Roentgenologic manifestations of pulmonary metastases in choriocarcinoma and invasive mole

Roentgenologic manifestations of pulmonary metastases in choriocarcinoma and invasive mole

Roentgenologic manifestations of pulmon::.ry metastases in choriocarcinoma and invasive mole HUNG-CHAO SUNG PAO-CHEN WU MAO-HUA HU HSUEH-TSENG SU Pek...

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Roentgenologic manifestations of pulmon::.ry metastases in choriocarcinoma and invasive mole HUNG-CHAO SUNG

PAO-CHEN WU MAO-HUA HU HSUEH-TSENG SU Peking, China From 1949 to 1975, a total of 3,915 chest films were taken for 429 cases of choriocarcinoma and 441 cases of invasive mole. The incidences of pulmonary metastases were 85.1% and 65.0%, respectively. The various forms of pulmonary metastases were studied and correlated with clinical symptoms and pathologic changes. In order to follow up the progression or regression of the various forms, serial chest films were taken at intervals of 10 to 14 days in 27 cases. In eight cases postmortem pulmonary arteriograms were obtained on the autopsied lung specimens for the study of vascular changes of metastatic lesions. Pathologic examinations and pulmonary arteriography were also done on the surgically resected lung specimens. As a result of this study, a relative comprehensive knowledge about the nature and development of the various forms of metastatic shadows has been deduced. It is rational to say that the various forms seen on the chest films represent only the various evolutionary changes of the same lesion. (AM. J. OBSTET. GYNECOL. 142:89, 1982.)

CHORIOCARCINOMA is a highly malignant trophoblastic tumor characterized histopathoiogicaiiy by abnormal trophoblast and the absence of any residual villous structure, while invasive mole is a less malignant disease characterized by abnormal trophoblast and residual molar villous structure. Both conditions are manifested by early metastases, particularly metastasis to the lungs. Therefore, roentgenologic examination is a very important and useful procedure in clinical practice. The presence of pulmonary lesions helps in making a diagnosis, and the extent of lesions is an important indicator of the development of these diseases. Progression and regression of the pulmonary changes provide a sound basis for evaluating the therapeutic effect and prognosis. In follow-up of the recovered patients, x-ray examination again affords an important

means for detection of recurrence. Therefore, a detailed study of the roentgenologic manifestations of pulmonary metastases is needed both for clinicians and for roentgenologists. The work has been carried out in the Capital Hospital since I949, and a preliminary report was published in 1964. 1 Since then, more cases have been studied and the findings and evaluation are reported here. Material and methods

Reprint requests: H. C. Sung, Department!![ Obstetrics and Gynecology, Capital Hospital, Peking, People's Republic of China.

From I 949 to 1975, 429 patients with choriocarcinoma and 441 patients with invasive mole were admitted to the hospitaL A totai of 3,915 chest fiims were taken during this period with an average of 4.5 films per patient. All these films were meticulously reviewed and analyzed. The x-ray examination included posteroanterior views of the chest in the standing position and a lateral view if necessary. In order to follow-up the process of progression and regression of pulmonary metastases, serial chest films were taken at intervals of 10 to 14 days in 27 cases. If the patient had a recent x-ray film and died, lung specimens were taken during autopsy with reference to the x-ray pictures so as to study the basic pathologic changes of different forms of roentgeno-

0002-9378/82/010089+09$00.90/0 © 1982 The C. V. Mosby Co.

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From the Department a[ Obstetrics and Gynecology and the Department a[ Radiology, Capital Hospital. Chinese

Academy of l'.,1edical Sciences.

Received for publication june 2, 1981. Revised August 10, 1981. Accepted August 19, 1981.

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Fig. 1. Pulmo nary metastases of choriocarcinoma, patch\' form (both lower lungs) . Fig. 2. I' ulmonary me tastases of choriocarcinuma, nodular form ( ll/J/Nr ngh!J and cotton-ball ft~rm ( up{Jer it.fiJ with well-defined margins. Fig. 3. Pulmo narv metastases of choriocarcinoma , nodular fo rm and cotton-ball f(mn with ha11 margins (both lower lungs).

