiopsy at! on therapy cervix
I
Adnexa
'Vagina or urethra
Lung
+
+
+
+
+
+
+
+
+ +
+
+
Died 3 years after operation
Died from hemiplegia, blindness, and sudden attack of severe abdominal pain
Living, 3 years
Fever similar to quartan fever disappeared dramatically after operation
No history of mole
Living, 1 year, 4 months
+
Living, 1 year, 2 months
Chest radiograph on Dec. 22, 1961, essentially negative
+
Living, 2 years, 8 months
Severe intraabdominal hemorrhage due to uterine perforation by mole, misdiagnosed for ectopic gestation
Living, 2 years, 9 months
+
+
Remarks
Had a normal delivery after curettage
Living, 1 year, 10 months
+ +
Outcome
Living, 3 years, 1 month
Living, 1 year, 10 months
+
+
Inguinal node
+
Died
Sudden death 2 weeks after operation. No autopsy
+
Living, 15 years
+
Living, 1 year, 7 months
Severe hemorrhage, fis· tula (vesicovaginal), sepsis
+
Living, 1 year, 4 months
Severe hemorrhage, vesicovaginal fistula, sepsis
Living, 4 months
1961, when hemiplegia and blindness set in followed by a sudden attack of severe abdominal pain. Death followed shortly, probably from brain metastasis. Comment. The absence of trophoblastic lesions in the uterus and the unique site of metas-
tasis illustrate the difficulty not only of preoperative but also of postoperative diagnosis of chorioadenoma destruens. Case 5. C. C. M., a Taiwanese housewife, aged 45, gravida xi, para x, had her last menstruation on Nov. 5, 1959. Irregular genital
1416 Hsu, Huang, and Chen Am.
Fig. 3. Case 5. Chorioadenoma destruens of the endocervix, showing invasion of a uterine sinus. bleeding had been noted for 2 to 3 months prior to admission on March 30, 1960. A curettage was done on Feb. 24, 1960, with at first cessation, but soon a return of bleeding. She was in critical condition when brought to our clinic, with pale face and indeterminable blood pressure. Vaginal examination disclosed an enlarged uterus with markedly hypertrophied cervix, and rectal examination an induration at the level of the isthmus. The frog test was positive with 1.0 c.c. of urine on March 31. Laparotomy on April 2, 1960, disdosed an anemic, enlarged uterus, which was removed with the adnexa. On cutting of the removed uterus a thumb-sized tumor, dark reddish in color, was found at the posterior wall of the endocervix. Microscopically this nodule proved to be a chorioadenoma destruens, as evidenced by several fibrotic or fading villi with marked trophoblastic proliferation and intact villi in a sinus of the endocervix (Fig. 3). The uterine cavity contained no abnormal tissue. On follow-up examination, May 16, 1960, the frog tes~ was negative and her general condition was excellent. She is living and well at the time of this report. Comment. This is a unique case of chorioadenoma destruens found in the posterior endocervical wall without a history of hydatidiform mole. Chorioadenoma destruens subsequent to latent hydatidiform mole developed from cervical pregnancy might be assumed, but this might also be explained as a secondary lesion after spontaneous regression of the primary tumor in the uterine cavity. Case 7. L. S., a Taiwanese housewife, aged 24, gravida ii, para i, was referred to us on Nov. 29, 1960, because of a tumor mass appearing at
December 1, 1962 Obst. & Gynec.
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the introitus of the vagina after a curettage 2 weeks previously for hydatidiform mole in the third month of gestation. The uterus was found to be normal in size and the adnexa normal. Speculum examination disclosed a thumb-sized grapelike mass at the right side of the urethra dislocating the urethral orifice to the left. Another tumor mass of similar gross appearance was found on the anterior vaginal wall. The frog test done on November 30 was positive with 1.0 c.c. of urine. The chest film taken on December 12 disclosed two round homogeneous densities in the lower lung fields and one in the right anterior third intercostal space. Excisional biopsy of the vaginal and urethral masses on December 5 revealed metastatic cho· rioadenoma destruens as evidenced by the presence of a few villi with trophoblasts in the vagi-
Fig. 4. Case 7. Vaginal metastasis showing a small distinct villus with some syncytial cells floating in the blood pool.
nal node, but only trophoblasts in the urethral node (Fig. 4 ). Simple total hysterectomy with bilateral salpingo-oophorectomy was performed on December 15. Pathologic study of the removed specimens revealed neither mole nor chorioadenoma destruens in the uterus or adnexa. The chest film taken on December 26 disclosed the disappearance of the round opaque mass in the right lung field, and repeated frog tests thereafter were negative. The patient was discharged on Dec. 31, 1960, without any further treatment. She is living and well with negative frog tests and essentially normal chest roentgenogram. Comment. This case is characterized clinically
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by the absence of trophoblastic disease in the uterus in spite of the concomitant metastatic lesions in the vaginal wall and the lungs, and spontaneous retrogression of lung lesions after hysterectomy and the removal of the vaginal and urethral lesions. Case 10. C. R . P. was a native of Taiwan, aged 34, gravida xi, para x. On Nov. 29, 1954, she had had an abortion of a hydatidiform mole followed by curettage. Because of long-standing vaginal bleeding, she was subjected to repeat curettage on May 17, 1955, but the bleeding did not diminish. Allegedly, prior to the first curettage she had already noted on occasion blackish bloody sputum, which persisted up to the time of admission. Pelvic examination revealed an anteverted, slightly enlarged uterus, enlarged adnexa, and slight bleeding from a dilated external os. On the anterior vaginal wall, to the left of the urethral meatus, there was a blackish nipplelike nodule about the size of a peanut. X-ray film of the chest disclosed numerous round shadows over the whole field of both lungs. Frog tests were positive with 0.5 c.c. of urine and negative with 0.1 c.c. The nodule below and lateral to the urethral meatus was removed and found on microscopic examination to be a metastatic chorioadenoma destruens. After removal of the tumor on the anterior vaginal wall on May 18, a tiny blackish spot was noted immediately beneath the urethra and it regained the size of the original tumor by May 24. Simple panhysterectomy and bilateral adnexectomy were performed. Pathologic examination revealed a chorioad enoma destruens with only a few fading villi and marked trophoblastic proliferation (Fig. 5).
Fig. 5. Case 10. Chorioadenoma destruens, showing marked trophoblastic proliferation with a fading villus.
Fig. 6A. Uterine curettings showing molar villi with little trophoblastic proliferation.
Fig. 68. Uterine curettings showing an area with a moderate degree of trophoblastic proliferation. She remained well after the operation till one evening, after reaching home from a movie, she had a sudden attack of severe headache and vomiting and soon lapsed into unconsciousness and Cheyne-Stokes respiration. She died soon afterward. No autopsy was permitted. Comment. This is one of the 2 cases in our series where the patient apparently died from brain metastases which, however, could not be confirmed because of the denial of an autopsy. This case is of importance because of a choice of two interpretations, namely: ( 1) if we assume this to be a case of chorioadenoma destruens because of the presence of villi, then the death of this patient would indicate that a benign tumor can cause death from a mechanical accident; (2) the multiple metastases, on the other hand, might justify the assumption that this was a choriocarcinoma, rather than chorioadenoma destruens, and, further, that the presence
1418 Hsu, Huang, and Chen
of a few fading villi "ferreted out" by unremitting search does not necessarily rule out the possibility of choriocarcinoma.
