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Angiography in trophoblastic tumors
Angiography
in
Trophoblastic
Tumors
By W. PETER COCKSHOTT, M.D.
T
ROPHOBLASTIC NEOPLASIA is rare but because of the present favorable therapeutic outlook, early recognition is vital. A big stumbling block in the study of this disorder has been the concept of rigid categories of trophoblast: normal placenta, hydatidiform mole, invasive mole (chorioadenoma destruens ), and chorion carcinoma; whereas in fact, there is a continuum extending from the physiologic to the highly malignant. Histologic grading is subjective and fraught with difficulties in these unique lesions derived from one individual, the conceptus, and existing in another, the mother. Consequently, all incidence figures in this field must be accepted with reservation. However, in order to appreciate the magnitude of the problem, one must realize that in North America hydatidiform mole occurs roughly in one of 2000 pregnancies and that perhaps 2 per cent of these become chorion carcinoma. Just under a third of chorion cancers follow a normal pregnancy, a similar proportion are preceded by an abortion, and the remainder are subsequent to a mole. By contrast, in the Philippines, southeast Asia, and Nigeria, the incidence of malignant trophoblastic tumor is considerably higher; for example, chorion epithelioma develops in 0.13 per cent of normal pregnancies in Hong Kong.3a0 Certain features common to all grades of trophoblastic tissue are of particular relevance to this discussion. First, all trophoblasts are invasive and require a rich blood supply. In normal pregnancy their invasive nature is limited, but at the malignant end of the spectrum the maternal barriers are inadequate. Second, all trophoblastic lesions produce gonadotrophin (HCG) and, though the measurement of the hormone level does not differentiate between the varieties of trophoblast, the serial estimation of HCG by a sensitive techand is vital to nique6 is invaluable in detecting the presence of trophoblast the proper management of these patients. Third, these friable vascular lesions drain by generous venous pathways which permit detached tissue elements to reach the pulmonary vascular bed. Even in normal pregnancy, villi detach and frequently pass to the pulmonary circulation where they are absorbed. The same process is greatly intensified in trophoblastic neoplasia where fragments may even cause car pulmonale from packed pulmonary emboli, pulmonary infarction, and, of course, metastases5 This is not the place to detail the features of the history and the clinical findings that may arouse the suspicion of trophoblastic disease. Suffice it to say that if the history is suggestive and the HCG titer is high, the usual next investigative steps are chest radiography and uterine curettage. The presence W. PETER COCKSHOTT, Department of Radiology, 280
CH.B., D.M.R.D., M.R.C.P.: Professor and M.D., McMaster University, Hamilton, Ontario, Canada. SEMINARS
IN ROENTGENOLOGY,
VOL.
4, No.
Chairman,
3 (JULY),
1969
..WGIOGRAPHY
IS
THOPHOBLASTIC
TUMORS
251
of pulmonary deposits does not provide a clear-cut differentiation between varieties of trophoblastic tissues since so-called “benign” hydatidiform mole may be accompanied by growing metastases. It is not surprising that in lesions prone to venous dissemination, curettage can also be followed by multiple tumor emboli, infarctions, and car pulmonale (Fig. 1). Curettage can provoke severe bleeding and, if infection is present, can cause septicemia or even septic shock. Apart from these physical dangers to the patient, the physician is also faced with the hazards of interpreting the histologic material which samples only part of the lesion, and not necessarily its most sinister elements. In addition, the exploring curette cannot reach lesions deep in the myometrium or outside the uterus. I may appear to be overemphasizing the pitfalls of curettage, but I feel strongly that the sequence of investigation of these tumors should be: pelvic angiography, biopsy of superficial vaginal secondaries, and only if there is still doubt should a careful curettage then be performed. Fortunately, the most puzzling cases are the least vascular and hence are probably the safest to curette. PELVIC
ANGIOGRAPHY
Angiography carries negligible risk, does not cause embolism and depicts lesions within the lumen, in the wall, and in the vicinity of the uterus. Finally, in the case of large moles it may even reveal a small localized vascular area of invasive tumor.