Fig. 4. Pulmonary metastases of choriocarcinoma , beading tmm (uppn lfj/i.

logic manifestations. In eight cases, postmortem pulmonary arteriograms were obtained on the autopsied lung specimens for the study of vascular changes in the vicinity of metastatic lesions . Pathologic studies and arteriography were also done on the surgically resected lung specimens. The diagnosis of each case was based on adequate clinical and hormonal evidence. In about 75% of the cases, the diagnosis was further confirmed by pathologic examination of surgically removed uteri, and

about 65(/r of the deceased patients underwent autopsy. The crite ria t()r pathologic differentiation of choriocarcinoma and invasive mole were based on the absence or presence of chorionic villi as proposed by Novak and Seah, 2 in 1954. When no pathologic specimen was available, differential diagnosis was made according to the nature of the antecedent pregnancy and, in pnstmolar cases, the time interval between evacuation of the mole and establishment of diagnosis of malignancy, as reported by us in 1967 .'1 In patients who

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Fig. 5. Pulmonary metastases of choriocarcinoma. miliary f(mn (right sidri and pneumothorax (left side).

Fig. 6. Choriocarcinoma with e nlargeme nt of right side of heart. A. Posteroanterior view. B, Left anterior-oblique.

developed malignancy after term pregnancy or abortion, the chance for choriocarcinoma was 9H.2~. If the antecendent pregnancy was a hydatidiform mole and the time interval after evacuation was within 5 months, the chance for invasive mole was 98 .6%, while if the interval was more than I year the chance of chorioca rcinoma was 89.9%. In cases with an interval of between 5 and 12 months, the chances of invasive mole and choriocarcinoma were almost equal, but for strict appraisal of the therapeutic results they we re analyzed in the category of invasive mole (a total of 57 cases). Before 1958, cases were treated mainly by ope ration with or without postoperative irradiation. Since 1958, chemotherapy in combination with operation has been the method of treatment. The chemotherape utic agents used were 6-mercaptopurine. 5-Huorouracil ,

KSM (a new antibiotic found in this country with a chemical structure quite similar to but not identical to that of actinomycin D), Tisupurine (a water-soluble derivative of 6-mercaptopurine), and Nitrocaphane (a deriYative of nitrogen mustard). These drugs were given either alternately or in combination for 8 to 10 days as a complete course. Treatment was continued until complete remission was achieved (i.e., total disappearance of symptoms and signs of the disease, normal human chorionic gonadotropin (hCG) determination, and complete resolution of pulmonary metastases as seen on the chest tilms). The patients were then followed up pe riodically. All 61H survivors were followed up tin at least 3 years . of which 520 (84.1%) were followed up for more than 5 years, 367 (59.4%) for more than 10 vears and 72 (I I .7%) for more than 15 years.

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71 Fig. 7A.P ulmonary metastases of an early case of malignant mole showing a homogeneous, translucent nodular opacity in th e first anterior intercostal space under the davide. Fig. 7B. Macroscopic view of the pulmonary metastasis of the same patiem, showing several ve.s ides of grain size inside a small cavity. Fig. 7C. Microscopic pictuJT of pulmonan metastasis nl the same patient. (Original magnihcation X 30.)

The therapeutic results of this series of cases have been reported in 1979. 4

Results Basic forms of x-ray manifestations. Choriocarcinoma. The basicforms might be divided into two categories. PATCHY FORM. The metastatic shadows looked like pieces of clouds scattered in the lung fields without any definite contour or shape (Fig. I). The amount of such changes varied from a small area to all over the whole lung field. They were quite difficult to differentiate from the infiltrative lesions of tuberculosis or atypical pneumonia in the absence of clinical hiswry and laboratory data. This form occm-red usually in early cases of choriocarcinoma. RouND FORM. The metastic shadows were round in shape and not very high in density, with either a hazy or well-defined margin. There was considerable varia-

tion in sit.es, distribution , and number of shadows 1\'ithin the lung lield. In correlation with clinical manifestations the round forms might be further divided into tlu-ee subgroups: (I) small size or nodular form. less than 3.0 em in diameter (Figs. 2 and:)); (2) medium size or cotton-ball form, 3 to 5 em in diameter (Figs. 2 and :3); C~) large size or tumefied form, greater than .~ em in diameter. In addition, some other manifestations were also seen nccasionally in the chest films prior to the appearance of the above forms: HEAVY Ll.' NG MARKIN(;s . In certain cases before the presenct of definite metastatic shadows, there a ppeared generalized increased lung markings. BEADING FORM AND DRUMSTI CK FORM. A series of small sacculations or dilatations seen along an increased lung marking giving rise to the appearance of a string of beads (Fig. 4) or an oval dilatation formed at the abrupt end of an increased lung marking.

