- Email: [email protected]
Benign trophoblastic lesions in Mathieu Chorionepithelioma Registry (hydatidiform mole, syncytial endometritis)
BENIGN TROPHOBLASTIC LESIONS IN MATHIEU CHORIONEPITHELIOMA REGISTRY (HYDATIDIFORM MOLE, SYNCYTIAL ENDOMETRITIS) $: EMIL
NOVAK,
XL).,
BALTIMORE, SINGAPORE,
MD., ANI) (1. S. SEAH, M.l).. MALAYA
E9 HAVE recently published a study of the 74 cases of choriocurcinoma which had been encountered in the material of the hlathieu Memorial C:horionepithelioma Registry of the American Association of Obstetricians, Gynecologists and Abdominal Surgeons up to Sept. 1, 1953. This, we believe, represents the largest number of authent,icated eases available for diretat study by any one group of investigators, and conclusions based on such a material would seem far more reliable than those yielded by collective studies based on cases reported in t,he literature, but, trftcn of doubtful authenticity. A very valuable by-product, of the ( ‘hol.ionrpitheliorna ( ‘ommittee ‘s primary purpose of collecting and stuclyin g malignant choriocarcinolrlas has been the accumulation of a large group of benign trophoblastic lesions. Thtk committee. in the early announcement of it,s ~~nrposes, deliberately al)pealctl to gynecologists, obstetricians, and pathologists to send to t,he Registry all types of pregnancy material in any way cognate with choriocarcinoma, illld this obviously included hydatidiform moles of various types, as well as snc*l~ benign trophoblastic lesions as the so-called syncytial endometritix. The pupose of this appeal was not nierelv the academic one of accumulating snc~lr material for comparative studies, but also hecalwe of the long-recognized fact that lesions of this benign trophohlastit a group are so oft,en incorrectly diagnosed as choriocarcinoma. The correctness of this suspicion has bern amply confirmed 1~7 the esl)erience of our committee, as reported in our previous paper. During the same period of our work which yielded ‘il cases of genuine choriocarcinoltla, there were no less than 85 Cases sent in to IIS with t,he diagnosis of ~horioci~.~ci~~olIla, but which our own study, t,ogether with follow-up stuclies, convinced us t,o be nonmalignant. IVe ought here to rlnphasize that the present l)ill)cr must be looked upon as a supl)lement, to 0~11’ l)rc\ious one 011 cho?~iocaI~~inollla, sinct3 there is some overlapping of’ their cacmtents because of the frequent nccessitv of contrasting t,he benign with the ~~~alignatlt, lesions. Since wf are anxious to avoid repetitiousness in either ~t~rbal or I,hotonli~I,ctgrnphic descriptions, the reader must he referred to t,he prrvic~us pul)lication for further elaboration.
W
*Published under the sponsorship of tile Mathiru Chorionepitheliom; Corurnitter of th(, American Association of Obstetricians, (:ynecologists ant1 Abdominal Surgeons. This coralmittee consists of Drs. John I. Brewer, Willard A. Cooke, R. A. Ross, and Enlil No\rak, Chairman. Dr. Seah’s participation in this study was mnde possible by a Fellowship of the worltf Health Organization. 376
\ ~~IllIIle 68 Numbe, I
BENIGN
LESIONS
IN
CHORIONEPITHELIOMA
REGISTRY
377
Malignancy as it occurs in trophoblastic lesions is determined by the microscope, as it is in all fields of pathology, and not by the clinical course. For example, if a trophoblastic neoplasm is microscopically an unquestionable choriocarcinoma, but the patient gets well, the honest conclusion is that some patients with this disease survive, and the incorrect one would be the cynical statement sometimes heard that the patient coulcl not have hacl a chorioc,arcinoma just because she got well. One might just as well deny the malignancy of innumerable invasive cervical cancers just because they were cured by treatment. We were greatly interested in the group of 85 cases which had been wrongly diagnosed as choriocarcinoma, and hence we have thought it would be of special interest to review this group of nonmalignant lesions, in an efYort to determine, if possible, the reasons for the incorrect diagnoses of malignancy which had been made in them. The microscopic chara,cteristics of choriocarcinoma are now so well established t,hat false negative diagnoses should be rare, i.e., a genuinely malignant, tumor will not often be called a benign lesion. The mistakes are almost always in the other direction, a benign lesion being incorrectly diagnosecl as choriocarcinoma. It should, therefore, be of value to try to explain the great incidence of the false positives which have done so much to vitiate the literature of the subject, and hence this review of our benign lesions, incdluding the 85 cases in which a false lmsitive diagnosis of malignancy had actually been made.
Material Up to Sept. 1, 1953, 154 cases of hydatidiform mole and 27 cases of syncytial endometritis were contributed to the Registry. The mole group included 120 which were classified as frankly benign and 34 which we put Parenunder the intermediate designation of chorioadenoma destruens. thetically, it is hardly necessary to say that the occurrence of only 154 cases of mole in the same general Registry material which yielded 74 cases of c*horiocarcinoma of course throws no light on the relative incidence of the benign and malignant groups, since the Registry material is so heavily weighted by its prima,ry interest in the malignant group. All of the 85 false positive diagnoses were made in the three lesions above Of these 7, there were 5 of simple enumerated except 7 (See Table VII). abortion? 1 of normal decidua with a very early ovum implantation, and 1 case of degenerated tissue showing no trophoblastic tissue at all. All these 7 mistaken diagnoses were of obvious crass type, and they call for no discussion, while the remaining ‘78 do throw light on some of the more common pitfalls of diagnosis. As in our recent study of the choriocarcinomas in the Registry material, our purpose has been an analysis and factual study of our own material rather than a dissertation on the general subject or a review of the literature. Moreover, as with the choriocarcinomas, we feel that the character and limitat,ions of the Registry material make it of somewhat less va,lue in the consideration of hormonology and associated ovarian changes than in the study of the pathology, pathologic differentiation, prognosis, and treatment of the benign trophoblastic lesions.
NOVAK
378
Benign
AND
8BAII
Hydatidiform
Mole
Though there are differences in the estimates of the incidence 01’ hydatidiform mole, the figure usually quoted is .1:2,500 pregnancies. It appears to ISP aeceptecl, also, that both the bcnigll ~tlolr a ncI c.horioc:a.l,cincllI,a ;I I’P disproportionately more common in certain geographic area.s of the oritlntj, especi:lllJ China, t,he Philippines, and Malaya. As a matter 01 fact, it, has IW~II estiroate~l (Reah) that. the incidence of hydatidiforttl mole in these src*tions is about 1 :200 to 300. No adequate explanation has Ijt:en ild\:allretl for this, though some have suggested that the higher illci
