Chorionepithelioma

CHORIONEPITHELIOMA J. HADLEY CALDWELL, Senior Surgeon, St. Eiizabeth

HospitaI, Covington, NEWPORT,

C

M.D.,

Kentucky,

F.A.C.S. and Speers Memorial Hospital,

Dayton

KENTUCKY

HORIONEPITHELIOMA, as the and infiltrates deep into the muscuIar waI1. name impIies, is a maIignant tuIt may be palpated when the abdomen is mor originating from the chorionic opened by grasping the uterus with one epithelium. It was first described in 1877 hand. by Chiari, who caIIed it carcinoma of The tumors resembIe either waI1 thrombi the uterus. In 1893, Sanger caIIed this neo- or interstitiar nodules with black, thrompIasm sarcoma uteri deciduocehulare, but bosed areas, the base of which may partly it remained for Marchand in 1895 to sIough away. Deep-seated uIcers then recognize the epitheIia1 nature as weII as develop, or more rareIy, there may be a the placentaI origin of this tumor and diffuse, fungating, corporea1 type of growth. appIy the correct name. In spite of these variations, a distinctIy Etiology. There is stiII a great deal of hemorrhagic appearance, with infiltration controversy among the leading authorities of the uterine wall, is noted in al1. The concerning the cause of these growths and tumor area is friabIe. The growth may penetrate the uterine waI1, rupturing through their exact histoIogic structure. The writer the peritoneal coat into the peritoneal wiI1 not attempt to explain aI the different theories and opinions that have been cavity. Ectopic. ChorionepitheIioma shows a advanced, except to state that it is generaIIy conceded that this disease, in the tumor having no direct anatomic connection with a previous pIacenta1 site. The great majority of cases, occurs sometime during the child bearing period of women uterus may be perfectIy norma or may show such hyperplasia of the mucosa and foIIowing shortIy after Iabor at term, muscuIature as usuaIIy accompanies tuba1 abortion or expuIsion of a hydatidiform moIe; in a few very rare cases also it has pregnancy. The site of the chorionepibeen found in very young girIs and eIderIy thehoma may be in the vagina, broad Iigaments or it may be intraperitoneal. women. It has also been reported deveIoping in teratoma of the testis. Most The mass resembles a hematoma or coheccommonIy, however, this type of tumor de- tion of thrombi, tumor ceIIs usuahy being veIops in the uterus of muItiparous women found onIy in the periphery, with the shortly after the expuIsion of a hydatidimain mass consisting of coagulum. The form mole. ectopic chorionepithehoma probabIy arises Pathology. Macroscopic. The gross ap- from a primary uterine tumor that has pearance of uterine chorionepitheIioma is regressed or been expeIIed with a pIacenta fairIy characteristic. The uterus in earIy or more, or from the transpIanted ceIIs of a possibly normal intra-uterine placenta. cases is only sIightIy enlarged, somewhat soft and boggy, the peritoneum covering ChorionepitheIioma of the FaIIopian the uterus, bIadder and broad Iigaments is tube is of very infrequent occurrence. The very paIe and if there are no metastases appearance and symptoms of these cases present or extension of growth into the are simiIar to those of tubal pregnancy, but broad Iigaments by continuity, the whoIe recurrence after operation is the ruIe. uterus is freeIy movable. In more advanced Microscopic. Marchand first conclucases the tumor mass in the uterine siveIy showed that the growth originated cavity is attached to the endometrium from the tropobIasts, and that Langhans 638

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cells and syncytium, encountered in the norn nal viIIus, aIso appeared in the maIignant ; tumors. The transition from the

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to some degree resembIing proliferation of carcinoma. Outgrowths of these ceIIs invade the musculature for a considerabIe

B

F IG. I. A, Case I. Gross specimen, showing tubes, ovaries and uterus, with body of uterus opened anteriorly, containing chorionepithehoma. B, sagittal section of uterus, with chorionepitheIioma trating deep into the muscutature of uterus.