Fig. 1.-Tumor embolism to the Iung in malignant trophoblastic tumor. The patient died of acute car pulmonale from packed tumor emboli dislodged cluring diagnosticuterine curettage.
282
W.
PETER
COCKSHOTT
Technique The X-ray beam is carefully collimated to the pelvis unless you are dealing with a large mole, when more of abdomen must be included. A standard femoral percutaneous approach provides access to the aorta. The catheter tip should be high enough to fill the ovarian vessels. Compression of the femoral vessels is not necessary and by altering the hemodynamics may create problems of interpretation. In patients with poor vascularity, selective hypogastric injection is warranted. A large volume of contrast medium must be used when there is a large uterus or indication of rapid circulation. Filming should be continued for at least 9 seconds. Unless arteriovenous fistulas are demonstrated, a rate of 2 films per second for 3 seconds and then 1 per second is adequate. Normal
Trophoblast
The technique of angiographic placental localization has made us familiar with the appearance of the normal trophoblastic circulation. In a normal gestation, the uterine arteries become dilated beyond the normal 2 mm. measured on films. The spiral myometrial arteries to the placental bed are larger than their fellows and fill earlier. Contrast material then enters the large, well-defined, intervillous spaces and drains into flattened myometrial veins. The pelvic and ovarian veins are not well shown. Early in pregnancy, the corpus luteum may show a ring opacification. Missed Abortion The angiographic appearance in missed abortion is similar to that of normal pregnancy in the initial phases but differs in the latter stages of the examination. The vascular spaces are larger and tend to coalesce toward a central draining vein, which may fill early and empty rapidly into uterine or ovarian veinslJ (Fig. 2). Hydutidiform
Mole
Once again the uterine vessels are separated, indicating the presence of an enlarged uterus. The uterine, and often the ovarian vessels are enlarged and all the myometrial spiral vessels are dilated. Paradoxically, this increased arterial supply to the uterus is not accompanied by large, obvious vascular spaces since these are encroached upon by the hydropic villi. Furthermore, the bulk of these lesions may lead to dilution of contrast unless a large volume (over 60 ml.) has been injected. Thus, the intervillous vascular spaces are not apparent when the myometrial vasculature is demonstrated. The intervillous spaces show crescentic or scalloped outlines because of the hydatidiform vesicles intruding into them (Fig. 5). In a benign mole there is no localized area of greatly increased vascularity nor do the veins fill early. Malignant
Trophoblmt
An invasive mole is a hydatidiform mole with greater invasive propensity. The concept of an intermediate stage (pathologically and temporally ) between benign mole and chorion carcinoma is useful; however, invasive mole should not be regarded as a separate category but is better considered to be
ANGIOGRAPHY
IN
TROPHOBLASTI
Fig. 2.-Pelvic angiogram in missed abortion. The uterus is enlarged. A. Large myometrial arteries are evident. B. Coalescence of the vascular spaces is seen. C. The uterine and ovarian veins are filled.
284
W.