An additional case. In the course of preparing this manuscript, an interesting case, that of a 24-year-old nullipara, came to our attention. A diagnosis of hydatidiform mole with possible lung metastasis was established by us on July 8, 1961, when she was in the second month of gestation. Her secont! visit on November 23 showed the uterine fundus to be 20 em. above the symphysis, consistent with the gestational age of 7 months. Bloody sputum and signs of toxemia were present. Chest x-ray showed a pigeon egg-sized mass in the left parahilar region and a suspicious shadow in the right base. After curettage on November 23, the signs of toxemia disappeared but the pulmonary lesions remained unchanged. The histologic examination revealed hydatidiform mole with some trophoblastic proliferation and decidua showing necrosis (Figs. 6A and 6B). The patient remained well until Dec. 22, 1961, when she suddenly became unconscious while she was eating dinner and in a cheerful mood. She died at midnight in spite of emergency treatment, apparently of cerebral metastasis of a benign lesion. Comment
Syncytial embolism (trophoblastic deportation) in normal pregnancy. In his historically famous monograph published in 1893, Schmorl 11 described embolic syncytium in the lungs of 14 of 17 patients with fatal eclampsia and his subsequent observations18-20 strongly indicated the pathogenetic relations between "placental embolism" and eclampsia, which were also observed by Lubarsch10 and Leusden.U However, Kassjanow9 could not find any significant difference between normal and eclamptic pregnancy, and postulated that "placental embolism" was an ordinary physiologic occurrence during gestation, an assertion which probably gives him credit for priority in the elucidation of this concept. The term "deportation" was coined in 1901 by Veit,Z 3 who found villi apparently free and floating within the maternal veins in a case of ectopic pregnancy. He took the position that deportation was a normal proc-
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ess occurring during any and all pregnancies with particularly marked frequency in gestational disorders. Bardawil and Toy1 reported 57 cases of definite trophoblastic embolism in 109 maternal deaths in Boston Lying-in Hospital. Syncytial embolism in normal pregnancy is now generally accepted as a common event with no serious implications.1 Metastasis in hydatidiform mole. Published reports of emboli composed of molar vesicles are not rare. Early in 1896, Neumann13 reported myometrial deportation in a case of mole and then in 1900 Poten and Vassmer16 described an early syncytioma with metastasis in hydatidiform mole. In 1905 SchmorP 9 • 30 also observed 3 cases involving syncytial transport to the lung in molar pregnancy. In 1923, Miller 12 presented the history of a girl of 18 who had succumbed to fatal hemorrhagic shock. At autopsy tumor nodules were found in the lung, bladder, and vagina. The lungs contained large syncytial cells enveloped in a granulomatous reaction as well as encysted molar villi. The vaginal wall was invaded by chorionic tissue with villi but none was observed in the vessels. Although in the uterus only typical mole was found, the final diagnosis was invasive mole. In Novak's15 series, 6 cases (CR 31, 42, 65, 113, 154, and 259) showed pulmonary nodular densities which were interpreted by radiologists as probable metastatic growths. In CR 113, metastasis to the spine and, in CR 154, metastasis to the femur were noted besides pulmonary metastasis. Bardawil and Toy1 described a case of hydatidiform mole in a 21-year-old nullipara, who died of cerebral hemorrhage. At autopsy, however, no trophoblastic cells were found in the cerebral hemorrhage, but the pulmonary hemorrhagic mass contained molar vesides and a number of discrete trophoblastic cells within small vessels. A case observed by Coe and Read was also cited by them, who considered it a textbook example of villous deportation of hydatidiform mole in the lungs. The patient snrvived after hysterectomy and thora-
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Metastases in benign mole and chorioadenoma destruens 1419
cotomy. Recently Tran Dinh-De and Hoang Ngoc Minh22 reported a case of hydatidiform mole with recurrent vaginal metastasis. In our series, metastases were found in 2 cases whiie the moles were still in the uterus, in 2 cases with negative findings in the uterus after abortion of moles, in 2 cases sometime after evacuation of moles, and in one case after an interval following hysterectomy for the mole. Unfortunately, pathologic examination was confined to the curettings in 2 cases (Cases 1 and 6), and in 2 more (Cases 4 and 12) no destructive mole in the uterus was demonstrable on gross examination; these specimens were not made available for pathologic examination. In Case 13 a huge amount of molar vesicles was observed grossly by the gynecologist. In only 2 cases (Cases 2 and 7) was histologic examination of the extirpated uteri performed. Five cases were therefore categorized as benign moles failing pathologic examination of the uterus, since, strict~y following Ewing's definition, no diagnosis of chorioadenoma destruens can be made without pathologic examination of the uterus. 3 • 6 Tran Dinh-De and Hoang Ngoc Minh 22 also categorized their case under hydatidiform mole without hysterectomy. It should be noted, however, that despite his strong opposition to Novak's diagnosis of chorioadenoma destruens made from curettings without uterus, Greene 3 categorized 4 cases as chorioadenoma destruens without hysterectomy, merely on the basis of the vaginal or vulvar metastases. If we assume that infiltration may have occurred at some site in the uterine wall which had evaded clinical or pathologic examination, our cases might also be included in the category of chorioadenoma destruens. Metastasis in chorioadenoma destruens. Before this topic is discussed, brief allusion should be made to moot points concerning the diagnosis of trophoblastic diseases. The term "chorioadenoma destruens" was first proposed by Ewing in 1910 and was meant to include moles that invade the uterine wall and/or metastasize and still maintain their villous structure. 3 As to whether this diag-
nosis can be made by pathologic examination of curettings rather than from examination of the entire uterus, there is a divergence of opinion between Novak and Greene. Novak15 stated, "When trophoblastic overgrowth is unduly exuberant the lesion may be designated as chorioadenoma destruens, although this criterion of the latter lesion is not so reliable as that of perforation of the uterine wall or infiltration of parametrium and/or vagina." Thus diagnosis can be made from curettings only. 3 Actually, in the material cross-filed in the Mathieu Registry as chorioadenoma destruens, 2 such specimens are included. 3 Greene, in opposing this proposition, agreed with Novak on only one of the 2 cases, i.e., that in which the myometrium included in the curettings showed obvious invasion. Since metastasis can occur in both benign and malignant moles (chorioadenoma destruens) the only means of distinguishing between the two lies in the pathologic findings in the uterus. Whether or not the invasion of the uterus by moles, i.e., chorioadenoma destruens, can be deduced simply from the presence of metastasis, omitting pathologic examination of the uterus, as Greene 3 did, is debatable. A further argument between the authorities concerns the question of whether a definite line can be drawn between chorioadenoma destruens and choriocarcinoma, on the basis of the presence or absence of villous structure, as has been proposed by Meyer and Novak, as a conclusion derived from the retrospective pathologic and clinical study of a large number of cases. The consensus of modern pathologists seems to be that chorioadenoma
destruens is characterized by the maintenance of villous structure in the primary or metastatic lesion, whereas choriocarcinoma is devoid of villi. Novak14 was of the opinion that the finding of well-formed villi justified one in at least leaning away from diagnosis of choriocarcinoma, but he did not believe that occasional finding of villi should exclude this diagnosis. Therefore he categorized the fatal case, CR 139, under choriocarcinoma despite the presence of villi. This
1420 Hsu, Huang, and Chen
is in some conflict with his statement15 that malignancy as it occurs in trophoblastic lesions is determined by the microscope, and not by the clinical course. Greene, however, considered as correct the designation of this case (CR 139) as chorioadenoma destruens since villi were present in the lesions in the uterine wall. One of us (T. Y. C.) 2 insisted in a previous paper that, on the basis of his material, the presence of villi in invasive or metastasizing trophoblastic diseases precludes the possibility of choriocarcinoma. In opposition to this view we must quote Hertig's statement6 to the effect that occasionally both an invasive mole and a true choriocarcinoma exist in the same uterus and the patient may die from the metastases of the choriocarcinoma. So far as the metastasis in chorioadenoma destruens is concerned, the 32 cases reported by Hertig 5 showed no metastases. In spite of his opinion that chorioadenoma destruens has little tendency to distant metastasis, Novak 14 believed in the possibility of pulmonary metastasis with chorioadenoma (CR 202) or, for that matter, with even hydatidiform mole. Wilson 25 reported a high incidence (60 per cent), i.e., 12 instances of lung metastases in a series of 20 cases of chorioadenoma destrucns. Obera collected 7 cases of proved metastases ( 4.9 per cent) out of 142 of chorioadenoma destruens culled from 4 series in the literature and concluded that chorioadenoma rarely metastasizes. Out of 42 cases of Greene's collection from the Mathieu Registry, 6 had metastases in the vulva and/or vagina and 6 in the lungs (28.6 per cent). In Wei's 24 series metastases were seen in 3 of 12 cases of chorioadenoma destruens ( 25 per cent). In our series no diagnosis of chorioadenoma destruens was made from curettings, but only from the removed uterus. Thus, metastases were found in 5 of 7 cases of chorioadenoma destruens. From CR 202 in Novak's series, 14 it is evident that some of our cases of benign mole should have been classified under chorioadenoma destruens had pathologic examination of the uterus
December 1, 1962 Am.]. Obst. & Gynec.