Below 20-30 31-40 41-50
Over Age Total
20
50 not
years
71 19 7
known
24
42 5 fi 7 8 9
-.___
I, ; 120
--_
3
Parity Total
__-.---..
20
:: 5 :3 3 1
unknown
1 10 120
__~.
As a matter of fact, one is impressed by the low degree of parity or the nulliparity in such a large proportion of our cases, 89 of our 120 patients No such having had no more than 2 pregnancies, and 38 being nulliparas. preponderance of low parity was seen in our choriocarcinoma eases, and the difference does not seem explainable by any differences in age incidence of the two groups. For example, the bulk of the malignant group, 59 out of 74, occurred between the ages of 20 and 40, while 97 of the 120 benign moles were noted in women of the same age group. Clinicnl Symptoms.-Since these are well known, they need not be here reviewed except to say that the chief initial symptom is usually the bleeding which manifests itself. most often at the third or fourth month of pregnancy. While the first suspicion is likely to be of threatened miscarriage, this may be thrown into doubt by the disproportionately large size of the uterus for the The inability to palpate the fetal parts even when the stage of gestation. uterus is enlarged to the umbilicus or beyond, the absence of fetal heart signs,
BENIGN
LESIONS
IN
CHORIONEPITHELlOMA
REGISTRY
379
the negative s-ray findings, the spontaneous expulsion of the characteristic vesicles, all these help to focus on the probability or certainty of hydatidiform mole. Hormone Tests in Hydatidifow~ Mole.-The biologic methods of study which have been employed for the past quarter of a century are often of great help, though they are not as diagnostically valuable as was once hoped. When their limitations are recognized, however, they are often very useful. It is obvious that a single gonadotrophic titer can have no diagnostic value in the early stages of pregnancy, when the normal titer is very high, sometimes higher than with a mole. If, however, the titer remains high or increases beyond the third month of pregnancy, its diagnostic value is far greater, though it still is not in any way helpful in the differentiation of benign and malignant lesions. Of our 120 cases of hydatidiform mole only 35 had any worth-while hormonal follow-up. In 18 of the 35 cases, the pregnancy test became negative within two months of the evacuation of the mole. Of the 17 cases in which the test was still positive two months after evacuation of the mole, hysterectomy was done in 6 cases (C.R. 7, 42, 138, 142, 169, 203). In these, microscopic examination showed residual but benign tissue in the uterus. In all these cases a negative pregnancy test was noted postoperatively. In another 3 cases (C.R. 38, 43, 224) the test became negative only after repeat dilat,ation and curettage removed some residual molar tissue. In another two cases (C.R. 1, 110) no residual molar tissue was found, but the removal of enlarged cystic ovaries resulted in an almost immediately negative pregnancy test. In another case (C.R. 22) the removal of residual molar tissue in the uterus, as well as enlarged cystic ovaries at laparotomy resulted in a negative pregnancy test. In C.R. 154, the pregnancy test remained positive for more than 3 months after subtotal hysterectomy for a benign mole. Interestingly enough, later examination of the cervix showed it to contain a trophoblastic node. After trachelectomy the test became negative. In C.R. 113 the tests remained positive until the death of the patient thirteen months after hysterectomy. As was stated in a previous section, t,he death of the patient was said to be due to trophoblastic m&stases in the lungs and spine although no autopsy was performed. In C.R. 194 the pregnancy tests remained positive from the time of evacuation of the mole until nine months later when choriocarcinoma was diagnosed at curettage. But in this nine mont,hs’ period there was a. six months’ period of amenorrhea, which brings up the strong possibility of another pregnancy. This case serves to illustrate how important it is for a patient who has had a molar pregnancy to avoicl an&her pregnancy for at, least another year so as not to confuse the hnrmone follow-up. In the remaining two cases (C.R’. 65 ancl 111) the pregnancy t&s did not become negat,ive until two and one-half months after evacuat,ion of the mole. We could find no reaspn why the tests remained positive this long. It may therefore be saicl that in the majority of cases the pregnancy test should become negative within two months after evacuation of the mole. If it is still positive after this period of time the possibilities are : 1. There is residual benign trophoblastic
tissue in the uterus.
2. Enlarged cystic ovxies, which apparently may s(‘rve as ;I reservoir for the h(Jrmones, ~nny 1~ IJrcsent. 2. (‘horioc.urcilloiii;l 01’ ~~I~Ot~il~il~d~~llOltl~l (IeStlYleIls ttlil?’ \‘(h tlcvelq,ed. 4. The patient stay be l)t*egtliltlt agaitl. flil
The most (~otnmon of these I~ossihilities is! of COIWH~.the firsi, but because chot.io~al.crillolrln is such a lethal disease, if the possibility of zrnothet~ I)rsgnancy (‘an IN rnle(l out, one woultl IJ~ .jitstif% in doing a h!-st~~l,cc.toitJ~. especially when a rrI)eat, curettage f‘ails to IJrotlnce :I negative test. Micro.sco@ ,I~,Pecr~cr,Ice.--The main IJathologicA changes whic?ll c~haracterizc: hydatidiform molt are : I. TroI~l~oI~lastic IJroIif(~ration. 2. Edema of stronlal cells. 3. Abscncc~or extreme scantiness of blood vessels.
I+%. l.-Normal uteroplacental junction of a able degree of trophoblastic proliferation. (Kindness of Obstetrics, Johns Hopkins Hospital.)
12 weeks’ of Dr.
pregnancy, George W.
showing Anderson,
R cunsidctDepartment
It is well to recall that it’ 011~’compares young normal placental tissue (ten to twelve weeks’ pregnancy) with MLt,erm placental tissues, the following points arc at once apparent. The young villi arc larger than the mature rilli and. their st,romal cells are much scantithr. The blood vessels in yoiuig villi are also much smaller than those in the: older villi. Not or~ly do the young villi have a fairly complete rovering of l~a~~ghans cells and syncytium, in romparison to the syncytial layer alone left in the older villi, but t,hcrc is also a nlodcrate degree of trophohlastic proliferation, cspcciallg at the placentonterine ,junct.ion, as shown in Fig. 1. It appears, therefore, that there is an abnormal persistence
mole, tending [ to of these immature characteristics in eases of hydatidiform the theory advanced by Hertig and Edmonds3 that such moles aI *e a SU ipport We mention this similarity between hydatidifc 3rm tY-pe of ‘missed abortion.” m ole au immature but otherwise normal trophoblastic tissue, bet :ause we beFig.
Fig.
Z.-Extruded molar w ith Fig. 3. Fig. 3 .-Portion of same Shl swing ITXarked trophoblastic in our pl. e, Gous paper.
co mpare
tissue
(CA
benign mole overgrowth.
2.
57) seen in Other
with
practically
no
trophoblz
Fig. 3 near to its attachment examples of these contrasts
Mic
cover
in the utt are illustr;
lieve that in the past mistakes have often been made in contusing one with t11(’ other, especially by those authors who have reported :I Iligh inc:j(lcnrc; 111 hydatidiform mole formation in ectopic pregnancies. Of all the changes that characterjxe hydatidiform mole 1.11~~~~o~)lloblastic~ proliferat,ion is the most interestin g ant1 most important. This ?liangc~ varies in different parts of the mole, being greats where it is nearest the tltcrine wal I or still implanted within it,, and less when the mole grows awq- from the. ntcrinc wall and its sonrec of blood supply (Figs. 2 and a). When tlici troplro blastie ovc*rgrowth is unduly exuberant lhc lesion may be designated a chorio a(lenoma destrucns, although this criterion of the latter lesion is not as reliable! as that of perforation of the uterine wall or infiltration 01’ paranictriam and.~ot* vagina.