normaI viIIus to hydatid moIe is gradua1, and a further step towards maIignancy is shown in chorionepitheIioma. The invasive character of the growth is aIways present. Marchand has divided chorionepitheIioma into two types, the typica aid the atypica1. The typica chorionepitheIioma resembIes the trophoblasts of early pregnancy. The cIearIy defined poIygona1 Langhans ceIIs, with weII-marked ceI1 outIine and Large nucIeus, appear mixed in with muItinucIear groups of dark wandering The growth contains ceIIs of syncytium. numerous bIood sinuses, some of which harbor tumor ceIIs as we11 as hemorrhagic and necrotic areas. No muItipIication of viIIi takes pIace. In the typica chorionepitheIioma there is a marked tendency for the ceI1 masses to arrange themseIves in alveolar groups,

shown infil-

Surrounding the hemorrhagic distance. tumor, there is an area of fibrin and hemorrhage, and stiI1 farther toward the periphery there is a marked reaction zone. Characteristic of this type of growth is the fact that no new formation of connective tissue or of blood vesseIs takes pIace. The bIood vesseIs of the host are frequentIy penetrated and intravascuIar extension is not uncommon. Even a so-called typical chorionepitheIioma may vary greatly in the number of Langhans ceIIs and syncytium, the one or the other form predominating in a given portion of the same tumor or in different tumors. The Langhans ceIIs vary more in size, shape and staining reaction of the nucIeus than do norma Langhans ceIIs. Mitosis may be present. The atypica1 form generaIly shows a more diffuse invasion of materna1 struc-

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tures by Iarge mono- or poIynuclear, deepIy staining cells, which may suggest sarcoma. The ceIIs may be discrete or form

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a definite prognosis. This seems to be asking too much of the pathoIogist, but probabIy a reIative prognosis may be given. Ewing takes a stand rather different from that of other pathoIogists, such as Marchand, Schlagenhaufer, Aschoff, Frank, Hirschmann and Cristoffette, who maintain that the histoIogic differentiation cannot be utilized in making a prognosis. In a review of the literature, Wimpfheimer found eighty-five cases of chorionepitheIioma that were cIassified into four types; a typica chorionepitheIioma with an approximateIy equal number of Langhans and syncytia1 ceIIs, and forty-nine cases cIassified by histoIogy and treatment as foIIows : No. hes

Typical chorionepitheliomo.

With

villi

Atypical cells nat,ng.

FIG. z. Microscopic section of specimen in Case I, showing the typical polygona Langhans’ cells.

Atypical cells

nat,ng

syncytia1 groups and masses. Langhans ceIIs are much Iess numerous than in the typica variety and may be so few as to escape observation, unIess diIigent search is made. As in the typical form, coaguIation necrosis, fibrin, and a surrounding reaction zone are found. From a microscopic pathoIogic view there are a number of subdivisions and gradations between the typica and the atypica1 types of this neopIasm; hence the controversy among the pathoIogists with reference to the diagnosis and prognosis in a given case. After an exhaustive study, Ewing has attempted to base prognosis upon histoIogy, and in the opinion of the writer this seems IogicaI. Ewing beIieves that the cIinica1 course can be correlated with the histoIogic structure in such a fashion as to enabIe’the pathoIogist to give

Unoperated Operated

VVeil

Died

18 31

Unoperated Operated

5 5

Unoperated Operated

4

Langhana predomi.

.

2

syncytium predomiUnopened Operated

I2 8 -

-

-

From these rather scant data, we concIude that the consensus of opinion that the histoIogic criteria cannot be reIied upon, is fully justified, except that where viIli are present radica1 operation offers exceIIent hope of cure, and that syncytia1 tumors are fuIIy as maIignant as the typica varieties. Out of the eighty-five cases, fifty-one, or 60 per cent, died and thirty-four, or 40 per cent, recovered. The writer beIieves that this or any other disease that has a 60 per cent mortahty is deserving of more thorough study and carefuI treatment. Metastases. Metastatic extension may occur earlier in this than in any other form of tumor. Dissemination takes place through the bIood stream. Metastases

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have been found in aImost every organ of the body, but the Iungs and the vagina are the two sites of eIection. Symptoms. The most important symptom of chorionepithehoma is hemorrhage. The bIeeding may first appear in the early months of pregnancy, shortly after the termination of pregnancy, whether this be normal or hydatidiform, or after a period of latency existing for months or sometimes years. The bIeeding is generahy sIight in the beginning and often repeated unti1 profuse uterine hemorrhages take place; in fact, hemorrhage may be a terminal symptom. It sometimes simulates ruptured ectopic pregnancy, i.e., when the uterus ruptures and there is profuse intraperitonea1 hemorrhage. The uterus may ‘be found enlarged,-boggy and resembling subinvolution. SuboeritoneaI noduIes may be feIt, and enlarged cystic ovaries may Iikewise be noted. There are generaIIy symptoms of anemia, sIight or moderate elevation of temperature, and a feeIing of intense Iassitude. A brief summary of a typica case wouId be: repeated or constant uterine hemorrhage, anemia with a Iow degree of sepsis, enIargement of uterus, metastases, cachexia and death. Differential Diagnosis. ChorionepitheIioma must be differentiated from ordinary non-malignant retained products of conception. Here the specimens removed with a sharp curette or a sponge forceps are rather characteristic. Such tumors as carcinoma, sarcoma and necrotic submucous fibroids may have to be excIuded by microscopic section. The most characteristic symptom of chorionepitheIioma is the repeated findings of smaI1 particIes of chorionic tissue in serosanguinous IIuid ffowing from a uterus that has been thoroughIy emptied. If this symptom occurs short17 after expuIsion of an hydatidiform moIe, rt is very suggestive of chorionepitheIioma. Major importance must now be accorded to the pregnancy urine test. The writer has used the Friedman modification of the Aschheim-Zondek test with much satisfaction. In a case where