PETER
COCKSHOTT
an occasional transition between benign and mahgnant trophobIastic disease. It can sometimes be recognized from the patient’s history and the subsequent behavior of the lesion. From the angiographic standpoint, the label can be applied to a lesion that shows the typical features of a mole except for a focal area of increased vascularity with large feeding vessels, persistent opacification, and perhaps, if the projection is good, indications of invasion (Fig. 3). If these features are seen and yet the histology of the aborted mole is reported as benign, the diagnosis should be questioned. At the highly malignant end of trophoblastic neoplasia (chorion carcinoma), the angiographic abnormalities are often gross (Fig. 4). The uterus is usually enlarged and the supplying arteries are dilated, sometimes greatly so. The spiral arteries feed directly into amorphous vascular spaces, there being no true tumor vessels. The contrast material may persist in the vascular area for a variable time or it may be rapidly flushed into the veins by the rapid circulation. Arteriovenous shunting rnay be so pronounced that large venous channels draining to the ovarian veins may become evident in the early arterial phase. Extrauterine deposits may be revealed by the presence of abnormal areas of opacification; the supplying vessels often are identifiable and lie lateral or inferior to the uterine arteries. DISCUSSION
The angiographic patterns described in this text are distinctive in most cases (Fig. 5)) but the features of the various disorders do overlap. Recognition of early pregnancy, early ectopic pregnancy, and missed abortion theoretically provide the main pitfalls, but in fact it is missed abortion that is the biggest diagnostic problem. If the fetus has died and yet the placenta remains perfused, gonadotrophin is still present, although its level may not be very high. The vascularity of the lesion may be great, yet it retains certain features of the normal placenta. The vessels supplying it are dilated and the opacified, enlarged, necrotic intervillous spaces are distributed in the shape of a placenta. The placenta is often low-lying in patients who present with bleeding. The central draining veins within the placenta are a helpful feature, and Brewis and Bagshawe” have emphasized that the presence of a dead fetus can be inferred from the avascular filling defect adjacent to the placenta. On occasion one encounters patients with minimal angiographic changes of neoplasm but with a high level of gonadotrophin. In these individuals, selective hypogastric injection will emphasize the abnormalities of the “flush” study. However, if confusion persists and the lesion is only scantily vascular, cautious fractional curettage may be of value. Though it is well documented and I have seen two cases,it is not generally known that the primary uterine tumor of even the more malignant trophoblastic lesions can regress spontaneously and yet distant metastatic deposits persist. Naturally this gives rise to a normal pelvic angiogram and normal curettings. In follow-up studies, it is important to understand that the angiographic abnormalities persist longer than the hormonal. Indeed, gross angiographic
,!i?;GIOGFiAPHT
IN
TROPHOBLASTIC
mole. The pelFig. 3 .-Invasive vic angiogram shows (A) an enlarged uterus with large feeding arteries, (B) dilated spiral vessels, and (C) scalloped intervillous spaces and a small vascular focus (arrows) in the fundus. Severe necessitated hysterecbleeding tomy.
TUh
286
Fig. 4.-Malignant shunting. A parametrial
W.
trophoblast (chorion carcinoma) with deposit is seen in B (arrowheads).
PETER
early
COCKSHOTT
arteriovenous
ANGIOGRAPHY
IN
TROPHOBLASTIC
TUhlORS
HYDATIDIFORM
MOLE
NORMALPREGNANCY
MISSED
Fig, 5.--Schematic
ABORTION
arterial
MALIGNANT
TROPHOBLASTIC
and early venous patterns
DISEASE
in \arious types of tropho-
blast. arteriovenous fistulas may be evident in a patient who by all other criteria has no trophoblastic disease at all. 4,7 The persistent arteriovenous fistulas differ from those seen during the active stage in that there is no longer any shunting via a tumor vascular space but instead, contrast material passesdirectly from artery to a plexus of pelvic veins which fill in a retrograde fashion.4 In our initial studies we had hoped we would be able to identify those tumors that would be resistant to conventional chemotherapy. There are no absolute criteria by which this can be done, but speaking empirically, I think that demonstrating persistent small tumor vessels rather than vascular spaces in the lesion may be predictive of a poor therapeutic outcome from antifolic acid antagonists. After treatment, the differentiation of a normal pregnancy from a recurrent tumor is usually not difficult on clinical grounds. I believe that chemotherapy should be instituted on the basis of positive angiographic findings of invasive mole, but if there is a reluctance to do so without histologic confirmation, it is important to insist on a repeat angiogram a week after uterine evacuation and to obtain serial quantitative gonadotrophin estimations over the next 4 months. The history, physical features, quantitative gonadotrophin estimations, and angiographic findings comprise the cornerstone of diagnosis of these tumors. It must be remembered that symptoms of this disease of women in the reproductive years are not confined to the pelvis and patients may present initially with cerebral, cardiac, or pulmonary manifestations. Curettage should be utilized with care and reservation because of the dangers to the patient and the interpretative problems it may raise. Angiography is a valuable addition to the diagnosis and treatment of these rare and perplexing tumors. They can be cured in a high proportion of patients so that suspicion of neoplasia is an indication for thorough study and close follow-up.