been carried out. The frequency of metastasis in one series, however, cannot be used to generalize on the incidence of metastasis in chorioadenoma destruens, since our hospital is heavily weig'hted with unusual or severe cases referred by other specialists. Implication of metastases. Ober3 does not consider the so-called vaginal metastasis as a sign of malignancy but feels that it is the result of a permeation of dependent venous channels by intravascular trophoblast and that true infiltration of maternal tissue rarely occurs. Likewise, x-ray evidence of pulmonary metastasis in cases of chorioadenoma may be due to a reaction in the lung tissues around embolic trophoblast with or without villi, but not necessarily to trophoblast invading the maternal lung tissues. According to Tran Dinh-De metastasis of trophoblastic cells to the vaginal wall associated with moles, as in their case, is generally accepted as retrograde venous embolization of trophoblast, rather than autonomous secondary deposits. Paten and Vassmer16 were of the opinion that deportation per se did not necessarily connote malignancy. Wilson 25 stated that in the past patients have been given a hopeless prognosis because of the presence of metastases, but on the basis of his results this is not indicated until thorough examination of the tissues from the pelvis, and, if necessary, from the lung or other metastatic sites shows the absence of villi in the trophoblastic tissue in all locations. Hitschmann 4 stated that pulmonary metastasis appears clinically to simulate pulmonary infarction and considered it necessary to determine through biologic tests whether proliferative elements are present in the embolus. Mortality rate of chorioadenoma destruens. Novakl 4 reported 6 deaths in 26 pathologically authenticated cases of chorioadenoma destruens. Wilson 25 reported no deaths in 20 cases, Greene 3 6 deaths in 43, Hertig 5 one death in 32, and Little 3 one death in 21 cases of chorioadenoma destruens. Park and Lees3 reported 17 deaths out of 47 cases of chorioadenoma destruens
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Metastases in benign mole and chorioadenoma destruens 1421
tabulated from the literature. ·When discussing Greene's paper, applying his rigid criteria to the above-mentioned four series (exclusive of Novak's), Ober3 estimated 25 deaths ( i i .6 per cent), two thirds of which, however, were those which Park and Lees summarized from the literature and many of them date back to the period when hemorrhage and sepsis were treated less effectively than they are today. In our series, one sudden death of a completely healthy woman occurred in the postoperative period and the other death was that of a patient who survived 3 years after hysterectomy. Besides these, because of profuse intra-abdominal or vaginal hemorrhage and/ or sepsis, 3 patients were on the verge of death from profound shock, and might not have survived without a modem blood bank, antibiotics, and adrenal hormones. The nature of chorioadenoma destruens and its treatment. There is considerable divergence of opinion regarding the nature of chorioadenoma destruens. Smalbraak 21 considered it not to be an adenoma, and rejected the term "chorioadenoma" in favor of the older designation "destructive hydatidiform mole." Others believed it is a locally destructive benign tumor of chorionic epithelium and designated it as "chorioadenoma destruens." However, Greene considered the over-all mortality of 14.3 per cent to be rather high for a lesion whose name implies benignancy. Ober 3 stated that the mere fact that a patient with chorioadenoma dies of the disease does not mean that it is truly a malignant tumor, because death can occur with benign tumors in other situations. Nevertheless, basing his case on the mortality rate, possible sepsis, and hemorrhage, he regarded chorioadenoma as a dangerous disease requiring hysterectomy. Tran Dinh-De stated that chorioadenoma destruens is not necessarily malignant, and, concurring with Novak and Seah's policy, expressed the view that hysterectomy would not be justified unless repeat curettage showed a more highly suspicious malignant change with a broad field of trophoblasts and no villi.
Fig. 7A. Case 1. Uterine curettings showing an area with marked, the most pronounced in this case, trophoblastic proliferation.
Fig. 7B. Case 1. Uterine curettings showing degenerated villi with least trophoblastic proliferation.
The famous case of Delfs14 of benign hydatidiform mole resulting in death from lung and ultimately spinal cord metastasis, the case cited by Bardawil and Toy of a hydatidiform mole occurring in a 17 -yearold white girl who suddenly died from cor pulmonale as a result of syncytial emboli which filled the smaller pulmonary vessels despite typical moles fi.iling the uterus, and probably our Cases 2 and 10 indicate the possibility of benign trophoblastic disease causing the death of the host. Death in these cases may be due not to invasion or the metabolic derangement resulting from malignancy, but to mechanical factors . On the basis of our experience with occasional severe hemorrhage and sepsis, we are inclined
1422 Hsu, Huang, and Chen
Fig. SA. Case 6. Uterine curettings showing several rather fibrotic villi without remarkable trophoblastic proliferation.
Fig. 8B. Case 6. Vaginal metastasis showing a long fibrotic villus with little trophoblastic proliferation.
Fig. 9. Uterine curettings from Patient C. H. F., showing a large mass of trophoblastic cells without villous structure around it, which is often incorrectly diagnosed as choriocarcinoma.
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to perform hysterectomy for this disease, particularly on multiparas who do not want further children. Relation of trophoblastic activity to metastasis. Hertig and Sheldon, 5 in recommending a routine study from at least 5, preferably 10, regions, classified the moles of their collection into six groups and claimed a marked but not absolute correlation between the degree of apparent molar activity and the tendency of the patient to develop a possibly fatal chorionic lesion. In their study to confirm Hertig's findings, Hunt, Dockerty, and RandalF concluded that the results of such analysis were not conclusivt enough to determine definite treatment, and careful observation of the clinical course of the patient following evacuation of a mole was considered more important than histologic study. Smalbraak 21 stated the opinion, based on his material, that the practical value of a classification of moles designed to serve as a guide in the treatment of patients proved disappointing. In disagreeing with Hertig's proposition, Novak 15 maintained that the histologic characteristics varied in different parts of the mole, change being greater when it is nearest the uterine wall or occurs as an implant within it, and less when the mole grows away from the uterine wall and its source of blood supply. However, he considered that Hertig's current division of cases into apparently benign, potentially malignant. and apparently malignant was a more logical one. Edmonds 3 was of the opinion that overemphasis on morphologic grading is misleading. Grady 3 testified to the difficulty of classifying moles into six groups on the basis of histologic structure, but subscribed to the belief that a grouping of three based on quantity and appearance of covering trophoblast is possible, in that it would at least give a rough approximation of the risk of subsequent choriocarcinoma. Greene has shown that his grading of the trophoblast of the invasive moles in his series did not tally with the molar aggressiveness evidenced by perforation, deportation, or death. In our two cases of hydatidiform mole
Volume 84 Number 11, Part I
Metastases in
(Cases 1 and 6), where metastasis was seen, no particular trophoblastic activity was proved (Figs. 7A, 7B, 8A, and 8B). On the other hand, Patient C. H. F. in our 1956 series8 showed abnormally high gonadotropin titer (3.2 million frog units), high estrogen excretion ( 178 to 1,000 p,g per day) and a histologic pattern consistent with Hertig's type VI, malignant (Fig. 9), for which the pathologist strongly advised hysterectomy. Because the patient was still anxious to have more children, only curettage was performed. She is living and well, having had 2 more children in the meantime. Our experience seems also to substantiate negative correlation between the aggressiveness of the moles and their histologic grading. Site of metastases. Physiologic metastases occur more frequently in the lungs than in the vulva or the vaginal mucosa. 22 In Wilson's 20 cases of chorioadenoma destruens, 8 exhibited metastasis to the lungs, 2 to the vagina, and 2 to the retroperitoneum. In Greene's series, 6 metastasized to the lungs and 6 to the vulva and/or vagina. In our series, 8 metastasized to the vagina and 3 to the lungs. In 2 cases metastases were detected in both lungs and the vagina. Very interestingly, metastasis was discovered after operation in the inguinal node, mesosalpinx, and possibly the endocervix. It is not clear whether or not the predominance of vaginal metastases over lung metastases in our series
beni~.. mole
and chorioadenoma destruens 1423
can be related to a racial peculiarity in the anastomosis between the uterine and vaginal blood vessels.