Fix. 4.-Histologically entirely benign mole (C.R. 240) from extruded 1951. Persistent bleeding and positive hormone tests, in spite of repeated curettage, hysterectomy July 7, 1952, death September 12, 1952, with extensive choriocarcinoma.
tissue, August, dilatation and metastasis of
We are frank to say that we have found no feature of the gross or microscopic picture of extruded or cur&ted molar tissue to be of much value as indicating whether a particular hydatidiform mole will pursue a benign or malignant course. Hertig and Sheldoq4 and lately Hunt, Randall, and Dockerty have tried to correlate the degree of t,rophoblastic proliferat,ion, anaplastic changes, and stromal invasion of trophoblast with the subsequent vowsv of the disease. From our study of these 120 cases of hydatidiform mole and the molar tissue submitted with our 26 cases of choriocarcinoma which have followed hydatidiform moles, we have been unable to support this proposition. The molar tissue in many cases which have eventually developed choriocarcinoma shows only very slight trophoblastic proliferation, while many of our cases of
Volume 68 Nuniber I
BRNIGN
LESIONS
IN
CHORIONEPITHELIOMA
REGISTRY
383
hydatidiform mole show marked trophoblastic proliferation, although they have pursued a benign course after only a dilatation and curettage (Figs. 4 and 5). As we have stated in our previous paper the question of anaplasia in trophoblastic tissue is a very difficult, one. We have found, as have Wislocki and Rennet and various other writers, that young cytotrophoblastic cells tend to show great variations in cell size and shape, nuclear size, shape, and staining. Then, too, the degenerative processes of pyknosis and karyorrhexis are oftun confused with cell anaplasia. As was shown in our previous paper, only 39.2 per cent of eases of choriocarcinoma resulted from hydatidiform mole. This is lower than the usual figure of 50 per cent and we believe it is so, because in the past cases of highly proliferative benign moles may have been classified as choriocarcinoma, a mistakr which we hope we have avoided.
Fig. 5.-Myometrial infiltration by rwegnancy or benign mole, led to incorrect Other instance.? of syncytial endometritis
trophoblastic diagnosis illustrated
cells,, which may be seen with normal of chonocarcinoma in this case (C.R. 22). in previous paper.
Treatmelht.-As can be seen in Table III, 99 moles were evacuated vaginally, 11 were evacuated by abdominal hysterotomy, in 8 cases hysterectomy was performed with the mole in situ, and in one case a cesarean section was performed on a mistaken diagnosis of placenta previa. Of the 99 cases which were evacuated vaginally, 36 patients eventually had hysterectomies and of the II evacuated by abdominal hysterotomy, 5 eventually had hysterectomies done. All in all, 49 patients had their uteri removed. A more detailed account of the treat,ment given is shown in Tables IV and V. We must again remind the reader that the preceding figures represent a factual report of the procedures actually carried out in these hydatidiform molts sent to the Regist,ry, by many different individuals and clinics in all parts of the country, and do not always represent ideal methods of therapy.
384
TABLE 6 further Hysterotomy Hysterotomy Hysterotorny Total
V.
surgery followotl follomcd followed
SURGERY
E'or.r.ow~n-c;
by 1 curettage by I~pstewctomy by 1 curettage
A~IXI~I
ant1
IS,IT, Tlvsmmwnr~ 5 1 ., ::
hvsterectom! II
The general plan of management of hydnticliform mule which set’llts safest and most rational to us is as follows : Evacuate the mole vaginally with OVUrll or sponge forceps and follow t,his, preferably four ur five (lays later, 1~s a careful curettage of the uterine cavity. It is probably bet,ter to wait these few days before curettage to permit the uterus to contract and thus lessen the danger of perforation. If, after this, there is no recurrence of hemorrhage, the uterus involutes normally, and the pregnancy test becon1r.s negative within two months, the danger of a malignant change may be cwtlsiclered over, though it would prohbl~lx safer to have a pwgnmqtest done and a physical checknl) monthly for anot,hcr sis months. 1f, however, the bleeding should persist, after the cnrct,tnge? and the uterus fail to involut,c l~roperly, especially in the presence of n persistent or rising gonttdotrophic~ titer a second dilatation ancl curettage is advisable. Following this, if thud symptoms should persist or the curettiugs aplJear highly suspicious of choriocarcinoma with broad fields of trophoblast ;Itld no villi, a hysttbrectomy is justified, but, in most instances, all that will IJC found in the nt,erus when it is removed will. be some residual benign molar tissue deep in the ut,crine ~vall beyond the reach of the curette. Occasionally, however, a true cahoriocarc-ijloma will be found, a.ncl the hysterectomy seems justified by the gravity of the IJrognosis in choriocarcinomn. The second c*nrettage appea.rs advisable I)+ cause of the uncertainty of complctcly removing all molar tissue at the tirsi curettage. We believe the short period of time 1tJ.d by this proeedurc is rnatle worth while when one considers the number of uteri it may save.
BENTGN
LESIONS
IN
CHORTONEPITHELIOMA
REGISTRY
385
If the patient is over 35 years old, and further pregnancies are not important, and the mole is large, total hysterectomy with the mole in situ may be considered. This is done not so much to save the patient and the doctor from a rather tedious follow-up but to avoid the rather massive hemorrhage which vaginal evacuation of a large mole may entail. The actual operation should not l)e any harder than a total hysterectomy for a rather large myoma. IlIetrrstnses.-In a discussion of troplioblastic lesions, it may be well to re~a11 that normal trophoblast exhibits some of the attributes which we normall!, associate with malignancy. The ovum is implanted in the enclometrium by a pl’ocess of destructive invasion and there is often a physiologic metastasis ol tt~ophoblast to the lungs, this being even at times associated with slight attacks of hemoptysis, even though no lesion may he demonstrated on s-ray examination. However, probably as a result of t,he still unknot-n local and systemic defensive mechanism the trophoblastic invasion of the uterine wall is held in normal restraint, and the trophoblast in the lungs apparently undergoes sl)ontaneous lysis. In our series 6 cases (C.R. 31, 42, 65, 113, 154, ancl 259) showed pulmonary nodular densities which were interpreted by radiologists as probably metastatic growths. Case (‘.R. 43 was also suffering from chronic nephritis with hypertension and died 1X months later of cerebral hemorrhage. At postmortem esamination, however, no evidence of trophoblastie metastasis was founcl in the brain, lnng, or other organs and the cause of death was attributed to chronic nephritis. In Case C.R. 113 the patient showecl clinical signs of a spinal tumor two weeks after a hysterectomy in which the uterus showed only residual molar t.issue. She died thirteen months later. No autopsy was performed, hut, tleath was said to be clue to metastases in the lungs and spine. Since the urinary Friedman test had remained positive right up to the time of the pn.tient’s cleath, the evidence is very much in favor of the metaxtases being trophoblastic in nature. Tn Case C.R. 154 there was x-ray evidence of metastases in the lungs and femur after hysterectomy. This case was treatecl by hysterectomy with the tnole in situ, and the only section sent to us was that of the uterine contents. This showed only a perfectly benign mole, though it is quite possible that c~horiocarcinomn, may have been present in other parts of the uterus. This is very improbable since the patient is still alive four years aft,er the hysterectomy. In Case C.R. 31 x-ray examination showed a density in the right lower lobe. The patient was given deep x-ray chest therapy. The lesion resolved, and the patient has stayed well. X-ray showed metastatic nodules in both lungs in Case C.R. 65. The lesions, however, regressed spontaneously, and t,he patient has stayed well. A similar picture was seen in Case C.R. 2~9, but since this case has been sent in to the Registry only recently, we have no follow-up on her. These cases serve to illustrate that while s-ray evitlence of metastases cases of choriocarcinoma is rightly considered a matter of grave import, same finding in cases where the uterus shows benign mole need not be garded with similar concern, though one cannot eliminate the possibility
in the reof
later choriocaarcinoma in primarily I)enign trc~phoblastic pulmonary ttletasti~s(~s. This could conceivably explain some of the T c’ascs of chu~ioc:al,cirlotlla ill 111~ Itegist,ry in which t,hc patient died 01’ lesiotts irl the lungs ant1 OI-her OI-~III~ with no evidence of c.lrlor,iocnrcinotn,z ill the ~~tt~t~~~s. In these V;IS(JStvr n~i~hl postulate the failure of a systemic2 deFtqlsi\-(L t’il(*tor in thus I)r(‘setlc’t’ 01’ :I II adequate local dcfensiYe Uactor in the itierus.