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the above symptoms are very definite and the Friedman test is very positive with onIy IO per cent of the amount of urine usuaIIy used, one is justified in making a diagnosis of chorionepitheIioma. The incidence of chorionepithelioma, as given by different authors, varies greatIy. With diIigent search of the Iiterature in rgrg, Vineberg found 533 we11 authenticated cases. It is stated by PoIIoson and VioIet that 45 per cent foIlowed hydatidiform moIe. The writer has personally encountered three cases, a11 foIIowing the expuIsion of hydatidiform moles, and after review of the Iiterature finds that few have personaIIy treated more cases; hence the difference of opinion. Prognosis. The viruIence of this disease varies tremendousIy. In many instances the fuIminating nature can be compared onIy to that of meIanoma. In other cases spontaneous regression appears to have occurred, but in the opinion of the writer this seems to be a mistaken diagnosis. Treatment. EarIy diagnosis is most essential. In fact, it is of the utmost importance. Where chorionepitheIioma is strongIy suspected, the writer wouId very emphaticaIIy advise against the use of the curette, since even in the hands of an expert, it is dangerous in such cases. As soon as a positive diagnosis is made, a compIete abdomina1 panhysterectomy is indicated. In earIy cases, where the ovaries are normaI, one ovary may be Ieft to continue the ovarian function without danger of metastases. If a positive diagnosis of chorionepitheIioma is made in young women and if there is an element of doubt, the patient shouId be prepared for radica1 operation; when the abdomen is opened, the surgeon, with the situation in perfect contro1, may do a hysterotomy safeIy, to be absoIuteIy sure of the diagnosis. If there has been an error, the uterus may be cIosed and no harm has been done. If the diagnosis is confirmed by the hysterotomy, a panhysterectomy is performed at once. In a11 such cases in which the diagnosis is made earIy and the

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growth and the prognosis

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is confined to the endometrium muscuIature of the uterus, the

FIG. 3. Case

is good,

II.

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if the proper

operation

Gross specimen, showing cavity

when she passed a hydatidiform mole the size of a grapefruit. Dr. RoIf kept her in bed one week after this. Then she resumed some of her

of uterus, with chorionepithelioma musculature.

and treatment is carried out. In inoperabIe cases, radiotherapy, using radium and x-ray, has been used with favorabIe resuIts by Keene, Lackner, Wintz and others; but Hofbauer has but IittIe, if any, faith in radiotherapy. The foIIpwing cases were encountered by the writer: CASE I. Referred by Dr. J. RoIf of Covington, Kentucky, Mrs. F. N., age 39, was the mother of five children, the youngest of whom was 5. She had had no miscarriages and no previous iIIness. Her Iast reguIar menstruation was October 23, 1934. On December 4, 1934, she menstruated for one day. On December 18, there was profuse menstruation Iasting four days, and then dribbling unti1 January 3, 1935, Thick bIood cIots were passed and were folIowed by irregular bIeeding. I first examined her on January 9, 1935, and found the uterus in norma position, somewhat enlarged, with a11 the symptoms and signs of a norma pregnancy that had been threatening to miscarry. I advised rest in bed and morphine as necessary. She remained in bed a few days, then was up part of the time. She had shght uterine hemorrhage at times unti1 February 24,