Summary
1. A series of cases of benign hydatidiform mole and chorioadenoma destruens showing a high incidence of metastasis has been presented. In sharp contrast to other series, a majority of metastases were found in the vagina and in the vicinity of the urethral meatus. 2. The results of this study and of others in the literature strongly indicate that the old belief that a trophoblastic lesion possessing villous structure would rarely metastasize, no longer hoids true. 3. All of our patients except 2 are living and well, despite the presence of metastases or conservative therapy in some. Metastases to the vagina and/or lungs in this small series has not had a hopeless implication. 4. The fatal cases in the literature, combined with 2 of our own, indicate the uncertainty of the correlation between the clinical course and histopathologic findings in the trophoblastic diseases. 5. Because of the vagaries of trophoblastic disease and the potentially malignant nature of hydatidiform mole, the sacrifice of the uterus may be in the interest of the patient when no further childbearing is desired.
REFERENCES 1. Bardawil, A., and Toy, B. L.: Ann. New York Acad. Sc. 80: 197, 1959. 2. Chen, T. Y., Pen, T. L., and Yeh, S.: Reports, Institute of Pathology, National Taiwan University, Special Issue in Commemoration of Its Tenth Anniversary, No. 8, p. 57, June, 1957. 3. Greene, R. R.: Ann. New York Acad. Sc. 80: 143, 1959. 4. Hitschmann, F.: In Halban, J., and Seitz, L., editors: Biologie und Pathologie des Weibes, Berlin, 1928, Urban & Schwarzenberg, Band VII, p. 535. 5. Hertig, A. T., and Sheldon, W. H.: AM. J. 0BST. & GYNEC. 53: 1, 1947. 6. Hertig, A. T.: Seminar on Tumors of the Gynecologic System, Proceedings, Eighteenth Seminar of the American Society of Clinical
7. 8.
9. 10. 11. 12.
Pathologists, Oct. 17, 1952, published by the American Society of Clinical Pathologists, Chicago, 1953, p. 43. Hunt,- W., Dockerty, M. B., and Randall, L. M.: Obst. & Gynec. 1: 539, 1953. Hsu, C. T., Lin, C. T., Lai, Y. H., and Ma, Y. M.: Racial Peculiarities in Obstetrics and Gynecology, Asiatic Congress of Obstetrics and Gynecology, published by the Japanese Obstetrical & Gynecological Society, Tokyo, 1957, p. 160. Kassjanow: Inaugural Dissertation, St. Petersburg, 1896, cited by Bardawil & Toy.l Lubarsch, 0.: Fortschr. Med. 11: 845, 1893. Leusden, P.: Virchows Arch. path. Anat. 142: 1, 1895. Miller, J.: Edinburgh M. J, Suppl. 217, 1923-1924.
1424 Hsu, Huang, and Chen
13. Neumann, J.: Monatsschr. Geburtsh. u. Gyniik. 3: 387, 1896. 14. Novak, E., and Seah, C. S.: AM. J. 0BST. & GYNEC. 67: 933, 1954. 15. Novak, E., and Seah, C. S.: AM. J. 0BsT. & GvNEC. 68: 376, 1954. 16. Poten, W., and Vassmer, W.: Arch. Gyniik. 61: 205, 1900. 17. Schmorl, C. G.: Pathologisch-anatomische Untersuchungen iiber puerperale Eklarnpsie, Leipzig, 1893, Vogel. 18. Schrnorl, C. G.: Arch. Gyniik. 65: 504, 1902. 19. Schmorl, C. G.: Verhandl. deutsch. path. Gesellsch. 8: 39, 1905.
Am.
December 1, 1962 Obst. & Gynec.
J.
20. Schmorl, C. G.: Zentralbl. Gyniik. 29: 129, 1905. 21. Smalbraak,
J.: Ann. New York Acad. Sc. 80: 105, 1959. 22. Tran Dinh-De and Hoang Ngoc Minh: AM. J. 0BST. & GvNEC. 82: 660, 1961. 23. Veit, J.: Ztschr. Geburtsh. u. Gynak. 44: 466, 1901. 24. Wei, P. Y., Ouyang, P. C., and Peng, T. L.: Reports, Institute of Pathology, National Taiwan University, No. 8 p. 29, 1957. 25. Wilson, R. B., Hunter, J. S., and Dockerty, M. B.: AM. J. 0BST. & GYNEC. 81: 546, 1961.
adding to the knowledge of these special points.
A c A s E of hydatidiform mole associated with bloody sputum and numerous round shadows in both lungs was observed by the author in 1937. The symptoms and signs disappeared spontaneously half a year after the evacuation of the mole and the patient has survived. Inasmuch as metastasis can occur in benign hydatidiform mole, the question arises as to what is the usual cause of such a metastasis. In recent years, the possibility of pulmonary spread of trophoblastic tissue has been well established not only in choriocarcinoma but also in normal pregnancy and in the intermediate group of moles. Novak15 stated in 1954 that, whereas x-ray evidence of metastases in cases where the uterus showed benign mole need not be of grave import, the possibility of choriocarcinoma subsequently developing from primarily benign trophoblastic pulmonary metastases cannot be excluded. Spontaneous regression of the metastasis as well as the primary lesion may also occur and make difficult the interpretation of radiation effects. We are presenting in this paper a series of cases of benign hydatidiform mole and chorioadenoma destruens from a distinct ethnic and geographic area, in the hope of
Material
This series consisted of the patients who presented themselves directly or were referred by other specialists to the Department of Gynecology and Obstetrics, Provincial Taipei Hospital, during a period of 3 years, from January, 1958, to December, 1960. The cases in which metastases were present while the moles were still in the uterus or developed sometime after their evacuation were included in the category of benign hydatidiform mole, even without a pathologic examination of the uterus. On the other hand, in all cases of chorioadenoma destruens, myometrial invasion was confirmed by pathologic examination of the removed uteri. There was, therefore, no case of chorioadenoma destruens in which the diagnosis was based merely on the pathologic examination of the curettings. During the 3 year period there were observed 48 cases of hydatidiform mole and 9 cases of choriocarcinoma. In addition, the following cases of chorioadenoma destruens or hydatidiform mole were seen : 1. Two cases (Cases 4 and 6) of hydatidiform mole with metastasis simultaneously with lesions in the uterus. 2. Three cases (Cases 8, 10, and 11) of chorioadenoma destruens, with metastases also appearing concomitantly with the lesions in the uterus.
From the Department of Obstetrics and Gynecology, Provincial Taipei Hospital, and Taipei Medical Callege, and from the Institute of Pathology, College of Medicine, the National Taiwan University.
1412
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Metastases in benign mole and chorioadenoma destruens 1413
3. Two cases (Cases 2 and 7) with metastases but with negative uterus after abortion of moles. 4. Three cases (Cases 1, 12, and 13) of hydatidiform mole in which metastases developed sometime after the evacuation of the moles. 5. One case of chorioadenoma destruens (Case 9) in which metastasis developed sometime after hysterectomy. 6. One case of chorioadenoma destruens (Case 5) in the endocervix with no history of hydatidiform mole. 7. Two cases (Cases 3 and 14) of chorioadenoma destruens showing no metastases. It should be noted that Cases 10 and 11 were included in this series although they were observed in 1954 and 1946. A summary of these cases is given in Table I and brief clinical histories and the pertinent pathologic findings of some of the particularly interesting cases follow.
Fig. 1. Case 1. Metastasis of hydatidiform mole to right inguinal node, showing several syncytial cells in the adenoid structure with coagulation
necrosis at left lower corner.