POZZOW-Up--As can he seen from our follow-up EO patients have died, and this calls for explanation.
table (Table \-1 ) 5
ot'
0111'
These are eases C.R. 42, 112, 113, 194, and 269. Cases C.1:. 42 and 11:: ( fasr C.R. 112 have already been discussed in the section under metaxtases. was one of hydatidifornl mole associated with cclampt,ic convulsions. Death occurred 18 hours after a hysterectomy, nncl must, therefore, 1~ labeled an operative death. Case C.R. 26-l alsO had very severe I)r’e-e~lamptic toxemia, and died before t,hr mole could be evacuated. At autopsy hemorrhages were found in the brain, lungs, and other organs, but no t,rophoblastic tissue could be demonstrated in the sections of the organs. Her deat,h was, therefore? probably due t,o t,he pre-eclamptic toxemia. Case C.R. 194 is of’ special interest because it is the only case originally registered as benign hydatidiform mole, which subsequently developed choriocarcinoma. The patient was a 17.year-old girl who in August, 1951, had a dilata,tion and curettage clone for hydatidiform mole. In September! 1951, she had a repeat dilatation and curettage for excessive bleeding, and the tissue evacuated again showed only benign ntc~lr. After six months amenolaThe eurettings rhea curettage was done in June 1952 because nf free bleeding. this time were very suspicious of choriocarcilloma. A total hysterectomy ancl left oophorectomy were done in March, 1953. I%ot,h the uterus and the left, S-rays of the chest were negative ovary were riddled with choriocarcinc,Ina. up to the time OS the last operation, but, two weeks postoperatively t,he s-r;14 showed rather tlefinite small metastatic t’oei. She died of mrtastases it1 September. 1953. The fact that there was :I six months’ period of amenorrhea prior t,o the discovery of choriocarcinoma in June, 1952, makes us suspect that Ihe choriocarcinoma may have developecl from an intercurrent pregnant-\ long after the molar ‘pregnancy in August, 1!)51, though the possibility of choriocarcinoma developing in residual molar tissue in the uterine wall out of reach of the curette must also be borne in mind.
Of the 71 patients in our have since had one full-term “several” full-term deliveries. and another has had an ectopic
series in whom the uterus was preserved 11 term deliveries and one delivery, 3 two-full One patient is pregnant at the time of writing. tubal pregnancy.
BENTGN
LESIONS
TN
CITORIONEPITJ-IELIOMA
Chorioadenoma
REGISTRY
387
Destruens
Our material includes, in addition to the 120 frankly benign hydatidiform moles, 34 cases of the intermediate type of lesion most often spoken of by Ewing’s original designation of chorioadenoma destruens. As this lesion SO often comes into both clinical and pathologic competition with the frankly malignant choriocsrcinoma, it seemed necessary for us to include a discussion of its characteristics in our recent paper on choriocarcinoma to which the reader will have to be referred. Since, however, there is a very definite overlap in the clinical and pathologic features of chorioadenoma destrurns and benign hydatidiform mole, we may perhaps be forgiven for including a brief: comment on the clifferentiation of the two lesions. While we do not consider that the term chorioadenoma destruens is a good one, it has been accepted by most writers and seems no more objectionable than others which have been used, such as malignant mole, penetrative mole, invasive mole, destructive mole, et,c. Neither Ewing2 nor anyone else seems ever to have defined it, but we have suggested two chief criteria: ( 1) an inordinate degree of trophoblastic overgrowth and (2) undue penetrativeness of the trophoblastic elements, including the villi, into the depths 01 the uterine wall, extending into the peritoneum or into the adjacent parainetrium or vaginal vault. Such moles can therefore be locally invasive, but, they have little tendency to the distant metastasis which cha,racterizes choriocarcinoma, though there are certainly exceptions tco this. We shall not here again go into details as to the microscopic differentiat,ions of such moles from either the frankly benign ones or from the frankly malignant choriocarcinomas. As cont,rasted with the former, chorioadenoma destruens shows usually large fields of trophoblast, but even very benign moles with very little trophoblast may show the extreme penetrativeness which constitutes the other criterion of this lesion. As contrasted with choriocarcinoma, we have laid great stress on the fact that chorioadenoma shows a well-preserved vill.ous pattern, and that with rare exceptions choriocarcinorna shows a complete absence of the villi from which the malignant tumor had its source. In only 1 of our 74 cases were a few villi found. In some cases the diagnosis of chorioadenoma destruens cannot be made until after hysterectomy, but in a good many it can be made presumptively or at least suspected by the occurrence of intra-abclominal hemorrhage or by the findings by palpation of parametrial invasion or the demonstration of vaginal extension. Such clinical features, combined with cnrettings showing benign moles, with or without trophoblastic overgrowth, but with well-preserved villi, make it almost certain that the lesion is a chorioadenoma destruens rather than a choriocarcinoma, which might ot,herwise be neglected. Honnon.e Tests in Chorioadenoma Destruen.s.-Of the 34 cases of chorionclrnoma destruens only 13 had any sort of hormone follow-up.
In 9 cases (C.R. 51, 67, 97, 116, 126, 149, 170, 213, 255) the pregnancy test was negative within two months after hysterectomy. In 2 cases (C.R. 64 and 65) the pregnancy tests did not become negative until three months after hysterectomy.
quently excessive trophoblastic proliferation shown by these lesions near or in the uterine wall. However, we must stress that in t,hese two lesions welll)reserved villi are also present, and their presence even with fairly large c~ollections of trophoblastic cells should always make one lean away from the diagnosis of choriocarcinoma.