288
W.
PETER
COCKSHOTT
REFERENCES 1. Borell, U., Fernstrom, I., Moberger, G., and Ohlson, L.: The Diagnosis of Hydatidiform Mole, Malignant Hydatidiform Mole and Choriocarcinoma with Special Reference to the Diagnostic Value of Pelvic Arteriography. Springfield, Ill., Charles C Thomas, Publisher, 1966. 2. Brewis, R. A. L., and Bagshawe, K. K.: Pelvic arteriography in invasive trophoblastic neoplasia. Brit. J. Radiol. 41:486, 1968. 3. Chan, P. C. D.: Chorionepithelioma. Brit. Med. J. 2:953, 1962. 4. Cockshott, W. P., and Hendrickse, J. P. de V.: Persistent arteriovenous fistulae following chemotherapy of malignant tro-
phoblastic disease. Radiology 88:329, 1967. 5. Evans, K. T., Cockshott, W. P., and Hendrickse, P. de V.: Pulmonary changes in malignant trophoblastic disease. Brit. J. Radiol. 38:161, 1965. 6. Hendrickse, J. P. de V., Cockshott, W. P., Evans, K. T. E., and Barton, C. J.: Pelvic angiography in the diagnosis of malignant trophoblastic disease. New Eng. J. Med. 271: 859, 1964. 7. Stern, W. Z., Lopez, F., Herzig, N.: Persistent angiographic abnormalities after cure of malignant trophoblastic disease. Radiology 91:1019, 1968.
in
Trophoblastic
Tumors
By W. PETER COCKSHOTT, M.D.
T
ROPHOBLASTIC NEOPLASIA is rare but because of the present favorable therapeutic outlook, early recognition is vital. A big stumbling block in the study of this disorder has been the concept of rigid categories of trophoblast: normal placenta, hydatidiform mole, invasive mole (chorioadenoma destruens ), and chorion carcinoma; whereas in fact, there is a continuum extending from the physiologic to the highly malignant. Histologic grading is subjective and fraught with difficulties in these unique lesions derived from one individual, the conceptus, and existing in another, the mother. Consequently, all incidence figures in this field must be accepted with reservation. However, in order to appreciate the magnitude of the problem, one must realize that in North America hydatidiform mole occurs roughly in one of 2000 pregnancies and that perhaps 2 per cent of these become chorion carcinoma. Just under a third of chorion cancers follow a normal pregnancy, a similar proportion are preceded by an abortion, and the remainder are subsequent to a mole. By contrast, in the Philippines, southeast Asia, and Nigeria, the incidence of malignant trophoblastic tumor is considerably higher; for example, chorion epithelioma develops in 0.13 per cent of normal pregnancies in Hong Kong.3a0 Certain features common to all grades of trophoblastic tissue are of particular relevance to this discussion. First, all trophoblasts are invasive and require a rich blood supply. In normal pregnancy their invasive nature is limited, but at the malignant end of the spectrum the maternal barriers are inadequate. Second, all trophoblastic lesions produce gonadotrophin (HCG) and, though the measurement of the hormone level does not differentiate between the varieties of trophoblast, the serial estimation of HCG by a sensitive techand is vital to nique6 is invaluable in detecting the presence of trophoblast the proper management of these patients. Third, these friable vascular lesions drain by generous venous pathways which permit detached tissue elements to reach the pulmonary vascular bed. Even in normal pregnancy, villi detach and frequently pass to the pulmonary circulation where they are absorbed. The same process is greatly intensified in trophoblastic neoplasia where fragments may even cause car pulmonale from packed pulmonary emboli, pulmonary infarction, and, of course, metastases5 This is not the place to detail the features of the history and the clinical findings that may arouse the suspicion of trophoblastic disease. Suffice it to say that if the history is suggestive and the HCG titer is high, the usual next investigative steps are chest radiography and uterine curettage. The presence W. PETER COCKSHOTT, Department of Radiology, 280
CH.B., D.M.R.D., M.R.C.P.: Professor and M.D., McMaster University, Hamilton, Ontario, Canada. SEMINARS
IN ROENTGENOLOGY,
VOL.