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Fig. 8. Microscopic picture of the patchy shadow of pulmonary metastases of choriocarcinoma. (Origina l magnification x 100.) Fig. 9. Microscopic picture of round form (with hazy margins) of pulmonary metastasis of choriocarcinoma. (Original magnification xI 00.) Fig. 10. Microscopic picture of round form (with well-de fined margins) of pulmonary metastasis of choriocarcinoma. (Original magnification xI 00.) Fig. 11. Pathologic picture of the round form of pulmonary metastases of choriocarcinoma after treatment, showing a fibrotic band between the diseased and surrounding lung tissue. (Original magnification X I 00.)

DISSEMINATED OR MILIARY FORM. Diffused multiple mottlings were seen in the lung field and resembled the miliary form of tuberculosis: however, they were usually more coarse and evenly distributed (Fig. 5). AMORPHOUS CHANGES. In very early cases , occasionally a questionable shadow could be demonstrated on the chest film. In follow-up they sometimes became patchy or disappeared spontaneously.

Some other forms might occur after the basic forms as a result of complications. PLEURAL EFFUSION . Effusion was usually found in a large amount and proved to be the result of hemorrhage. Effusion may occur on either side and disappear completely without any apparent late effect following treatment. ATELECTASIS . This usually occurred in lobar distri-

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Fig. l2A. Postmortem pulmonan arteriographv :'\omnal lungs showing normal distribution ,.f pulmonarv arte rie,. Fig. 128. Postmonem pulmonan arteriograpl11·. Pulmonan rnctastast·s of choriocarcinoma. patchy lorm. showing terminal dilatation along til!' 'mall p11h11 o n.tn ;~ rl! · ric <.. Fig. l2C. Postmortem pulmonan arteriograpl11. l'nlntonarv llH 't;tslast·s of choriocarcinoma, rmmd form, show ing tenninal dil ata ti on of~t bran ch ~~f rl:e pultnun<~ r~ artt' r~· and presence of radiopaque material in th e metastatic mas ' .

bmion without any predilection to e itfwr side. Conl plete recovery was possible after treatntent. PNEUMOTHORAX. This was usuallv due to rupture ol ;1 surface metastatic nodul e (Fig-. 5). Both lungs mav lw affected. CARDIAC ENLARGEMENT AND PROMINE!'IT Pl' LMONARY

6). These we re seen occasionally a~ the result of complications. One or more of these forms of pulmonary metastases may appear. In advanced disease the shadows may bt' uniform in appearance or in various forms coexisting in the same film. Jnvasirw mole. The x-ray manifestations of pulmonary CONUS (FIG.

mel;lst;,ses of im·asive mole \·aried with the stage of the disease. In earl\' cases the pulmonarv metastases appeared ;,, homogeneous semi translucent nodular opacitic, :tbout I ctn in diameter. few in number, and distributed at the peripherY of the lung fteld (Figs. 7 A to i'C). so that they we re easily overshadowed by ribs , cl
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SUSPICIOUS LESIONS

EARLY LESIONS

LATE LESIONS

CQ\1PL I CATIONS

IATELECTAsrsl

I PNEUMOTHORAX

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IHEMOTHORAX I

Fig. 13. Diagram showing relationship of various forms of x-ray manifestations in choriocarcinoma.

were coughing, hemoptysis, chest pain, and dyspnea, of which hemoptysis was the most frequent. It might be found even before the appearance of shadows on the chest film, but it was found more often in patients with metastasis in patchy form or in round form with a hazy margin. Chest pain and dyspnea were infrequent. Se\'ere chest pain occurred only when the pumonary lesions involved the pleura, and dyspnea was evident only in cases with very extensive metastases complicated by infections or hemorrhage of the lungs. Severe dyspnea in the absence of extensive lung lesions may suggest the presence of a cardiac problem. Correlation of roentgenologic manifestations with pathologic findings. Pathologic examinations were performed in 56 cases of choriocarcinoma, of which 27 were of autopsy material and 29 were surgically resected lung specimens. The microscopic views of the patchy shadows were studied in seven autopsies and the following changes were found: (l) clumps of trophoblastic cells inside the lumina of small arteries with thrombus formation; (2) weakening of a portion of the vascular wall by the tumor cells with saccular formation; (3) erosion of some of the vessels, which resulted in the invasion of tumor cells into the adjacent alveoli: (4) extensive cellular filtration, edema, and hemorrhage seen in the surrounding lung tissue, thus forming an irregularly shaped mass under the microscope (Fig. 8) and a patchy appearance in the chest film. The pathologic picture of round forms was studied in 20 cases of autopsy material and found to be essentially the same for different sizes. There was a central necrotic and hemorrhagic mass with aggregation of trophoblastic cells at the periphery. However, there were