Case reports
Case 1. C. T., a Formosan housewife, aged 33, para iv, gave a history of a hydatidiform mole evacuated by dilatation and curettage at her second pregnancy, and a normal pregnancy 2 years before admission. The last menstruation was Sept. 19, 1958, lasting one week, and vaginal bleeding started 10 days prior to admission on Dec. 8, 1958. Pelvic examination disclosed a uterus the size of a newborn infant's head and a fist-sized mass probably emanating from the right ovary. The frog test was positive with 0.01 c.c. of urine. Curettings grossly showed hydatidiform mole, which was confirmed pathologically. The tumor in the right adnexal region gradually diminished in size and disappeared 2 weeks later. Frog tests on follow-up examination were all negative. About 4 months after the curettage, the patient noted a growing mass, the size of a thumb, in the right inguinal region, while frog tests still remained negative. Excisional biopsy revealed tissue interpreted as chorioadenoma destruens with hemorrhage and with young trophoblasts infiltrating the inguinal lymph node, but no villi (Fig. 1). A chest film showed no metastasis. She is living and well after a normal pregnancy which terminated in February, 1960. Comment. This case is of particular interest
Fig. 2. Case 2. Molar villi in left ovarian vein. The villi on the top and at left corner are of quite benign appearance, showing distinct central cystic degeneration with little trophoblastic proliferation. The other two villi are slightly fibrotic in appearance without cystic degeneration. Mild trophoblastic proliferation is seen around the smallest villus in the center. because of the metastasis to the inguinal node, occurring either primarily in the gland itself or extending thither from the periadenoidal vascular structure. Conservative excision of the metastatic lesion was followed by a subsequent pregnancy a.t1d survival of the patient. Case 2. C. M., a Formosan housewife, aged 49, gravida x, para vii, was referred to us on Oct. 7, 1958, because of vaginal bleeding and a positive frog test which had persisted even after repeated curettage for hydatidiform mole in March and May of the same year. Pelvic examination on admission revealed a retro-
1414
Hsu, Huang, and Chen
Am.
December l, 1962 Obst. & Gynec.
J.
Table I. Summary of clinical history and pertinent findings in 14 cases of hydatidiform mole wit j
Pre- ' I vious I molar
preg- Parnancy ity
Case
Lesion in the uterus when metastases were seen
Interval between the
I
Interval between
Tre~
d:!~~~~:~oof / d::::::;o;n;t noma and 'I
I f
metastases
33
6
4
? Postmolar uterus 4 months
2
49
11
7
Negative (postmolar uterus)
3
35
5
3
Chorioadenoma destruens
4
34
5
4
Nfole
5
"t5
11
10
............. .,,_,...,.,.,...,-
metastasis
Operation
Curettage
5 months
Sim ul tan eous
Chorioadenoma
10,000
Simple panhysterectomy
1,000
Simple panhysterectomy
1,000
Subtotal hysterectomy
1,000
Simple panhysterectomy
destruens 6
19
7
24
3
8
36
5
3
Chorioadenoma destruens
Simultaneous
50,000
Subtotal hysterectomy
9
52
13
10
No uterus (re-
2 months
30,000
Simple panhysterectomy
2,000
Simple panhysterectomy
0
Mole
Simultaneous
1,000
Curettage
Negative (postmolar uterus)
1 week
1,000
Simple panhysterectomy
moved for chorioadenoma) 10
34
11
11
25
2
12
35
7
13
22
14
26
3
10
Chorioadenoma destruens
6 months
Chorioadenoma destruens
Simultaneous
6
No uterus (re2 Y2 months moved for mole)
0
? Postmo!ar uterus
2
Chorioadenoma destruens
verted, enlarged uterus with negative adnexa. The frog test was positive with 0.1 c.c. of urine. Simple total hysterectomy with bilateral salpingo-oophorectomy was carried out on Oct. 10, 1958. The pathologic examination revealed no abnormality in the uterus or the adnexa, but an
Simultaneous
3 months
( 20,000)
Simple panhysterectomy
1,000
Simple panhysterectomy
1,000
Curettage
1,000
pan·
isolated tumor about 2 em. in diameter was found in the left mesosalpinx. This proved to be chorioadenoma destruens invading the left ovarian vein (Fig. 2). According to a report received recently from her family, the patient was living and apparently well until last November,
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Metastases m benign mole and chorioadenoma destruens
1415
metastases or of chorioadenoma destruens
ment
Site of metastasis
Excision llrr?di- Chemo- Endobiopsy at! on therapy cervix
I
Adnexa
'Vagina or urethra
Lung
+
+
+
+
+
+
+
+
+ +
+
+
Died 3 years after operation
Died from hemiplegia, blindness, and sudden attack of severe abdominal pain
Living, 3 years
Fever similar to quartan fever disappeared dramatically after operation
No history of mole
Living, 1 year, 4 months
+
Living, 1 year, 2 months
Chest radiograph on Dec. 22, 1961, essentially negative
+
Living, 2 years, 8 months
Severe intraabdominal hemorrhage due to uterine perforation by mole, misdiagnosed for ectopic gestation
Living, 2 years, 9 months
+
+
Remarks
Had a normal delivery after curettage
Living, 1 year, 10 months
+ +
Outcome
Living, 3 years, 1 month
Living, 1 year, 10 months
+
+
Inguinal node
+
Died
Sudden death 2 weeks after operation. No autopsy
+
Living, 15 years
+
Living, 1 year, 7 months
Severe hemorrhage, fis· tula (vesicovaginal), sepsis
+
Living, 1 year, 4 months
Severe hemorrhage, vesicovaginal fistula, sepsis
Living, 4 months
1961, when hemiplegia and blindness set in followed by a sudden attack of severe abdominal pain. Death followed shortly, probably from brain metastasis. Comment. The absence of trophoblastic lesions in the uterus and the unique site of metas-
tasis illustrate the difficulty not only of preoperative but also of postoperative diagnosis of chorioadenoma destruens. Case 5. C. C. M., a Taiwanese housewife, aged 45, gravida xi, para x, had her last menstruation on Nov. 5, 1959. Irregular genital
1416 Hsu, Huang, and Chen Am.
Fig. 3. Case 5. Chorioadenoma destruens of the endocervix, showing invasion of a uterine sinus. bleeding had been noted for 2 to 3 months prior to admission on March 30, 1960. A curettage was done on Feb. 24, 1960, with at first cessation, but soon a return of bleeding. She was in critical condition when brought to our clinic, with pale face and indeterminable blood pressure. Vaginal examination disclosed an enlarged uterus with markedly hypertrophied cervix, and rectal examination an induration at the level of the isthmus. The frog test was positive with 1.0 c.c. of urine on March 31. Laparotomy on April 2, 1960, disdosed an anemic, enlarged uterus, which was removed with the adnexa. On cutting of the removed uterus a thumb-sized tumor, dark reddish in color, was found at the posterior wall of the endocervix. Microscopically this nodule proved to be a chorioadenoma destruens, as evidenced by several fibrotic or fading villi with marked trophoblastic proliferation and intact villi in a sinus of the endocervix (Fig. 3). The uterine cavity contained no abnormal tissue. On follow-up examination, May 16, 1960, the frog tes~ was negative and her general condition was excellent. She is living and well at the time of this report. Comment. This is a unique case of chorioadenoma destruens found in the posterior endocervical wall without a history of hydatidiform mole. Chorioadenoma destruens subsequent to latent hydatidiform mole developed from cervical pregnancy might be assumed, but this might also be explained as a secondary lesion after spontaneous regression of the primary tumor in the uterine cavity. Case 7. L. S., a Taiwanese housewife, aged 24, gravida ii, para i, was referred to us on Nov. 29, 1960, because of a tumor mass appearing at
December 1, 1962 Obst. & Gynec.
