GYNECOLOGIC ONCOLOGY 28, 330-336 (1987)

Clinical Problems of Invasive Hydatidiform Mole in Patients Aged 40 or More

KOJI KANAZAWA, M.D., TAKAAKI SUZUKI, M.D., MOTOI SASACAWA, M.D., AND SHOSHICHI TAKEUCHI, M.D.

Department of Obstetrics and Gynecology, School of Medicine, Niigata University, Asahi-Machi-Dori-l-757, Niigata City, Japan

Received May 27, 1986

Seventy-six patients with invasive hydatidiform mole (HM) were reviewed as to clinical course, particularly treatment and outcome, in relation to their age. The results were as follows: (i) metastatic cases showed approximately a twofold increase in patients over 40 compared with younger patients, (ii) more courses of chemotherapy were required to achieve a cure in patients over 40 than in younger patients and (iii) 4 of I9 patients (21.1%) over 40 developed choriocarcinoma. whereas none of younger patients did. o 19x7 Academic

Press. Inc.

In recent years, the majority of authors of various clinical and basic investigations seem to agree that hydatidiform mole (HM) is a benign lesion, whereas chorio- carcinoma is a malignant tumor that can develop after all kinds of pregnancy [l]. It is well known that the incidence of conceptual abnormalities, such as spontaneous abortion and HM, is high in the pregnancies of older women [2- 41. Furthermore, there are several reports which suggest that HM, when it occurs in older patients, includes invasive HM at a relatively high incidence [2,51. It is still unclear whether HM, especially invasive HM, is a true neoplasm or a variant of missed abortion [6-81. However, invasive HM is assumed to be a risk lesion for choriocarcinoma, because molar trophoblast has a greater chance of persisting in a maternal host than in noninvasive HM. The current study was undertaken to clarify the clinical problems involved with invasive HM in older patients. Seventy-six patients with invasive HM, picked through the registration system for gestational trophoblastic disease in our prefecture, were analyzed as to clinical course, particularly treatment and outcome, in relation to their age.

MATERIALS AND METHODS

Patients. During a 14-year period from 1971 through 1984, 1839 patients with HM were reported to the registry of Niigata Prefecture, an area located in the northern part of Japan that has a population of about 2,500,OOO. The annual registration rate of the system was documented to be almost 100%. Of 1839 patients, 111 were recorded as invasive HM according to the diagnostic criteria

330

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INVASIVE HM IN PATIENTS OVER 40 331

TABLE 1 INCIDENCE OF METASTASTIS IN INVASIVE HM

Age group: 20s 30s 40s Total

Invasive HM 42 15 19 76 Nonmetastatic 29 10 8 47 Metastatic 13 (30.9%) 5 (33.3%) 11 (57.9%) 29 (38.2%)

a Including one case of vaginal metastasis.

outlined below. This study dealt with 76 of the 111 registered invasive HM patients who were referred to and treated at Niigata University Hospital.

Diagnosis of Invasive HM. Of 76 subjects, three cases were hysterectomized at the state of “mole in utero” and confirmed to have invasive HM by histological evaluation of the surgical specimen. The other 73 cases, who had undergone evacuation of intrauterine molar tissue as the first step of treatment, were clinically suspected of having invasive HM by the prolonged regression pattern of urinary and/or serum human chorionic gonadotropin (HCG) after evacuation and by the existence of unequivocal abnormal shadows in the uterine wall imaged by pelvic angiography (PAG), ultrasonography (USG), and/or computerized tomography (CT). As the next step of treatment, 47 of these 73 cases received hysterectomy or focal excision of myometrial deposits for their disease within 6.5 months, and all of them were proven to have invasive HM by histopathological examination of the extirpated specimen. The remaining 26 cases had the disease, designated as invasive HM as diagnosed by clinical observation but not confirmed by his- tological examination, since they did not receive any surgical manipulation but evacuation only.

RESULTS

Incidence of Metastatic Patients in Invasive HM (Table 1)

Seventy-six subjects with invasive HM were divided into three age groups, 20s 30s and 40s with 42 cases under 30 years of age, 15 between 30 and 39, and 19 over 40. As shown in Table 1, the incidence of metastatic patients was observed to rise steeply in the 40s showing an approximately twofold increase compared with the other age groups. Sites of metastatic involvement were the lungs in 28 cases and the vagina in 1.