infiltrating

deep into the

househoId duties, but soon began to bIeed again when she moved about. There was a continuous serous discharge, containing occasiona small pieces of chorionic tissue. This continued with occasiona moderate hemorrhage unti1 March 24, 1935. 1 examined her again, finding her somewhat pale and complaining of a feehng of Iassitude. The peIvic organs were norma except for a sIight emargement of uterus with indication of subinvolution, as one wouId expect to find shortIy after a miscarriage. On March 24, 1935, a Friedman modification of the Aschheim-Zondek pregnancy test was done, using 12 and 6 C.C. of urine on successive days. The rest&s were positive. The test was repeated three days Iater using only 2 and I C.C. of urine, and the rest&s were again positive. The patient entered the St. EIizabeth HospitaI, and three days after the second urine test, a panhysterectomy was done, removing both tubes and ovaries and covering a11 raw surfaces with peritoneum as usua1. The appendix was aIso removed. Clinical Findings. There were no adhesions. The uterus, tubes and ovaries seemed approximateIy normaI, except that the uterus was sIightIy enlarged and soft. The peritoneal covering of the uterus, bladder and broad

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ligaments was very pale, out of al1 proportion a chorionepitheIioma attached to and fiIIing to the moderate anaemia present. A chorionthe fundus, infiItrating deep into the uterine epithehoma the size of a Iarge oIive was found waI1. (Fig. 3.) Recovery was uneventful. in the fundus, attached to and infiItrating deep into the posterior waI1 of the uterus. (Fig. I.) Another Friedman test was made tweIve days after operation and found negative. The patient made an uninterrupted recovery and Ieft the hospital two weeks after operation. She has remained we11 with no signs of metastases up to the present writing (eighteen months after operation). CASE II. Referred by Dr. J. E. Dawson. Mrs. M. K. age 23, had been married three years and was the mother of one chiId, 16 months of age. Her famiIy history was negative, and she herserf had had no previous serious iIIness. Her menstrual history before the first pregnancy was normaI, but menstruation became irregular after the birth of her baby. The Iast menstruation had occurred October 2, I 935 ; there was continuous sIight bIeeding from November 8 to December 20, 1935, when she passed a hydatidiform mole, accompanied by a very profuse hemorrhage. She was removed to the hospita1 at that time and remained there ten days. After this hemorrhage her red ceI1 count was 1,900,000. She improved, but continued to have a serous watery discharge with the intermittent passage FIG. 4. Microscopic section of specimen in Case II, of smaI1 pieces of chorionic tissue unti1 Janshowing the presence of Langhans’ celIs. uary 16, 1936, when a moderate uterine The Friedman test was repeated February hemorrhage occurred. Another bIood count 26, 1936, just sixteen days after operation, was made January 22, 1936, which revealed using I 5 and I o C.C. of urine on successive days. 3,440,ooo red cells and I 1,880 white. She again This test was negative. entered Speers HospitaI on February I, 1936. The patient Ieft the hospita1 February 29, A Friedman modification of the Aschheim1936, and has made a compIete recovery. Zondek test was done February 6, 1936, using She has gained 15 pounds in weight and feels onIy 2 and I C.C. of urine on successive days. weI1. Another bIood count was made ApriI 16, The result was strongIy positive. She had a 1936, about two months after the operation, sIight hemorrhage February 9, 1936. which was as foIIows: We operated February IO, 1936, doing a Red. 5,300,000 panhysterectomy, removing both tubes and White. 9,750 Ieft ovary. The right ovary, which seemed per70 per cent Hb................. fectIy normaI, was Ieft in pIace, since the 54 per cent Polys patient was young (23), and since the writer Lymphocytes. 35 per cent 3 per cent believes that there is no danger of metastases Monocytes. 7 per cent Eosinophiles. in this case. The appendix was aIso removed. r per cent Basophiles. Clinical Findings. The appendix was norCASE III. This case was reported in the ma1; there were no adhesions; the tubes and Cincinnati Lancet CIinic, March 29, 1914, but ovaries appeared normal, the uterus sIightIy enIarged, soft with a patulous external OS. as it resembles the other two cases, I will review it briefly. This patient was referred to me by The peritoneum covering the uterus, bladder and broad Iigaments was very pale, out of a11 Dr. 0. W. Brown. Mrs. M., age 20, had been married one year and had no chiIdren. She proportion to the moderate anemia present had had one miscarriage at three months in at that time. The uterus, on section, reveaIed