some differences between the two forms with different contours. In the round form with a hazy margin, the trophoblastic cells were very active in growth and the surrounding lung tissue was compressed by the necrotic mass to become atelectatic with marked edema, hemorrhage, and extensive cellular infiltration, so that there was no clear demarcation between the central mass and surrounding lung parenchyma (Fig. 9). In round forms with well-defined margins, the peripheral trophoblastic cells were not active in growth, and edema, hemorrhage, and cellular infiltration were mostly absorbed and the adjacent lung tissue was mainly reexpanded, so that there was a relatively dear line of demarcation between the metastatic nodules and surrounding lung tissue (Fig. 10). These findings explained not only why the x-ray manifestations were different in the two types of round forms but also why hemoptysis was often seen in the patchy form and round form with hazy contours but rarely in the round form with a well-defined margin. Of the 29 patients operated upon, the indication for lobectomy in 12 cases was persistent residual nodular metastatic shadow in the lung in spite of repeated courses of chemotherapy after the hCG level had become normal. Pathologic examination of the resected lung specimen showed a distinct layer of fibrotic tissue encapsulating the central necrotic mass with or without a few degenerated trophoblastic cells at the periphery, apparently indicating that the lesion was in a process of healing (Fig. 11). In the remaining cases, in which lobectomy was done because of drug resistance, pathologic examination of the resected lung specimens revealed the same picture as in the round form of meta-

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static shadow, with well-defined margins seen in autopsy material. As there were no deaths occurring in patients with beading or the miliary form of metastatic shadows or any indication for surgical resection of the lesions, no pathologic study was done. The same was true formalignant mole. However, one specimen was obtained from a patient \Vho had a typical semi translucent round shadow in the chest film and died of severe intraperit
The beading or miliary form usuallv represented the very earlv stage of the disease. These limns become patchy or nodular on further development or disappear spontaneouslv alter removal oftlw primarv lt>siou in the uterus. Following treatment, the proces;, of 1egression rook place in a reverse direction. The patchv form usualh disappeared rapidly in a period of about 2 \·veeks. 1~he round form usually regressed bv a process ot diminishing in size concentrically or disintegrating into multiple small patches and eventually disappearing totally, ]e;n·ing no detectable scar in most cases. The whole process of disappearance of the nodular form tuok about I to 2 months. while that of the cotton-balllonn took a much longer time. sometimes as long as fi months. [ n the same patient, while some of the shadows regressed satisfactorily, some others remained unchanged n1 even enlarged. Further, at times new le-,ions dneloped w nue ute otu testons a1sappearen. 1 n trlt' tlllnenen 1 orm of metastasis, the regression sometimes had a special course. A central cavity with an apparent water level inside appeared first, and then the whole mass shrank or collapsed rapidly until nothing was perceptible in the film. This form of regression was seen in II cases in this series. 1

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Comment

Pulmonarv metastases are freguenth seen in choriocarcinoma and invasive mole, vet there have been onlv a few reports on a limited number of cases in the literature."-" Through a careful study of a large series of cases, a relatively comprehensive knO\\~Iedge about the nature and development of various radiologic manifestations has been deduced. It seems to be logical to say that various forms of metastatic shadows on the chest films represent only the various evolutionarv changes of the same lesion. The trophoblastic cells separated from the primary or secondary lesions in the uterus or other pelvic organs are transported along the venous svstem to the right side of the heart and then to the pulmonary arteries, in which the cells are lodged in certain small branches, resulting in tumor embolism. This gives rise to a stagnation of blood and a picture of increased lung markings and sometimes pulmonary hypertension and enlargement of the right side of the heart. The tumor cells in the emboli develop further and erode the vascular wall, which results in saccular formation and eventual rupture of the vessels. The tumor cells are then disseminated into the alveoli. As a result of cellular reaction, the surrounding lung tissues become infiltrated, hemorrhagic, and edematous, so that many of the alveolar changes coalesce into an irregular mass. This gives rise to rhe parchy appearance in the chest