Modality of Treatment for Invasive HM (Table 2)

The treatments applied to the 76 patients are summarized according to age group in Table 2. Among the 42 patients in their 20s hysterectomy was performed in 2, while in 19 focal excision was performed for myometrial molar deposits persisting after evacuation of molar tissue in the uterine cavity with the intention of retaining patients’ uteri. Seventeen of these patients were also given che- motherapy before and/or after operation. The remaining 21 cases were treated with chemotherapy alone, since hysterectomy or focal excision was not indicated for their myometrial deposits by size and/or location in the uterine wall. In

332 KANAZAWA ET AL.

TABLE 2 MODALITY OF TREATMMENT FOR INVASIVE HM

Age group: 20s

Invasive HM 42 Hysterectomy S chemotherapy 2 Hysterectomy C chemotherapy 0 Focal excision S chemotherapy 2 Focal excision C chemotherapy 17 Chemotherapy alone 21

30s 40s Total

I5 19 76 5 5 12 4 12 16 2 0 4 1 0 18 3 2 26

contrast, among the 19 patients in their 40s group, hysterectomy was performed in 17 and only 2 were treated with chemotherapy alone. It was noteworthy that neither of the 2 hysterectomized patients in their 20s needed chemotherapy, whereas 12 of 17 hysterectomized patients in their 40s did. Among the 15 patients in their 30s surgery and/or chemotherapy were carried out with a treatment modality that was transitional between those used in the other two groups.

Thus, almost all 76 patients were successfully cured. To date, 72 of these patients have been free from any secondary sequalae of trophoblastic disease, but 4 have suffered from subsequent choriocarcinoma, as described later.

Chemotherapy for Invasive HM (Table 3)

As shown in Table 3, chemotherapy with a single use of methotrexate, acti- nomycin D, or etoposide was performed in 60 of 76 patients with invasive HM, an overall rate of 78.9%. In the group in their 2Os, chemotherapy was given in 38 of 42 patients (90.5%). The finding suggested that chemotherapy played a central role in the treatment strategy for the group in which hysterectomy was not advised in order that patients could retain their uteri. On the other hand, for the group in their 40s chemotherapy was unavoidable in 14 out of 19 patients (73.7%), in spite of the fact that 17 hysterectomized cases were included in the group. It appeared that these unexpected results could be attributed to the high incidence of patients in the group who were metastatic and/or had persistent abnormal elevation of HCG after hysterectomy.

TABLE 3 CHEMOTHERAPY GIVEN IN PATIENTS WITH INVASIVE HM

Age Group: 20s 30s 40s Total

Invasive HM 42 Chemotherapy 38 (90.5%)

One course 6 Two courses 17 Three courses 8 Four courses- 7

Average 2.4 No chemotherapy 4

I5 19 76 8 (53.3%) 14 (73.7%) 60 (78.9%)

2 0 8 1 5 23 4 0 12 1 9 17

2.8 4.0 7 5 16

INVASIVE HM IN PATIENTS OVER 40 333

With regard to the number of courses of chemotherapy needed to cure patients, the average of 4.0 courses was given to those in their 4Os, compared with 2.4 and 2.8 for those in their 20s and 30s respectively (Table 3). Here it was easy to speculate that the metastatic patients received more chemotherapeutic courses to achieve their cure than the nonmetastatic patients. The patients in their 40s included a high incidence of metastatic cases, as mentioned above. For this reason, the number of courses of chemotherapy required in the metastatic patients, consisting of 13 in their 2Os, 5 in their 3Os, and 11 in their 4Os, was investigated. The average of 3.6 courses for the older group was revealed to be more than 2.6 and 2.8 for those in their 20s and 30s respectively. Thus, it was seen that invasive HM occurring in patients aged 40 or more was relatively resistant to chemotherapy compared with that in younger patients.