J.
the introitus of the vagina after a curettage 2 weeks previously for hydatidiform mole in the third month of gestation. The uterus was found to be normal in size and the adnexa normal. Speculum examination disclosed a thumb-sized grapelike mass at the right side of the urethra dislocating the urethral orifice to the left. Another tumor mass of similar gross appearance was found on the anterior vaginal wall. The frog test done on November 30 was positive with 1.0 c.c. of urine. The chest film taken on December 12 disclosed two round homogeneous densities in the lower lung fields and one in the right anterior third intercostal space. Excisional biopsy of the vaginal and urethral masses on December 5 revealed metastatic cho· rioadenoma destruens as evidenced by the presence of a few villi with trophoblasts in the vagi-
Fig. 4. Case 7. Vaginal metastasis showing a small distinct villus with some syncytial cells floating in the blood pool.
nal node, but only trophoblasts in the urethral node (Fig. 4 ). Simple total hysterectomy with bilateral salpingo-oophorectomy was performed on December 15. Pathologic study of the removed specimens revealed neither mole nor chorioadenoma destruens in the uterus or adnexa. The chest film taken on December 26 disclosed the disappearance of the round opaque mass in the right lung field, and repeated frog tests thereafter were negative. The patient was discharged on Dec. 31, 1960, without any further treatment. She is living and well with negative frog tests and essentially normal chest roentgenogram. Comment. This case is characterized clinically
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Metastases in benign mole and chorioadenoma destruens 1417
by the absence of trophoblastic disease in the uterus in spite of the concomitant metastatic lesions in the vaginal wall and the lungs, and spontaneous retrogression of lung lesions after hysterectomy and the removal of the vaginal and urethral lesions. Case 10. C. R . P. was a native of Taiwan, aged 34, gravida xi, para x. On Nov. 29, 1954, she had had an abortion of a hydatidiform mole followed by curettage. Because of long-standing vaginal bleeding, she was subjected to repeat curettage on May 17, 1955, but the bleeding did not diminish. Allegedly, prior to the first curettage she had already noted on occasion blackish bloody sputum, which persisted up to the time of admission. Pelvic examination revealed an anteverted, slightly enlarged uterus, enlarged adnexa, and slight bleeding from a dilated external os. On the anterior vaginal wall, to the left of the urethral meatus, there was a blackish nipplelike nodule about the size of a peanut. X-ray film of the chest disclosed numerous round shadows over the whole field of both lungs. Frog tests were positive with 0.5 c.c. of urine and negative with 0.1 c.c. The nodule below and lateral to the urethral meatus was removed and found on microscopic examination to be a metastatic chorioadenoma destruens. After removal of the tumor on the anterior vaginal wall on May 18, a tiny blackish spot was noted immediately beneath the urethra and it regained the size of the original tumor by May 24. Simple panhysterectomy and bilateral adnexectomy were performed. Pathologic examination revealed a chorioad enoma destruens with only a few fading villi and marked trophoblastic proliferation (Fig. 5).
Fig. 5. Case 10. Chorioadenoma destruens, showing marked trophoblastic proliferation with a fading villus.
Fig. 6A. Uterine curettings showing molar villi with little trophoblastic proliferation.
Fig. 68. Uterine curettings showing an area with a moderate degree of trophoblastic proliferation. She remained well after the operation till one evening, after reaching home from a movie, she had a sudden attack of severe headache and vomiting and soon lapsed into unconsciousness and Cheyne-Stokes respiration. She died soon afterward. No autopsy was permitted. Comment. This is one of the 2 cases in our series where the patient apparently died from brain metastases which, however, could not be confirmed because of the denial of an autopsy. This case is of importance because of a choice of two interpretations, namely: ( 1) if we assume this to be a case of chorioadenoma destruens because of the presence of villi, then the death of this patient would indicate that a benign tumor can cause death from a mechanical accident; (2) the multiple metastases, on the other hand, might justify the assumption that this was a choriocarcinoma, rather than chorioadenoma destruens, and, further, that the presence
1418 Hsu, Huang, and Chen
of a few fading villi "ferreted out" by unremitting search does not necessarily rule out the possibility of choriocarcinoma.
An additional case. In the course of preparing this manuscript, an interesting case, that of a 24-year-old nullipara, came to our attention. A diagnosis of hydatidiform mole with possible lung metastasis was established by us on July 8, 1961, when she was in the second month of gestation. Her secont! visit on November 23 showed the uterine fundus to be 20 em. above the symphysis, consistent with the gestational age of 7 months. Bloody sputum and signs of toxemia were present. Chest x-ray showed a pigeon egg-sized mass in the left parahilar region and a suspicious shadow in the right base. After curettage on November 23, the signs of toxemia disappeared but the pulmonary lesions remained unchanged. The histologic examination revealed hydatidiform mole with some trophoblastic proliferation and decidua showing necrosis (Figs. 6A and 6B). The patient remained well until Dec. 22, 1961, when she suddenly became unconscious while she was eating dinner and in a cheerful mood. She died at midnight in spite of emergency treatment, apparently of cerebral metastasis of a benign lesion. Comment
Syncytial embolism (trophoblastic deportation) in normal pregnancy. In his historically famous monograph published in 1893, Schmorl 11 described embolic syncytium in the lungs of 14 of 17 patients with fatal eclampsia and his subsequent observations18-20 strongly indicated the pathogenetic relations between "placental embolism" and eclampsia, which were also observed by Lubarsch10 and Leusden.U However, Kassjanow9 could not find any significant difference between normal and eclamptic pregnancy, and postulated that "placental embolism" was an ordinary physiologic occurrence during gestation, an assertion which probably gives him credit for priority in the elucidation of this concept. The term "deportation" was coined in 1901 by Veit,Z 3 who found villi apparently free and floating within the maternal veins in a case of ectopic pregnancy. He took the position that deportation was a normal proc-
Dt·<'"mb"' 1. Am.
J.
196~
Ob>t. & Gyncc.
ess occurring during any and all pregnancies with particularly marked frequency in gestational disorders. Bardawil and Toy1 reported 57 cases of definite trophoblastic embolism in 109 maternal deaths in Boston Lying-in Hospital. Syncytial embolism in normal pregnancy is now generally accepted as a common event with no serious implications.1 Metastasis in hydatidiform mole. Published reports of emboli composed of molar vesicles are not rare. Early in 1896, Neumann13 reported myometrial deportation in a case of mole and then in 1900 Poten and Vassmer16 described an early syncytioma with metastasis in hydatidiform mole. In 1905 SchmorP 9 • 30 also observed 3 cases involving syncytial transport to the lung in molar pregnancy. In 1923, Miller 12 presented the history of a girl of 18 who had succumbed to fatal hemorrhagic shock. At autopsy tumor nodules were found in the lung, bladder, and vagina. The lungs contained large syncytial cells enveloped in a granulomatous reaction as well as encysted molar villi. The vaginal wall was invaded by chorionic tissue with villi but none was observed in the vessels. Although in the uterus only typical mole was found, the final diagnosis was invasive mole. In Novak's15 series, 6 cases (CR 31, 42, 65, 113, 154, and 259) showed pulmonary nodular densities which were interpreted by radiologists as probable metastatic growths. In CR 113, metastasis to the spine and, in CR 154, metastasis to the femur were noted besides pulmonary metastasis. Bardawil and Toy1 described a case of hydatidiform mole in a 21-year-old nullipara, who died of cerebral hemorrhage. At autopsy, however, no trophoblastic cells were found in the cerebral hemorrhage, but the pulmonary hemorrhagic mass contained molar vesides and a number of discrete trophoblastic cells within small vessels. A case observed by Coe and Read was also cited by them, who considered it a textbook example of villous deportation of hydatidiform mole in the lungs. The patient snrvived after hysterectomy and thora-
Volume 84 Number 11, Part l
Metastases in benign mole and chorioadenoma destruens 1419