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radiograph. On further development of the lesion, a central necrotic mass with active trophoblastic cells at the periphery is seen in the pathologic section and a roundish form of metastatic shadow appears on the x-ray film. As the trophoblastic cells extend outward, the central necrotic mass increases in size. This is the process by which the nodular form develops into cotton-ball and tumefied forms. When the disease is controlled either by treatment or by local tissue resistance, the activity of trophoblast is reduced and a layer of fibrous material is formed around the mass. If the pulmonary lesion extends to involve the pleural surface, it may eventually rupture, and hemothorax or pneumothorax may ensue. If the tumor mass of an enlarged metastatic hilar lymph node presses against a branch of the bronchus, atelectasis of a lobe can result. This is a speculative picture of the development of pulmonary metastasis. On this basis, the various forms of x-ray manifestations of metastatic shadows are summarized as shown in Fig. 13. The beading and miliary forms are considered as suspicious lesions because of lack of pathologic confirmation, and there is a tendency to spontaneous disappearance in some cases. The patchy shadow is denoted as an early lesion because it usually appears in

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early cases and may disappear promptly following treatment. The nodular, cotton-ball, and tumid forms have the same morpholology and pathology but different clinical manifestations. The nodular form not only appears earlier but also disappears more readily than the other two forms, usually in I to 2 months. The tumefied form usually appears in very late cases and is often accompanied by various complications. In some cases it regresses through a peculiar process of liquefaction and cavitation rarely seen in other forms. Therefore, the round forms are divided into three subgroups for clinical purposes. Atelectasis, pneumothorax, and hemothorax often appear secondarily to other forms of metastatic shadows; therefore. they are categorized as complications of metastasis. On the basis of this classification, overt pulmonary metastases were seen in 365 (85.1 %) of the 429 cases of choriocarcinoma and in 286 (65.0%) of the 441 cases of invasive mole. The cardiac changes seen in the chest films are apparently a special form of acute cor pulmonale caused by massive dissemination of tumor cells into the pulmonary arteries with extensive vasoconstriction, formation of emboli, and pulmonary hypertension. A detailed study on 34 cases will be reported later.

REFERENCES I. Su, H. T., and Sung, H. C.: Roentgenologic manifestations of pulmonary metastases of choriocarcinoma and chorioadenoma destruens. A preliminary report, Chirl. J. Radio!. 9:24, 1964. 2. Novak, E., and Seah, C. S.: Choriocarcinoma of the uterus, AM. j. 0BSTET. GYNECOL. 67:933, 1954. 3. Department of Obstetrics and Gynecology, Peking Fanti Hospital, Chinese Academy of Medical Sciences: Clinical diagnosis of trophoblastic tumors, China Med. 86:61,

+.

7. 8. 9.

1967.

Sung, H. C., Xia, A. F., Wu, P. C., and Wang, Y.: Twenty years experience in chemotherapy of choriocarcinoma and malignant mole, Chin. Med.J. 92:677, 1979. 5. Hilbish, T. F., and Schulz, E. S.: Roentgenologic manifestations of trophoblastic tumors, Am. J. Roentgenol. 83:

66, 1960. 6. Bagshawe, K. D., and Garrett, E. S.: Radiological changes

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in the lungs of patients with trophoblastic tumors, Br. ] . Radio!. 36:673, 1963. Evans, K. T., Cockshott, W. P., and Hendrickse, P. de V.: Pulmonary changes in malignant trophoblastic diseases, Br.J. Radiol. 36:161, 1965. Tow, S. H.: The pulmonary lesion in chorion carcinoma, Proc. R. Soc. Med. 60:239, 1967. Evert, C. S., Westcott, J. L., and Bragg, D. G.: Methotrexate therapy and pulmonary disease, Radiology 107: 539, 1973. Swett, H. A., and Westcott, J. L.: Residual nonmalignant pulmonary nodules in choriocarcinoma, Chest 65:560,

1974.

1 I. Libshitz, H. I., Baber, C. E., and Hammond, C. B.: The pulmonary metastases of choriocarcinoma, Obstet. Gynecol. 49:412, 1977.