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June, 1913, and was curetted a few days later to remove pieces of retained pIacenta. The famiIy history was negative. She had had no previous ilhress, but was neurotic and had attacks of hysteria. Her Iast normal menstruation was on October 20, 1913. Three or four weeks later she began to have a11 the symptoms of pregnancy, with nausea and vomiting, amenorrhea, etc. She had several slight uterine hemorrhages previous to January 23, 1914, when she had a copious hemorrhage. She entered Speers Hospital, and four days Iater passed a hydatidiform moIe. She made an uneventful recovery and returned home ten days after passing the mole. After being home two days, she began bIeeding sIightly again, at intervals. On February 20, she again had a profuse hemorrhage and entered the hospita1. A smaI1 mass was removed from inside the fundus of uterus with a smaI1 forcep. Dr. WooIIey (then Professor of Pathology, University of Cincinnati) made frozen sections of this tumor and pronounced it a chorionepitheIioma and advised immediate radica1 operation, which was done the next day, February 22, 1914. Both tubes, ovaries, the whole uterus and the appendix were removed. The patient made a rapid recovery and is Iiving and we11 at present-twenty-two years after operation. No pregnancy urine tests were made, as they were then unknown. CONCLUSIONS I. AI1 patients who have expeIIed hydatidiform moIes shouId be kept under observation six months or Ionger, with a pregnancy test done each month, this determines if any living chorionic tissue is present. 2. If there is a serosanguinous discharge from the uterus, containing particIes of chorionic tissue, soon after a pregnant uterus has been emptied at or before term, it is very suggestive of chorionepithehoma. 3. According to statistics given by some writers, chorionepitheIioma is very rare, and that to see three cases of chorionepithelioma, I shouId have to see IOO,OOO or 150,000 pregnancies. I do not beIieve

that it is such a rare disease as has been pictured in the literature. 4. I believe that if general practitioners, obstetricians and gynecoIogists are aIert,

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they

wil1 recognize the symptoms here described and diagnose more cases of chorionepithelioma. 5. The prognosis is good if the diagnosis

is made earIy as it was in a11 three cases here reported. These patients are Iiving and we& but the operation, as described in this report, must be performed earIy. I wish to thank Dr. Alfred Glazer, pathoIogist at St. Elizabeth HospitaI of Covington, Kentucky, for his cooperation and exceIIent pathoIogica1 work on these cases; also to express my appreciation and thanks to Professor Hofbauer, Professor of GynecoIogy and Professor Richard Austin, Professor of PathoIogy at the Cincinnati University, for their cooperation and reading of these sections. REFERENCES MATHIEU, ALBERT, and PALMER, ALLEN. The early diagnosis of chorionepithelioma. Surg., Gynec. t?” Obst., 61: 336 (Sept.) 1935. JOURAVIEFF, A. Hydatidiform mole and chorioepithelioma. Gynec. et obst., 27: 223 (March) 1933. CURTIS, A. H. Chorio-epithehoma of the uterus. Surg., Gynec. @ Obst., 54: 861-864 (June) 1932. LEWIS, DEAN. Practice of Surgery. Vol. I I. W. F. Prior Co., Hagerstown, Md. DAVIS, C. H. GynecoIogy and Obstetrics. W. F. Prior Co., Hagerstown, Md. Yearbook of Obstetrics and Gynecology. Yearbook Publishers, Chicago, 1935. NICHOLSON, W. P. Chorio-epithehoma. J. M. A Georgia. 17: 74-76 (Feb.) 1928. BOESE, A. Chorio-epithelioma. J. Kansas M. Sot., 27: 302-304 (Sept.) 1927. SIMS, H. V. Choriocarcinoma (chorioepithelioma) of the uterus. New Orleans M. CY S. J., 83: 882-885 (June) 1931. HINSELMANN, H. Contribution to the theory of cystic mole. Zentralbl. f. Gvniik., 55 : 261-269, 193 I. SCHAANNING,C. K.,“ChorioepitheIioma with an unusuaIIy Iong period of Iatency. Med. Rev., 48: 253 (June) 1931. SZATHMARY,Z. The significance of age and of roentgen and radium therapy in the treatment of moIe and of chorionepithelioma. Ztscbr. f. Geburtsb. u. Gyntik., 98: 444. 1930. BREWS. ALAN. A foIIow-up survey of cases of hydatidiform mole and chorion-epithelioma treated at the London HospitaI since 1912, hoc. Roy. Sot. Med., 28: 1213 (July) 1935. mole. Rev. med. de1 BORRAS, P. E. Hydatidiform Rosario, 23: 840 (Oct.) 1933. STOCKL, E. BioIogic and roentgenoIogic demonstration of metastasis in a case of malignant chorionepitheIioma. Monatscbr. f. Geburtsb. u. GynGk., IOO: 33, ‘935. FINK, K. Contribution to earIy diagnosis of chorionepithelioma following the birth of a child capable of living. Ztscbr. f. Geburtsb. u. Gyniik., 83: 63-79, ,921.