Choriocarcinoma after Invasive H&l (Table 4)

Of 76 patients with invasive HM in the present series, to date 4 have suffered from secondary malignancy, that is, choriocarcinoma, an occurrence rate of 5.3%. Their clinical data are summarized in Table 4. It was noteworthy that all 4 patients had experienced invasive HM and belonged to the over-40 age group. Alternatively, 4 out of 19 patients in the over-40 group developed choriocarcinoma, an occurrence rate of 21.1%. Moreover, three patients (cases T.E., I.Ta., and I.To.) had acquired pulmonary metastatic lesions of invasive HM; case A.Y. was also suggestive of pulmonary metastases of invasive HM which had not been detectable clinically, since choriocarcinoma was located only in her lungs. Thus, the significant point common to these 3 cases, who all belonged to the over-40 age group, was that they had once had metastatic invasive HM as an antecedent pregnancy to choriocarcinoma.

The incubation time, which was here defined as the interval between the end of preceding HM and the clinical manifestation of choriocarcinoma, was documented to range from 18 to 50 months in these patients. In regard to sites of involvement of choriocarcinoma, pulmonary lesions were detected radiographically in all four patients and uterine lesions were found in one. Three patients have achieved a state of remission but one died from systemic extension of the disease.

DISCUSSION

Invasive HM is differentiated from noninvasive HM by the existence of pen- etration of molar trophoblast into the myometrial tissue of the maternal host. Myometrial invasion of molar trophoblast should be verified by histopathological examination of surgical specimens. Clinically, the existence of myometrial lesions is recognizable when molar patients show abnormal shadows in the uterine wall by PAG, USG, and CT, in addition to the prolonged regression curve of HCG after molar evacuation. In the present series, all 47 patients who were submitted to surgery after clinical diagnosis of myometrial disease were shown to have invasive HM histopathologically. This fact indicates that the diagnosis of invasive HM could be made with high accuracy by prudent analysis of clinical findings.

Although the biological nature of invasive HM still remains unsolved, recent advances in clinical and fundamental investigations on trophoblastic disease seem

TABL

E 4

CHOR

IOCA

RCIN

OMA

FOLL

OWIN

G IN

VASI

VE

HM

IN

THE

CURR

ENT

SERI

ES

Cas

e

Y.E.

Age”

47

Parit

y

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gnos

is

Met

asta

tic

Inva

sive

HM

A.Y.

48

8G

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ITa.

53

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lP

I.To.

43

lO

G3P

Non

-Met

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tic

Inva

sive

HM

M

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In

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ve

HM

Met

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Inva

sive

HM

Trea

tmen

t fo

r In

vasi

ve

HM

Evac

uatio

n H

yste

rect

omy

Che

mot

hera

py

Evac

uatio

n H

yste

rect

omy

Hys

tere

ctom

y C

hem

othe

rapy

Ev

acua

tion

Che

mot

hera

py

Incu

batio

n Ti

me”

Si

tes

of

dise

ase’

O

utco

me

x 49

Lu

ng

Rem

issi

on

5;

2

32

Lung

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emis

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50

Lung

18

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rus

Rem

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on

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ed

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n Ag

e at

dia

gnos

is of

inv

asiv

e HM

. ’

Inte

rval

in

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ths

betw

een

the

end

of p

rece

ding

HM

an

d th

e cli

nica

l m

anife

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ion

of c

horio

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wi

th

chor

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- _

- _

- -

-

INVASIVE HM IN PATIENTS OVER 40 335

to stress that invasive HM is a benign nonneoplastic condition [l]. The results of treatment and follow-up in Ringertz’s series [2] and in our current series attest to a pronounced difference in prognosis between invasive HM and choriocarcinoma since all but one patient with invasive HM in both series were successfully cured. Kato et al. [7] studied the behavior of trophoblastic disease following transplantation into athymic immunosuppressed nude mice. They observed that molar tissue of both noninvasive and invasive HM became avascular and atrophic after trans- plantation and thus did not behave like a trophoblastic neoplasm, that is, cho- riocarcinoma, which exhibited tumorigenicity with successful serial transplantation. Furthermore, one of the authors (M. S.) [g] demonstrated by immunohistochemical analysis that invasive HM resembled noninvasive HM rather than choriocarcinoma in terms of morphology and regularity in expression of human lymphocyte antigen (HLA) of trophoblast.