4, No.
Chairman,
3 (JULY),
1969
..WGIOGRAPHY
IS
THOPHOBLASTIC
TUMORS
251
of pulmonary deposits does not provide a clear-cut differentiation between varieties of trophoblastic tissues since so-called “benign” hydatidiform mole may be accompanied by growing metastases. It is not surprising that in lesions prone to venous dissemination, curettage can also be followed by multiple tumor emboli, infarctions, and car pulmonale (Fig. 1). Curettage can provoke severe bleeding and, if infection is present, can cause septicemia or even septic shock. Apart from these physical dangers to the patient, the physician is also faced with the hazards of interpreting the histologic material which samples only part of the lesion, and not necessarily its most sinister elements. In addition, the exploring curette cannot reach lesions deep in the myometrium or outside the uterus. I may appear to be overemphasizing the pitfalls of curettage, but I feel strongly that the sequence of investigation of these tumors should be: pelvic angiography, biopsy of superficial vaginal secondaries, and only if there is still doubt should a careful curettage then be performed. Fortunately, the most puzzling cases are the least vascular and hence are probably the safest to curette. PELVIC
ANGIOGRAPHY
Angiography carries negligible risk, does not cause embolism and depicts lesions within the lumen, in the wall, and in the vicinity of the uterus. Finally, in the case of large moles it may even reveal a small localized vascular area of invasive tumor.
Fig. 1.-Tumor embolism to the Iung in malignant trophoblastic tumor. The patient died of acute car pulmonale from packed tumor emboli dislodged cluring diagnosticuterine curettage.
282
W.
PETER
COCKSHOTT
Technique The X-ray beam is carefully collimated to the pelvis unless you are dealing with a large mole, when more of abdomen must be included. A standard femoral percutaneous approach provides access to the aorta. The catheter tip should be high enough to fill the ovarian vessels. Compression of the femoral vessels is not necessary and by altering the hemodynamics may create problems of interpretation. In patients with poor vascularity, selective hypogastric injection is warranted. A large volume of contrast medium must be used when there is a large uterus or indication of rapid circulation. Filming should be continued for at least 9 seconds. Unless arteriovenous fistulas are demonstrated, a rate of 2 films per second for 3 seconds and then 1 per second is adequate. Normal
Trophoblast
The technique of angiographic placental localization has made us familiar with the appearance of the normal trophoblastic circulation. In a normal gestation, the uterine arteries become dilated beyond the normal 2 mm. measured on films. The spiral myometrial arteries to the placental bed are larger than their fellows and fill earlier. Contrast material then enters the large, well-defined, intervillous spaces and drains into flattened myometrial veins. The pelvic and ovarian veins are not well shown. Early in pregnancy, the corpus luteum may show a ring opacification. Missed Abortion The angiographic appearance in missed abortion is similar to that of normal pregnancy in the initial phases but differs in the latter stages of the examination. The vascular spaces are larger and tend to coalesce toward a central draining vein, which may fill early and empty rapidly into uterine or ovarian veinslJ (Fig. 2). Hydutidiform
Mole
Once again the uterine vessels are separated, indicating the presence of an enlarged uterus. The uterine, and often the ovarian vessels are enlarged and all the myometrial spiral vessels are dilated. Paradoxically, this increased arterial supply to the uterus is not accompanied by large, obvious vascular spaces since these are encroached upon by the hydropic villi. Furthermore, the bulk of these lesions may lead to dilution of contrast unless a large volume (over 60 ml.) has been injected. Thus, the intervillous vascular spaces are not apparent when the myometrial vasculature is demonstrated. The intervillous spaces show crescentic or scalloped outlines because of the hydatidiform vesicles intruding into them (Fig. 5). In a benign mole there is no localized area of greatly increased vascularity nor do the veins fill early. Malignant
Trophoblmt
An invasive mole is a hydatidiform mole with greater invasive propensity. The concept of an intermediate stage (pathologically and temporally ) between benign mole and chorion carcinoma is useful; however, invasive mole should not be regarded as a separate category but is better considered to be
ANGIOGRAPHY
IN
TROPHOBLASTI
Fig. 2.-Pelvic angiogram in missed abortion. The uterus is enlarged. A. Large myometrial arteries are evident. B. Coalescence of the vascular spaces is seen. C. The uterine and ovarian veins are filled.