NO. REGISTRY
TOTAL
Benign mole Ryncytixl cndometritis Cllorioxdcnonla drstrums Ahortion Normal deridua of caxly Degenerating tissue (no Total
ovum trophohlast
)
120 Or 3; 5 1 1 188
IN
X0. OF WRONG IIIARNOSES
46 19 15 3 1 1 85
One must also remember that in any one section it is possible to obtain a tangential cut of the trophoblastic covering of the villi in such a way as to show only large clumps of trophoblastic cells without any villi. One should not, therefore, jump to a diagnosis of choriocarcinoma, but should examine several other sections to exclude this possibility. As we have stated in our previous paper, well-formed villi are almost always absent in cases of choriocarcinoma. We noted a few villi among large masses of trophoblastic cells in only 1 of our 74 cases of choriocarcinoma. Another source of error is the tendency to rely too much upon the socalled anaplastic changes in the trophoblast. For reasons we have already mentioned we have found this factor to be of very little help in gauging the benign or malignant nature of the lesion. The presence of hemorrhagic or trophoblastic nodes in t,he uterine wdl has also apparently been thought by some to be characteristic of choriocarcinoma. In the 49 cases of benign mole in which hysterectomies were performed. no less than 26 of the uteri contain one or more of these nodes. On microscopic examination these nodes were seen to consist of benign residual molar tissue with a variable quant,ity of old blood. At times, however, these nodes will contain only blood clots and a few scattered atrophic trophohlastic cells. Only when these nodes contain the characteristic large masses of wellpreserved t,rophoblast with no villi can one be justified in calling the lesion choriocarcinoma. The presence of these hemorrhagic nodes in the vagina in cases of chorioatlenoma destruens has also been assumed by some to be indicative of chorioc~arcinoma. One must remember that this local vaginal invasion occurs in (dases of chorioadenoma destruens, as well as in cases of choriocarcinoma, but that in the former villi will often be present in the vaginal lesion as well as in the primary lesion in the uterus. As we can see in Table VII no less than 19 of our 29 cases of syncytial endometritis were misdiagnosed as choriocarcinoma. We believe that this was because t,he pathologists concerned confused the infiltration of small clumps or narrow columns of syncytial cells characteristic of syncytial endometritis
one s11011ld rt’lll~~llll)t~t~. the trophololastic invasion of choriocal~cilloltla. t,hat in the c?ho~ioearcinoma the invasion is by bulky Inasses 01 t,rophohlastic cells with usually considerable hemorrhage at~tl llc~c~rosis. III syncytial endometritis there is no Iie(*rcbsis uf the snrromidin~ rllllsc~lr ;Intl III) \vt’ INLanghans cells arc prest>nt. .rf these tlift’rl.t~litidionrss are reinrnll)t~l*vfl licve this confusion will IW c~lea~tl 111)14I a great est,ent. with
however,
Summary 1. This is a report of 120 casts III’ I)ellig:lr hydatitiiform moit~, :S eases 01’ chorioadenoma destraens, and 37 01’ syllcytial elldometritis in the Mathicu Memorial Chorionepithelioma Registr>.. 2. The gross and microscol)ic aJ)t)(‘i~t’iIlI(~t~S of these two lesions are I’c’viewed. 3. Contrary to the findings of some authors, we have heen ~mahle IO derive mnch help from the gross ant1 micarosc*opic appearanc:e 0.C CVHcuat et1 molar tissue in predicting whether a given mole will or will llot later develop malignant histologic or clinical characteristics. i. The lesion called syncytia.1 endometritis is a rcsithnurl c~f norll)a I pregnaney, abortion, or hydntidifornl nlolc. ant1 not, an atypical variet.\- of’ c*lioriocarcinoma. Our follow-up of these ~ase’s suppol-ts this viewpoint. 5. Once again WC stress t,he freqnency with which cases of hptlat,idifornl mole, chorioadenoma destruens, a~(1 syncytiwl endomet,ritis are mistliagnosc~tl as ehoriocarcinoma. The ~‘ommon sonrces of error are diacnsscil antI we h:tyr tried to show how most of these pitfalls Iuxy 1~ avoidetl. References E.: Ah1. J. OBST. $ GYNEC. 15: 694, l!M. Ewing, J.: Surg., Gynec?. 85 OhYt‘. 10: :mi. 1910. Arch. Path 30: 2Ml, t9411, Hertig, A. T., and Edmonds, H. W.: Hertig, A. T., and Sheldon, W. H.: 91~1. .J. OHST: & (:Yh-EC.53: 1, 1947. Monatsehr. f. Geburtsh. u. UynLik. 1: 419, 513, 1895. Marchand, F.: Internat. Abstr. Surg. 68: 52, 181, 1939; in Surg., Gynw. Mathieu, A.: & Feb., 1939. J. A. M A. 78: 1771, 1932. Novak, E.: AM. J. &ST. & GYNEC. 59: 15, 1950. Novak, E.: Novak, E., and Seah, C. S.: AXC. .J. OBST. & (:YNE('. 67: $1::::. l!lii-&. Park, W. W., and Lees, J. C.: Arch. Path. 49: 73, 205, 1950. Ahr. J. OHHT. & GYMW. 56: 584, l!L48. Reis, R. A., and DeCosta, E. J.:
1. illlen,
2. 3. 4. 5. 6. 7.
8. 9. IO. 11.
6i Obst.,
Jan.
NOVAK,
XL).,
BALTIMORE, SINGAPORE,
MD., ANI) (1. S. SEAH, M.l).. MALAYA
E9 HAVE recently published a study of the 74 cases of choriocurcinoma which had been encountered in the material of the hlathieu Memorial C:horionepithelioma Registry of the American Association of Obstetricians, Gynecologists and Abdominal Surgeons up to Sept. 1, 1953. This, we believe, represents the largest number of authent,icated eases available for diretat study by any one group of investigators, and conclusions based on such a material would seem far more reliable than those yielded by collective studies based on cases reported in t,he literature, but, trftcn of doubtful authenticity. A very valuable by-product, of the ( ‘hol.ionrpitheliorna ( ‘ommittee ‘s primary purpose of collecting and stuclyin g malignant choriocarcinolrlas has been the accumulation of a large group of benign trophoblastic lesions. Thtk committee. in the early announcement of it,s ~~nrposes, deliberately al)pealctl to gynecologists, obstetricians, and pathologists to send to t,he Registry all types of pregnancy material in any way cognate with choriocarcinoma, illld this obviously included hydatidiform moles of various types, as well as snc*l~ benign trophoblastic lesions as the so-called syncytial endometritix. The pupose of this appeal was not nierelv the academic one of accumulating snc~lr material for comparative studies, but also hecalwe of the long-recognized fact that lesions of this benign trophohlastit a group are so oft,en incorrectly diagnosed as choriocarcinoma. The correctness of this suspicion has bern amply confirmed 1~7 the esl)erience of our committee, as reported in our previous paper. During the same period of our work which yielded ‘il cases of genuine choriocarcinoltla, there were no less than 85 Cases sent in to IIS with t,he diagnosis of ~horioci~.~ci~~olIla, but which our own study, t,ogether with follow-up stuclies, convinced us t,o be nonmalignant. IVe ought here to rlnphasize that the present l)ill)cr must be looked upon as a supl)lement, to 0~11’ l)rc\ious one 011 cho?~iocaI~~inollla, sinct3 there is some overlapping of’ their cacmtents because of the frequent nccessitv of contrasting t,he benign with the ~~~alignatlt, lesions. Since wf are anxious to avoid repetitiousness in either ~t~rbal or I,hotonli~I,ctgrnphic descriptions, the reader must he referred to t,he prrvic~us pul)lication for further elaboration.
W
*Published under the sponsorship of tile Mathiru Chorionepitheliom; Corurnitter of th(, American Association of Obstetricians, (:ynecologists ant1 Abdominal Surgeons. This coralmittee consists of Drs. John I. Brewer, Willard A. Cooke, R. A. Ross, and Enlil No\rak, Chairman. Dr. Seah’s participation in this study was mnde possible by a Fellowship of the worltf Health Organization. 376
\ ~~IllIIle 68 Numbe, I
BENIGN
LESIONS
IN
CHORIONEPITHELIOMA
REGISTRY
377
Malignancy as it occurs in trophoblastic lesions is determined by the microscope, as it is in all fields of pathology, and not by the clinical course. For example, if a trophoblastic neoplasm is microscopically an unquestionable choriocarcinoma, but the patient gets well, the honest conclusion is that some patients with this disease survive, and the incorrect one would be the cynical statement sometimes heard that the patient coulcl not have hacl a chorioc,arcinoma just because she got well. One might just as well deny the malignancy of innumerable invasive cervical cancers just because they were cured by treatment. We were greatly interested in the group of 85 cases which had been wrongly diagnosed as choriocarcinoma, and hence we have thought it would be of special interest to review this group of nonmalignant lesions, in an efYort to determine, if possible, the reasons for the incorrect diagnoses of malignancy which had been made in them. The microscopic chara,cteristics of choriocarcinoma are now so well established t,hat false negative diagnoses should be rare, i.e., a genuinely malignant, tumor will not often be called a benign lesion. The mistakes are almost always in the other direction, a benign lesion being incorrectly diagnosecl as choriocarcinoma. It should, therefore, be of value to try to explain the great incidence of the false positives which have done so much to vitiate the literature of the subject, and hence this review of our benign lesions, incdluding the 85 cases in which a false lmsitive diagnosis of malignancy had actually been made.