cotomy. Recently Tran Dinh-De and Hoang Ngoc Minh22 reported a case of hydatidiform mole with recurrent vaginal metastasis. In our series, metastases were found in 2 cases whiie the moles were still in the uterus, in 2 cases with negative findings in the uterus after abortion of moles, in 2 cases sometime after evacuation of moles, and in one case after an interval following hysterectomy for the mole. Unfortunately, pathologic examination was confined to the curettings in 2 cases (Cases 1 and 6), and in 2 more (Cases 4 and 12) no destructive mole in the uterus was demonstrable on gross examination; these specimens were not made available for pathologic examination. In Case 13 a huge amount of molar vesicles was observed grossly by the gynecologist. In only 2 cases (Cases 2 and 7) was histologic examination of the extirpated uteri performed. Five cases were therefore categorized as benign moles failing pathologic examination of the uterus, since, strict~y following Ewing's definition, no diagnosis of chorioadenoma destruens can be made without pathologic examination of the uterus. 3 • 6 Tran Dinh-De and Hoang Ngoc Minh 22 also categorized their case under hydatidiform mole without hysterectomy. It should be noted, however, that despite his strong opposition to Novak's diagnosis of chorioadenoma destruens made from curettings without uterus, Greene 3 categorized 4 cases as chorioadenoma destruens without hysterectomy, merely on the basis of the vaginal or vulvar metastases. If we assume that infiltration may have occurred at some site in the uterine wall which had evaded clinical or pathologic examination, our cases might also be included in the category of chorioadenoma destruens. Metastasis in chorioadenoma destruens. Before this topic is discussed, brief allusion should be made to moot points concerning the diagnosis of trophoblastic diseases. The term "chorioadenoma destruens" was first proposed by Ewing in 1910 and was meant to include moles that invade the uterine wall and/or metastasize and still maintain their villous structure. 3 As to whether this diag-
nosis can be made by pathologic examination of curettings rather than from examination of the entire uterus, there is a divergence of opinion between Novak and Greene. Novak15 stated, "When trophoblastic overgrowth is unduly exuberant the lesion may be designated as chorioadenoma destruens, although this criterion of the latter lesion is not so reliable as that of perforation of the uterine wall or infiltration of parametrium and/or vagina." Thus diagnosis can be made from curettings only. 3 Actually, in the material cross-filed in the Mathieu Registry as chorioadenoma destruens, 2 such specimens are included. 3 Greene, in opposing this proposition, agreed with Novak on only one of the 2 cases, i.e., that in which the myometrium included in the curettings showed obvious invasion. Since metastasis can occur in both benign and malignant moles (chorioadenoma destruens) the only means of distinguishing between the two lies in the pathologic findings in the uterus. Whether or not the invasion of the uterus by moles, i.e., chorioadenoma destruens, can be deduced simply from the presence of metastasis, omitting pathologic examination of the uterus, as Greene 3 did, is debatable. A further argument between the authorities concerns the question of whether a definite line can be drawn between chorioadenoma destruens and choriocarcinoma, on the basis of the presence or absence of villous structure, as has been proposed by Meyer and Novak, as a conclusion derived from the retrospective pathologic and clinical study of a large number of cases. The consensus of modern pathologists seems to be that chorioadenoma
destruens is characterized by the maintenance of villous structure in the primary or metastatic lesion, whereas choriocarcinoma is devoid of villi. Novak14 was of the opinion that the finding of well-formed villi justified one in at least leaning away from diagnosis of choriocarcinoma, but he did not believe that occasional finding of villi should exclude this diagnosis. Therefore he categorized the fatal case, CR 139, under choriocarcinoma despite the presence of villi. This
1420 Hsu, Huang, and Chen
is in some conflict with his statement15 that malignancy as it occurs in trophoblastic lesions is determined by the microscope, and not by the clinical course. Greene, however, considered as correct the designation of this case (CR 139) as chorioadenoma destruens since villi were present in the lesions in the uterine wall. One of us (T. Y. C.) 2 insisted in a previous paper that, on the basis of his material, the presence of villi in invasive or metastasizing trophoblastic diseases precludes the possibility of choriocarcinoma. In opposition to this view we must quote Hertig's statement6 to the effect that occasionally both an invasive mole and a true choriocarcinoma exist in the same uterus and the patient may die from the metastases of the choriocarcinoma. So far as the metastasis in chorioadenoma destruens is concerned, the 32 cases reported by Hertig 5 showed no metastases. In spite of his opinion that chorioadenoma destruens has little tendency to distant metastasis, Novak 14 believed in the possibility of pulmonary metastasis with chorioadenoma (CR 202) or, for that matter, with even hydatidiform mole. Wilson 25 reported a high incidence (60 per cent), i.e., 12 instances of lung metastases in a series of 20 cases of chorioadenoma destrucns. Obera collected 7 cases of proved metastases ( 4.9 per cent) out of 142 of chorioadenoma destruens culled from 4 series in the literature and concluded that chorioadenoma rarely metastasizes. Out of 42 cases of Greene's collection from the Mathieu Registry, 6 had metastases in the vulva and/or vagina and 6 in the lungs (28.6 per cent). In Wei's 24 series metastases were seen in 3 of 12 cases of chorioadenoma destruens ( 25 per cent). In our series no diagnosis of chorioadenoma destruens was made from curettings, but only from the removed uterus. Thus, metastases were found in 5 of 7 cases of chorioadenoma destruens. From CR 202 in Novak's series, 14 it is evident that some of our cases of benign mole should have been classified under chorioadenoma destruens had pathologic examination of the uterus
December 1, 1962 Am.]. Obst. & Gynec.
been carried out. The frequency of metastasis in one series, however, cannot be used to generalize on the incidence of metastasis in chorioadenoma destruens, since our hospital is heavily weig'hted with unusual or severe cases referred by other specialists. Implication of metastases. Ober3 does not consider the so-called vaginal metastasis as a sign of malignancy but feels that it is the result of a permeation of dependent venous channels by intravascular trophoblast and that true infiltration of maternal tissue rarely occurs. Likewise, x-ray evidence of pulmonary metastasis in cases of chorioadenoma may be due to a reaction in the lung tissues around embolic trophoblast with or without villi, but not necessarily to trophoblast invading the maternal lung tissues. According to Tran Dinh-De metastasis of trophoblastic cells to the vaginal wall associated with moles, as in their case, is generally accepted as retrograde venous embolization of trophoblast, rather than autonomous secondary deposits. Paten and Vassmer16 were of the opinion that deportation per se did not necessarily connote malignancy. Wilson 25 stated that in the past patients have been given a hopeless prognosis because of the presence of metastases, but on the basis of his results this is not indicated until thorough examination of the tissues from the pelvis, and, if necessary, from the lung or other metastatic sites shows the absence of villi in the trophoblastic tissue in all locations. Hitschmann 4 stated that pulmonary metastasis appears clinically to simulate pulmonary infarction and considered it necessary to determine through biologic tests whether proliferative elements are present in the embolus. Mortality rate of chorioadenoma destruens. Novakl 4 reported 6 deaths in 26 pathologically authenticated cases of chorioadenoma destruens. Wilson 25 reported no deaths in 20 cases, Greene 3 6 deaths in 43, Hertig 5 one death in 32, and Little 3 one death in 21 cases of chorioadenoma destruens. Park and Lees3 reported 17 deaths out of 47 cases of chorioadenoma destruens
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Metastases in benign mole and chorioadenoma destruens 1421
tabulated from the literature. ·When discussing Greene's paper, applying his rigid criteria to the above-mentioned four series (exclusive of Novak's), Ober3 estimated 25 deaths ( i i .6 per cent), two thirds of which, however, were those which Park and Lees summarized from the literature and many of them date back to the period when hemorrhage and sepsis were treated less effectively than they are today. In our series, one sudden death of a completely healthy woman occurred in the postoperative period and the other death was that of a patient who survived 3 years after hysterectomy. Besides these, because of profuse intra-abdominal or vaginal hemorrhage and/ or sepsis, 3 patients were on the verge of death from profound shock, and might not have survived without a modem blood bank, antibiotics, and adrenal hormones. The nature of chorioadenoma destruens and its treatment. There is considerable divergence of opinion regarding the nature of chorioadenoma destruens. Smalbraak 21 considered it not to be an adenoma, and rejected the term "chorioadenoma" in favor of the older designation "destructive hydatidiform mole." Others believed it is a locally destructive benign tumor of chorionic epithelium and designated it as "chorioadenoma destruens." However, Greene considered the over-all mortality of 14.3 per cent to be rather high for a lesion whose name implies benignancy. Ober 3 stated that the mere fact that a patient with chorioadenoma dies of the disease does not mean that it is truly a malignant tumor, because death can occur with benign tumors in other situations. Nevertheless, basing his case on the mortality rate, possible sepsis, and hemorrhage, he regarded chorioadenoma as a dangerous disease requiring hysterectomy. Tran Dinh-De stated that chorioadenoma destruens is not necessarily malignant, and, concurring with Novak and Seah's policy, expressed the view that hysterectomy would not be justified unless repeat curettage showed a more highly suspicious malignant change with a broad field of trophoblasts and no villi.
Fig. 7A. Case 1. Uterine curettings showing an area with marked, the most pronounced in this case, trophoblastic proliferation.
Fig. 7B. Case 1. Uterine curettings showing degenerated villi with least trophoblastic proliferation.