It has been described in several reports [2,5] that HM occurring in older patients shows a high incidence of invasive HM. However, the data reported by Ringertz [2] and Tsukamoto et al. [5] were not sufficient for elucidation of the possibility because they dealt with a small number of patients and did not clearly distinguish invasive HM from choriocarcinoma in their studies. The data obtained in this study may support theirs, because of a considerable amount of evidence indicating that invasive HM develops at a higher incidence in older HM patients than in younger ones. In addition, our study showed that, in patients with invasive HM, the incidence of metastatic cases increased with age; this was most striking in the over-40 group. Thus, in HM which occurred in older patients, molar trophoblast seemed to have a strong tendency to invade the myometrium and to metastasize hematogeneously. It is conceivable that some chronological changes in interaction between the biological activity of molar trophoblast and the defense mechanism of maternal host lead to local and systemic extension of the disease. Such a condition, which is assumed to occur in older HM patients, also appears to be reflected in the observation that invasive HM in patients aged 40 or more requires more courses of chemotherapy to obtain a cure than in younger patients.

Focal or local excision of myometrial deposits in invasive HM was described in 1961 by Wilson et ul. [9]. In principle, the operative procedure was employed in HM patients who wanted to conserve their uterus to maintain reproductive function. The advantages of the surgical modality of treatment are that a surgical specimen is available for correct diagnosis of invasive HM and that chemotherapy in which anticancer agents with mutagenic action are used is avoidable or reducible in the treatment of the disease. In the present study, all 22 patients who underwent operation were histologically proved to be affected by molar penetration in the myometrium. The operative procedure is not necessarily accepted, however, by the majority of authors since recent advances in chemotherapy for trophoblastic disease have yielded wide consensus that invasive HM is successfully and safely controllable with chemotherapy alone.

Finally, 4 out of 76 patients with invasive HM have suffered from subsequent choriocarcinoma. It should be stressed again that all 4 of these patients had once experienced invasive HM and were over 40 years of age; moreover, 3 had metastatic pulmonary disease. In other words, choriocarcinoma in these cases

336 KANAZAWA ET AL

was limited to those who had had invasive HM and were aged 40 or more. Consequently, invasive HM in older patients is considered to be an extremely high-risk lesion for subsequent choriocarcinoma. In this context, it is proposed that treatment for invasive HM should be carried out more thoroughly in older patients than in younger ones. In addition to this, follow-up after the termination of treatment should be continued carefully for early detection of choriocarcinoma following the disease, since molar trophoblast is presumed to tend to persist and undergo a malignant change in the maternal host.

REFERENCES 1. Takeuchi, S. Nature of invasive mole and its rational management, Semin. in Oncol. 9, 195-203

(1982). 2. Ringer& N. Hydatidiform mole, invasive mole and choriocarcinoma, Acta Obsfet. Gynecol.

Stand. 49, 195-203 (1970). 3. Wei, P. L., and Ouyang, P. C. Trophoblastic disease in Taiwan, Amer. J. Obstet. Gynecol. 85,

844-849 (1963). 4. Toeh, E. S., Dawood, M. Y., and Ratnam, S. S. Epidemiology of hydatidiform mole in Singapore,

Amer. J. Obstet. Gynecol. 110, 415-420 (1971). 5. Tsukamoto, N., Iwasaka, T., Kashimura, Y., Uchino, H., Kashimura, M., and Matsuyama, T.

Gestational trophoblastic disease in women aged 50 or more, Gynecol. Oncol. 20, 53-61 (1985). 6. Hertig, A. T., and Mansell, H. Tumors of the female sex organs. Part I. Hydatidiform mole and

choriocarcinoma, in Atlas of rumor pathology, Armed Forces Inst. of Pathol., Washington, DC (1956).

7. Kato, M., Tanaka, K., and Takeuchi, S. The nature of trophoblastic disease initiated by transplantation into immunosuppressed animals, Amer. J. Obsfer. Gynecol. 142, 497-505 (1982).

8. Sasagawa, M., Ohmomo, Y., Kanazawa, K., and Takeuchi, S. HLA expression by trophoblasts in invasive mole, Placenta, 8, 11 I-118 (1987).

9. Wilson, R. B., Hunter J. S., Jr. and Dockerty, M. B. Choriocarcinoma destruens, Amer. J. Obstet. Gynecol. 81, 546-559 (1961).