Material Up to Sept. 1, 1953, 154 cases of hydatidiform mole and 27 cases of syncytial endometritis were contributed to the Registry. The mole group included 120 which were classified as frankly benign and 34 which we put Parenunder the intermediate designation of chorioadenoma destruens. thetically, it is hardly necessary to say that the occurrence of only 154 cases of mole in the same general Registry material which yielded 74 cases of c*horiocarcinoma of course throws no light on the relative incidence of the benign and malignant groups, since the Registry material is so heavily weighted by its prima,ry interest in the malignant group. All of the 85 false positive diagnoses were made in the three lesions above Of these 7, there were 5 of simple enumerated except 7 (See Table VII). abortion? 1 of normal decidua with a very early ovum implantation, and 1 case of degenerated tissue showing no trophoblastic tissue at all. All these 7 mistaken diagnoses were of obvious crass type, and they call for no discussion, while the remaining ‘78 do throw light on some of the more common pitfalls of diagnosis. As in our recent study of the choriocarcinomas in the Registry material, our purpose has been an analysis and factual study of our own material rather than a dissertation on the general subject or a review of the literature. Moreover, as with the choriocarcinomas, we feel that the character and limitat,ions of the Registry material make it of somewhat less va,lue in the consideration of hormonology and associated ovarian changes than in the study of the pathology, pathologic differentiation, prognosis, and treatment of the benign trophoblastic lesions.
NOVAK
378
Benign
AND
8BAII
Hydatidiform
Mole
Though there are differences in the estimates of the incidence 01’ hydatidiform mole, the figure usually quoted is .1:2,500 pregnancies. It appears to ISP aeceptecl, also, that both the bcnigll ~tlolr a ncI c.horioc:a.l,cincllI,a ;I I’P disproportionately more common in certain geographic area.s of the oritlntj, especi:lllJ China, t,he Philippines, and Malaya. As a matter 01 fact, it, has IW~II estiroate~l (Reah) that. the incidence of hydatidiforttl mole in these src*tions is about 1 :200 to 300. No adequate explanation has Ijt:en ild\:allretl for this, though some have suggested that the higher illci
Below 20-30 31-40 41-50
Over Age Total
20
50 not
years
71 19 7
known
24
42 5 fi 7 8 9
-.___
I, ; 120
--_
3
Parity Total
__-.---..
20
:: 5 :3 3 1
unknown
1 10 120
__~.
As a matter of fact, one is impressed by the low degree of parity or the nulliparity in such a large proportion of our cases, 89 of our 120 patients No such having had no more than 2 pregnancies, and 38 being nulliparas. preponderance of low parity was seen in our choriocarcinoma eases, and the difference does not seem explainable by any differences in age incidence of the two groups. For example, the bulk of the malignant group, 59 out of 74, occurred between the ages of 20 and 40, while 97 of the 120 benign moles were noted in women of the same age group. Clinicnl Symptoms.-Since these are well known, they need not be here reviewed except to say that the chief initial symptom is usually the bleeding which manifests itself. most often at the third or fourth month of pregnancy. While the first suspicion is likely to be of threatened miscarriage, this may be thrown into doubt by the disproportionately large size of the uterus for the The inability to palpate the fetal parts even when the stage of gestation. uterus is enlarged to the umbilicus or beyond, the absence of fetal heart signs,
BENIGN
LESIONS
IN
CHORIONEPITHELlOMA
REGISTRY
379
the negative s-ray findings, the spontaneous expulsion of the characteristic vesicles, all these help to focus on the probability or certainty of hydatidiform mole. Hormone Tests in Hydatidifow~ Mole.-The biologic methods of study which have been employed for the past quarter of a century are often of great help, though they are not as diagnostically valuable as was once hoped. When their limitations are recognized, however, they are often very useful. It is obvious that a single gonadotrophic titer can have no diagnostic value in the early stages of pregnancy, when the normal titer is very high, sometimes higher than with a mole. If, however, the titer remains high or increases beyond the third month of pregnancy, its diagnostic value is far greater, though it still is not in any way helpful in the differentiation of benign and malignant lesions. Of our 120 cases of hydatidiform mole only 35 had any worth-while hormonal follow-up. In 18 of the 35 cases, the pregnancy test became negative within two months of the evacuation of the mole. Of the 17 cases in which the test was still positive two months after evacuation of the mole, hysterectomy was done in 6 cases (C.R. 7, 42, 138, 142, 169, 203). In these, microscopic examination showed residual but benign tissue in the uterus. In all these cases a negative pregnancy test was noted postoperatively. In another 3 cases (C.R. 38, 43, 224) the test became negative only after repeat dilat,ation and curettage removed some residual molar tissue. In another two cases (C.R. 1, 110) no residual molar tissue was found, but the removal of enlarged cystic ovaries resulted in an almost immediately negative pregnancy test. In another case (C.R. 22) the removal of residual molar tissue in the uterus, as well as enlarged cystic ovaries at laparotomy resulted in a negative pregnancy test. In C.R. 154, the pregnancy test remained positive for more than 3 months after subtotal hysterectomy for a benign mole. Interestingly enough, later examination of the cervix showed it to contain a trophoblastic node. After trachelectomy the test became negative. In C.R. 113 the tests remained positive until the death of the patient thirteen months after hysterectomy. As was stated in a previous section, t,he death of the patient was said to be due to trophoblastic m&stases in the lungs and spine although no autopsy was performed. In C.R. 194 the pregnancy tests remained positive from the time of evacuation of the mole until nine months later when choriocarcinoma was diagnosed at curettage. But in this nine mont,hs’ period there was a. six months’ period of amenorrhea, which brings up the strong possibility of another pregnancy. This case serves to illustrate how important it is for a patient who has had a molar pregnancy to avoicl an&her pregnancy for at, least another year so as not to confuse the hnrmone follow-up. In the remaining two cases (C.R’. 65 ancl 111) the pregnancy t&s did not become negat,ive until two and one-half months after evacuat,ion of the mole. We could find no reaspn why the tests remained positive this long. It may therefore be saicl that in the majority of cases the pregnancy test should become negative within two months after evacuation of the mole. If it is still positive after this period of time the possibilities are : 1. There is residual benign trophoblastic
tissue in the uterus.
2. Enlarged cystic ovxies, which apparently may s(‘rve as ;I reservoir for the h(Jrmones, ~nny 1~ IJrcsent. 2. (‘horioc.urcilloiii;l 01’ ~~I~Ot~il~il~d~~llOltl~l (IeStlYleIls ttlil?’ \‘(h tlcvelq,ed. 4. The patient stay be l)t*egtliltlt agaitl. flil
The most (~otnmon of these I~ossihilities is! of COIWH~.the firsi, but because chot.io~al.crillolrln is such a lethal disease, if the possibility of zrnothet~ I)rsgnancy (‘an IN rnle(l out, one woultl IJ~ .jitstif% in doing a h!-st~~l,cc.toitJ~. especially when a rrI)eat, curettage f‘ails to IJrotlnce :I negative test. Micro.sco@ ,I~,Pecr~cr,Ice.--The main IJathologicA changes whic?ll c~haracterizc: hydatidiform molt are : I. TroI~l~oI~lastic IJroIif(~ration. 2. Edema of stronlal cells. 3. Abscncc~or extreme scantiness of blood vessels.