The famous case of Delfs14 of benign hydatidiform mole resulting in death from lung and ultimately spinal cord metastasis, the case cited by Bardawil and Toy of a hydatidiform mole occurring in a 17 -yearold white girl who suddenly died from cor pulmonale as a result of syncytial emboli which filled the smaller pulmonary vessels despite typical moles fi.iling the uterus, and probably our Cases 2 and 10 indicate the possibility of benign trophoblastic disease causing the death of the host. Death in these cases may be due not to invasion or the metabolic derangement resulting from malignancy, but to mechanical factors . On the basis of our experience with occasional severe hemorrhage and sepsis, we are inclined
1422 Hsu, Huang, and Chen
Fig. SA. Case 6. Uterine curettings showing several rather fibrotic villi without remarkable trophoblastic proliferation.
Fig. 8B. Case 6. Vaginal metastasis showing a long fibrotic villus with little trophoblastic proliferation.
Fig. 9. Uterine curettings from Patient C. H. F., showing a large mass of trophoblastic cells without villous structure around it, which is often incorrectly diagnosed as choriocarcinoma.
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to perform hysterectomy for this disease, particularly on multiparas who do not want further children. Relation of trophoblastic activity to metastasis. Hertig and Sheldon, 5 in recommending a routine study from at least 5, preferably 10, regions, classified the moles of their collection into six groups and claimed a marked but not absolute correlation between the degree of apparent molar activity and the tendency of the patient to develop a possibly fatal chorionic lesion. In their study to confirm Hertig's findings, Hunt, Dockerty, and RandalF concluded that the results of such analysis were not conclusivt enough to determine definite treatment, and careful observation of the clinical course of the patient following evacuation of a mole was considered more important than histologic study. Smalbraak 21 stated the opinion, based on his material, that the practical value of a classification of moles designed to serve as a guide in the treatment of patients proved disappointing. In disagreeing with Hertig's proposition, Novak 15 maintained that the histologic characteristics varied in different parts of the mole, change being greater when it is nearest the uterine wall or occurs as an implant within it, and less when the mole grows away from the uterine wall and its source of blood supply. However, he considered that Hertig's current division of cases into apparently benign, potentially malignant. and apparently malignant was a more logical one. Edmonds 3 was of the opinion that overemphasis on morphologic grading is misleading. Grady 3 testified to the difficulty of classifying moles into six groups on the basis of histologic structure, but subscribed to the belief that a grouping of three based on quantity and appearance of covering trophoblast is possible, in that it would at least give a rough approximation of the risk of subsequent choriocarcinoma. Greene has shown that his grading of the trophoblast of the invasive moles in his series did not tally with the molar aggressiveness evidenced by perforation, deportation, or death. In our two cases of hydatidiform mole
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Metastases in
(Cases 1 and 6), where metastasis was seen, no particular trophoblastic activity was proved (Figs. 7A, 7B, 8A, and 8B). On the other hand, Patient C. H. F. in our 1956 series8 showed abnormally high gonadotropin titer (3.2 million frog units), high estrogen excretion ( 178 to 1,000 p,g per day) and a histologic pattern consistent with Hertig's type VI, malignant (Fig. 9), for which the pathologist strongly advised hysterectomy. Because the patient was still anxious to have more children, only curettage was performed. She is living and well, having had 2 more children in the meantime. Our experience seems also to substantiate negative correlation between the aggressiveness of the moles and their histologic grading. Site of metastases. Physiologic metastases occur more frequently in the lungs than in the vulva or the vaginal mucosa. 22 In Wilson's 20 cases of chorioadenoma destruens, 8 exhibited metastasis to the lungs, 2 to the vagina, and 2 to the retroperitoneum. In Greene's series, 6 metastasized to the lungs and 6 to the vulva and/or vagina. In our series, 8 metastasized to the vagina and 3 to the lungs. In 2 cases metastases were detected in both lungs and the vagina. Very interestingly, metastasis was discovered after operation in the inguinal node, mesosalpinx, and possibly the endocervix. It is not clear whether or not the predominance of vaginal metastases over lung metastases in our series
beni~.. mole
and chorioadenoma destruens 1423
can be related to a racial peculiarity in the anastomosis between the uterine and vaginal blood vessels.
Summary
1. A series of cases of benign hydatidiform mole and chorioadenoma destruens showing a high incidence of metastasis has been presented. In sharp contrast to other series, a majority of metastases were found in the vagina and in the vicinity of the urethral meatus. 2. The results of this study and of others in the literature strongly indicate that the old belief that a trophoblastic lesion possessing villous structure would rarely metastasize, no longer hoids true. 3. All of our patients except 2 are living and well, despite the presence of metastases or conservative therapy in some. Metastases to the vagina and/or lungs in this small series has not had a hopeless implication. 4. The fatal cases in the literature, combined with 2 of our own, indicate the uncertainty of the correlation between the clinical course and histopathologic findings in the trophoblastic diseases. 5. Because of the vagaries of trophoblastic disease and the potentially malignant nature of hydatidiform mole, the sacrifice of the uterus may be in the interest of the patient when no further childbearing is desired.
REFERENCES 1. Bardawil, A., and Toy, B. L.: Ann. New York Acad. Sc. 80: 197, 1959. 2. Chen, T. Y., Pen, T. L., and Yeh, S.: Reports, Institute of Pathology, National Taiwan University, Special Issue in Commemoration of Its Tenth Anniversary, No. 8, p. 57, June, 1957. 3. Greene, R. R.: Ann. New York Acad. Sc. 80: 143, 1959. 4. Hitschmann, F.: In Halban, J., and Seitz, L., editors: Biologie und Pathologie des Weibes, Berlin, 1928, Urban & Schwarzenberg, Band VII, p. 535. 5. Hertig, A. T., and Sheldon, W. H.: AM. J. 0BST. & GYNEC. 53: 1, 1947. 6. Hertig, A. T.: Seminar on Tumors of the Gynecologic System, Proceedings, Eighteenth Seminar of the American Society of Clinical
7. 8.
9. 10. 11. 12.
Pathologists, Oct. 17, 1952, published by the American Society of Clinical Pathologists, Chicago, 1953, p. 43. Hunt,- W., Dockerty, M. B., and Randall, L. M.: Obst. & Gynec. 1: 539, 1953. Hsu, C. T., Lin, C. T., Lai, Y. H., and Ma, Y. M.: Racial Peculiarities in Obstetrics and Gynecology, Asiatic Congress of Obstetrics and Gynecology, published by the Japanese Obstetrical & Gynecological Society, Tokyo, 1957, p. 160. Kassjanow: Inaugural Dissertation, St. Petersburg, 1896, cited by Bardawil & Toy.l Lubarsch, 0.: Fortschr. Med. 11: 845, 1893. Leusden, P.: Virchows Arch. path. Anat. 142: 1, 1895. Miller, J.: Edinburgh M. J, Suppl. 217, 1923-1924.
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13. Neumann, J.: Monatsschr. Geburtsh. u. Gyniik. 3: 387, 1896. 14. Novak, E., and Seah, C. S.: AM. J. 0BST. & GYNEC. 67: 933, 1954. 15. Novak, E., and Seah, C. S.: AM. J. 0BsT. & GvNEC. 68: 376, 1954. 16. Poten, W., and Vassmer, W.: Arch. Gyniik. 61: 205, 1900. 17. Schmorl, C. G.: Pathologisch-anatomische Untersuchungen iiber puerperale Eklarnpsie, Leipzig, 1893, Vogel. 18. Schrnorl, C. G.: Arch. Gyniik. 65: 504, 1902. 19. Schmorl, C. G.: Verhandl. deutsch. path. Gesellsch. 8: 39, 1905.
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J.
20. Schmorl, C. G.: Zentralbl. Gyniik. 29: 129, 1905. 21. Smalbraak,
J.: Ann. New York Acad. Sc. 80: 105, 1959. 22. Tran Dinh-De and Hoang Ngoc Minh: AM. J. 0BST. & GvNEC. 82: 660, 1961. 23. Veit, J.: Ztschr. Geburtsh. u. Gynak. 44: 466, 1901. 24. Wei, P. Y., Ouyang, P. C., and Peng, T. L.: Reports, Institute of Pathology, National Taiwan University, No. 8 p. 29, 1957. 25. Wilson, R. B., Hunter, J. S., and Dockerty, M. B.: AM. J. 0BST. & GYNEC. 81: 546, 1961.