284
W.
PETER
COCKSHOTT
an occasional transition between benign and mahgnant trophobIastic disease. It can sometimes be recognized from the patient’s history and the subsequent behavior of the lesion. From the angiographic standpoint, the label can be applied to a lesion that shows the typical features of a mole except for a focal area of increased vascularity with large feeding vessels, persistent opacification, and perhaps, if the projection is good, indications of invasion (Fig. 3). If these features are seen and yet the histology of the aborted mole is reported as benign, the diagnosis should be questioned. At the highly malignant end of trophoblastic neoplasia (chorion carcinoma), the angiographic abnormalities are often gross (Fig. 4). The uterus is usually enlarged and the supplying arteries are dilated, sometimes greatly so. The spiral arteries feed directly into amorphous vascular spaces, there being no true tumor vessels. The contrast material may persist in the vascular area for a variable time or it may be rapidly flushed into the veins by the rapid circulation. Arteriovenous shunting rnay be so pronounced that large venous channels draining to the ovarian veins may become evident in the early arterial phase. Extrauterine deposits may be revealed by the presence of abnormal areas of opacification; the supplying vessels often are identifiable and lie lateral or inferior to the uterine arteries. DISCUSSION
The angiographic patterns described in this text are distinctive in most cases (Fig. 5)) but the features of the various disorders do overlap. Recognition of early pregnancy, early ectopic pregnancy, and missed abortion theoretically provide the main pitfalls, but in fact it is missed abortion that is the biggest diagnostic problem. If the fetus has died and yet the placenta remains perfused, gonadotrophin is still present, although its level may not be very high. The vascularity of the lesion may be great, yet it retains certain features of the normal placenta. The vessels supplying it are dilated and the opacified, enlarged, necrotic intervillous spaces are distributed in the shape of a placenta. The placenta is often low-lying in patients who present with bleeding. The central draining veins within the placenta are a helpful feature, and Brewis and Bagshawe” have emphasized that the presence of a dead fetus can be inferred from the avascular filling defect adjacent to the placenta. On occasion one encounters patients with minimal angiographic changes of neoplasm but with a high level of gonadotrophin. In these individuals, selective hypogastric injection will emphasize the abnormalities of the “flush” study. However, if confusion persists and the lesion is only scantily vascular, cautious fractional curettage may be of value. Though it is well documented and I have seen two cases,it is not generally known that the primary uterine tumor of even the more malignant trophoblastic lesions can regress spontaneously and yet distant metastatic deposits persist. Naturally this gives rise to a normal pelvic angiogram and normal curettings. In follow-up studies, it is important to understand that the angiographic abnormalities persist longer than the hormonal. Indeed, gross angiographic
,!i?;GIOGFiAPHT
IN
TROPHOBLASTIC
mole. The pelFig. 3 .-Invasive vic angiogram shows (A) an enlarged uterus with large feeding arteries, (B) dilated spiral vessels, and (C) scalloped intervillous spaces and a small vascular focus (arrows) in the fundus. Severe necessitated hysterecbleeding tomy.