I+%. l.-Normal uteroplacental junction of a able degree of trophoblastic proliferation. (Kindness of Obstetrics, Johns Hopkins Hospital.)
12 weeks’ of Dr.
pregnancy, George W.
showing Anderson,
R cunsidctDepartment
It is well to recall that it’ 011~’compares young normal placental tissue (ten to twelve weeks’ pregnancy) with MLt,erm placental tissues, the following points arc at once apparent. The young villi arc larger than the mature rilli and. their st,romal cells are much scantithr. The blood vessels in yoiuig villi are also much smaller than those in the: older villi. Not or~ly do the young villi have a fairly complete rovering of l~a~~ghans cells and syncytium, in romparison to the syncytial layer alone left in the older villi, but t,hcrc is also a nlodcrate degree of trophohlastic proliferation, cspcciallg at the placentonterine ,junct.ion, as shown in Fig. 1. It appears, therefore, that there is an abnormal persistence
mole, tending [ to of these immature characteristics in eases of hydatidiform the theory advanced by Hertig and Edmonds3 that such moles aI *e a SU ipport We mention this similarity between hydatidifc 3rm tY-pe of ‘missed abortion.” m ole au immature but otherwise normal trophoblastic tissue, bet :ause we beFig.
Fig.
Z.-Extruded molar w ith Fig. 3. Fig. 3 .-Portion of same Shl swing ITXarked trophoblastic in our pl. e, Gous paper.
co mpare
tissue
(CA
benign mole overgrowth.
2.
57) seen in Other
with
practically
no
trophoblz
Fig. 3 near to its attachment examples of these contrasts
Mic
cover
in the utt are illustr;
lieve that in the past mistakes have often been made in contusing one with t11(’ other, especially by those authors who have reported :I Iligh inc:j(lcnrc; 111 hydatidiform mole formation in ectopic pregnancies. Of all the changes that characterjxe hydatidiform mole 1.11~~~~o~)lloblastic~ proliferat,ion is the most interestin g ant1 most important. This ?liangc~ varies in different parts of the mole, being greats where it is nearest the tltcrine wal I or still implanted within it,, and less when the mole grows awq- from the. ntcrinc wall and its sonrec of blood supply (Figs. 2 and a). When tlici troplro blastie ovc*rgrowth is unduly exuberant lhc lesion may be designated a chorio a(lenoma destrucns, although this criterion of the latter lesion is not as reliable! as that of perforation of the uterine wall or infiltration 01’ paranictriam and.~ot* vagina.
Fix. 4.-Histologically entirely benign mole (C.R. 240) from extruded 1951. Persistent bleeding and positive hormone tests, in spite of repeated curettage, hysterectomy July 7, 1952, death September 12, 1952, with extensive choriocarcinoma.
tissue, August, dilatation and metastasis of
We are frank to say that we have found no feature of the gross or microscopic picture of extruded or cur&ted molar tissue to be of much value as indicating whether a particular hydatidiform mole will pursue a benign or malignant course. Hertig and Sheldoq4 and lately Hunt, Randall, and Dockerty have tried to correlate the degree of t,rophoblastic proliferat,ion, anaplastic changes, and stromal invasion of trophoblast with the subsequent vowsv of the disease. From our study of these 120 cases of hydatidiform mole and the molar tissue submitted with our 26 cases of choriocarcinoma which have followed hydatidiform moles, we have been unable to support this proposition. The molar tissue in many cases which have eventually developed choriocarcinoma shows only very slight trophoblastic proliferation, while many of our cases of
Volume 68 Nuniber I
BRNIGN
LESIONS
IN
CHORIONEPITHELIOMA
REGISTRY
383
hydatidiform mole show marked trophoblastic proliferation, although they have pursued a benign course after only a dilatation and curettage (Figs. 4 and 5). As we have stated in our previous paper the question of anaplasia in trophoblastic tissue is a very difficult, one. We have found, as have Wislocki and Rennet and various other writers, that young cytotrophoblastic cells tend to show great variations in cell size and shape, nuclear size, shape, and staining. Then, too, the degenerative processes of pyknosis and karyorrhexis are oftun confused with cell anaplasia. As was shown in our previous paper, only 39.2 per cent of eases of choriocarcinoma resulted from hydatidiform mole. This is lower than the usual figure of 50 per cent and we believe it is so, because in the past cases of highly proliferative benign moles may have been classified as choriocarcinoma, a mistakr which we hope we have avoided.
Fig. 5.-Myometrial infiltration by rwegnancy or benign mole, led to incorrect Other instance.? of syncytial endometritis
trophoblastic diagnosis illustrated
cells,, which may be seen with normal of chonocarcinoma in this case (C.R. 22). in previous paper.
Treatmelht.-As can be seen in Table III, 99 moles were evacuated vaginally, 11 were evacuated by abdominal hysterotomy, in 8 cases hysterectomy was performed with the mole in situ, and in one case a cesarean section was performed on a mistaken diagnosis of placenta previa. Of the 99 cases which were evacuated vaginally, 36 patients eventually had hysterectomies and of the II evacuated by abdominal hysterotomy, 5 eventually had hysterectomies done. All in all, 49 patients had their uteri removed. A more detailed account of the treat,ment given is shown in Tables IV and V. We must again remind the reader that the preceding figures represent a factual report of the procedures actually carried out in these hydatidiform molts sent to the Regist,ry, by many different individuals and clinics in all parts of the country, and do not always represent ideal methods of therapy.
384
TABLE 6 further Hysterotomy Hysterotomy Hysterotorny Total
V.
surgery followotl follomcd followed
SURGERY
E'or.r.ow~n-c;
by 1 curettage by I~pstewctomy by 1 curettage
A~IXI~I
ant1
IS,IT, Tlvsmmwnr~ 5 1 ., ::
hvsterectom! II
The general plan of management of hydnticliform mule which set’llts safest and most rational to us is as follows : Evacuate the mole vaginally with OVUrll or sponge forceps and follow t,his, preferably four ur five (lays later, 1~s a careful curettage of the uterine cavity. It is probably bet,ter to wait these few days before curettage to permit the uterus to contract and thus lessen the danger of perforation. If, after this, there is no recurrence of hemorrhage, the uterus involutes normally, and the pregnancy test becon1r.s negative within two months, the danger of a malignant change may be cwtlsiclered over, though it would prohbl~lx safer to have a pwgnmqtest done and a physical checknl) monthly for anot,hcr sis months. 1f, however, the bleeding should persist, after the cnrct,tnge? and the uterus fail to involut,c l~roperly, especially in the presence of n persistent or rising gonttdotrophic~ titer a second dilatation ancl curettage is advisable. Following this, if thud symptoms should persist or the curettiugs aplJear highly suspicious of choriocarcinoma with broad fields of trophoblast ;Itld no villi, a hysttbrectomy is justified, but, in most instances, all that will IJC found in the nt,erus when it is removed will. be some residual benign molar tissue deep in the ut,crine ~vall beyond the reach of the curette. Occasionally, however, a true cahoriocarc-ijloma will be found, a.ncl the hysterectomy seems justified by the gravity of the IJrognosis in choriocarcinomn. The second c*nrettage appea.rs advisable I)+ cause of the uncertainty of complctcly removing all molar tissue at the tirsi curettage. We believe the short period of time 1tJ.d by this proeedurc is rnatle worth while when one considers the number of uteri it may save.