TUh
286
Fig. 4.-Malignant shunting. A parametrial
W.
trophoblast (chorion carcinoma) with deposit is seen in B (arrowheads).
PETER
early
COCKSHOTT
arteriovenous
ANGIOGRAPHY
IN
TROPHOBLASTIC
TUhlORS
HYDATIDIFORM
MOLE
NORMALPREGNANCY
MISSED
Fig, 5.--Schematic
ABORTION
arterial
MALIGNANT
TROPHOBLASTIC
and early venous patterns
DISEASE
in \arious types of tropho-
blast. arteriovenous fistulas may be evident in a patient who by all other criteria has no trophoblastic disease at all. 4,7 The persistent arteriovenous fistulas differ from those seen during the active stage in that there is no longer any shunting via a tumor vascular space but instead, contrast material passesdirectly from artery to a plexus of pelvic veins which fill in a retrograde fashion.4 In our initial studies we had hoped we would be able to identify those tumors that would be resistant to conventional chemotherapy. There are no absolute criteria by which this can be done, but speaking empirically, I think that demonstrating persistent small tumor vessels rather than vascular spaces in the lesion may be predictive of a poor therapeutic outcome from antifolic acid antagonists. After treatment, the differentiation of a normal pregnancy from a recurrent tumor is usually not difficult on clinical grounds. I believe that chemotherapy should be instituted on the basis of positive angiographic findings of invasive mole, but if there is a reluctance to do so without histologic confirmation, it is important to insist on a repeat angiogram a week after uterine evacuation and to obtain serial quantitative gonadotrophin estimations over the next 4 months. The history, physical features, quantitative gonadotrophin estimations, and angiographic findings comprise the cornerstone of diagnosis of these tumors. It must be remembered that symptoms of this disease of women in the reproductive years are not confined to the pelvis and patients may present initially with cerebral, cardiac, or pulmonary manifestations. Curettage should be utilized with care and reservation because of the dangers to the patient and the interpretative problems it may raise. Angiography is a valuable addition to the diagnosis and treatment of these rare and perplexing tumors. They can be cured in a high proportion of patients so that suspicion of neoplasia is an indication for thorough study and close follow-up.
288
W.
PETER
COCKSHOTT
REFERENCES 1. Borell, U., Fernstrom, I., Moberger, G., and Ohlson, L.: The Diagnosis of Hydatidiform Mole, Malignant Hydatidiform Mole and Choriocarcinoma with Special Reference to the Diagnostic Value of Pelvic Arteriography. Springfield, Ill., Charles C Thomas, Publisher, 1966. 2. Brewis, R. A. L., and Bagshawe, K. K.: Pelvic arteriography in invasive trophoblastic neoplasia. Brit. J. Radiol. 41:486, 1968. 3. Chan, P. C. D.: Chorionepithelioma. Brit. Med. J. 2:953, 1962. 4. Cockshott, W. P., and Hendrickse, J. P. de V.: Persistent arteriovenous fistulae following chemotherapy of malignant tro-
phoblastic disease. Radiology 88:329, 1967. 5. Evans, K. T., Cockshott, W. P., and Hendrickse, P. de V.: Pulmonary changes in malignant trophoblastic disease. Brit. J. Radiol. 38:161, 1965. 6. Hendrickse, J. P. de V., Cockshott, W. P., Evans, K. T. E., and Barton, C. J.: Pelvic angiography in the diagnosis of malignant trophoblastic disease. New Eng. J. Med. 271: 859, 1964. 7. Stern, W. Z., Lopez, F., Herzig, N.: Persistent angiographic abnormalities after cure of malignant trophoblastic disease. Radiology 91:1019, 1968.