BENTGN
LESIONS
IN
CHORTONEPITHELIOMA
REGISTRY
385
If the patient is over 35 years old, and further pregnancies are not important, and the mole is large, total hysterectomy with the mole in situ may be considered. This is done not so much to save the patient and the doctor from a rather tedious follow-up but to avoid the rather massive hemorrhage which vaginal evacuation of a large mole may entail. The actual operation should not l)e any harder than a total hysterectomy for a rather large myoma. IlIetrrstnses.-In a discussion of troplioblastic lesions, it may be well to re~a11 that normal trophoblast exhibits some of the attributes which we normall!, associate with malignancy. The ovum is implanted in the enclometrium by a pl’ocess of destructive invasion and there is often a physiologic metastasis ol tt~ophoblast to the lungs, this being even at times associated with slight attacks of hemoptysis, even though no lesion may he demonstrated on s-ray examination. However, probably as a result of t,he still unknot-n local and systemic defensive mechanism the trophoblastic invasion of the uterine wall is held in normal restraint, and the trophoblast in the lungs apparently undergoes sl)ontaneous lysis. In our series 6 cases (C.R. 31, 42, 65, 113, 154, ancl 259) showed pulmonary nodular densities which were interpreted by radiologists as probably metastatic growths. Case (‘.R. 43 was also suffering from chronic nephritis with hypertension and died 1X months later of cerebral hemorrhage. At postmortem esamination, however, no evidence of trophoblastie metastasis was founcl in the brain, lnng, or other organs and the cause of death was attributed to chronic nephritis. In Case C.R. 113 the patient showecl clinical signs of a spinal tumor two weeks after a hysterectomy in which the uterus showed only residual molar t.issue. She died thirteen months later. No autopsy was performed, hut, tleath was said to be clue to metastases in the lungs and spine. Since the urinary Friedman test had remained positive right up to the time of the pn.tient’s cleath, the evidence is very much in favor of the metaxtases being trophoblastic in nature. Tn Case C.R. 154 there was x-ray evidence of metastases in the lungs and femur after hysterectomy. This case was treatecl by hysterectomy with the tnole in situ, and the only section sent to us was that of the uterine contents. This showed only a perfectly benign mole, though it is quite possible that c~horiocarcinomn, may have been present in other parts of the uterus. This is very improbable since the patient is still alive four years aft,er the hysterectomy. In Case C.R. 31 x-ray examination showed a density in the right lower lobe. The patient was given deep x-ray chest therapy. The lesion resolved, and the patient has stayed well. X-ray showed metastatic nodules in both lungs in Case C.R. 65. The lesions, however, regressed spontaneously, and t,he patient has stayed well. A similar picture was seen in Case C.R. 2~9, but since this case has been sent in to the Registry only recently, we have no follow-up on her. These cases serve to illustrate that while s-ray evitlence of metastases cases of choriocarcinoma is rightly considered a matter of grave import, same finding in cases where the uterus shows benign mole need not be garded with similar concern, though one cannot eliminate the possibility
in the reof
later choriocaarcinoma in primarily I)enign trc~phoblastic pulmonary ttletasti~s(~s. This could conceivably explain some of the T c’ascs of chu~ioc:al,cirlotlla ill 111~ Itegist,ry in which t,hc patient died 01’ lesiotts irl the lungs ant1 OI-her OI-~III~ with no evidence of c.lrlor,iocnrcinotn,z ill the ~~tt~t~~~s. In these V;IS(JStvr n~i~hl postulate the failure of a systemic2 deFtqlsi\-(L t’il(*tor in thus I)r(‘setlc’t’ 01’ :I II adequate local dcfensiYe Uactor in the itierus.
POZZOW-Up--As can he seen from our follow-up EO patients have died, and this calls for explanation.
table (Table \-1 ) 5
ot'
0111'
These are eases C.R. 42, 112, 113, 194, and 269. Cases C.1:. 42 and 11:: ( fasr C.R. 112 have already been discussed in the section under metaxtases. was one of hydatidifornl mole associated with cclampt,ic convulsions. Death occurred 18 hours after a hysterectomy, nncl must, therefore, 1~ labeled an operative death. Case C.R. 26-l alsO had very severe I)r’e-e~lamptic toxemia, and died before t,hr mole could be evacuated. At autopsy hemorrhages were found in the brain, lungs, and other organs, but no t,rophoblastic tissue could be demonstrated in the sections of the organs. Her deat,h was, therefore? probably due t,o t,he pre-eclamptic toxemia. Case C.R. 194 is of’ special interest because it is the only case originally registered as benign hydatidiform mole, which subsequently developed choriocarcinoma. The patient was a 17.year-old girl who in August, 1951, had a dilata,tion and curettage clone for hydatidiform mole. In September! 1951, she had a repeat dilatation and curettage for excessive bleeding, and the tissue evacuated again showed only benign ntc~lr. After six months amenolaThe eurettings rhea curettage was done in June 1952 because nf free bleeding. this time were very suspicious of choriocarcilloma. A total hysterectomy ancl left oophorectomy were done in March, 1953. I%ot,h the uterus and the left, S-rays of the chest were negative ovary were riddled with choriocarcinc,Ina. up to the time OS the last operation, but, two weeks postoperatively t,he s-r;14 showed rather tlefinite small metastatic t’oei. She died of mrtastases it1 September. 1953. The fact that there was :I six months’ period of amenorrhea prior t,o the discovery of choriocarcinoma in June, 1952, makes us suspect that Ihe choriocarcinoma may have developecl from an intercurrent pregnant-\ long after the molar ‘pregnancy in August, 1!)51, though the possibility of choriocarcinoma developing in residual molar tissue in the uterine wall out of reach of the curette must also be borne in mind.
Of the 71 patients in our have since had one full-term “several” full-term deliveries. and another has had an ectopic
series in whom the uterus was preserved 11 term deliveries and one delivery, 3 two-full One patient is pregnant at the time of writing. tubal pregnancy.
BENTGN
LESIONS
TN
CITORIONEPITJ-IELIOMA
Chorioadenoma
REGISTRY
387
Destruens
Our material includes, in addition to the 120 frankly benign hydatidiform moles, 34 cases of the intermediate type of lesion most often spoken of by Ewing’s original designation of chorioadenoma destruens. As this lesion SO often comes into both clinical and pathologic competition with the frankly malignant choriocsrcinoma, it seemed necessary for us to include a discussion of its characteristics in our recent paper on choriocarcinoma to which the reader will have to be referred. Since, however, there is a very definite overlap in the clinical and pathologic features of chorioadenoma destrurns and benign hydatidiform mole, we may perhaps be forgiven for including a brief: comment on the clifferentiation of the two lesions. While we do not consider that the term chorioadenoma destruens is a good one, it has been accepted by most writers and seems no more objectionable than others which have been used, such as malignant mole, penetrative mole, invasive mole, destructive mole, et,c. Neither Ewing2 nor anyone else seems ever to have defined it, but we have suggested two chief criteria: ( 1) an inordinate degree of trophoblastic overgrowth and (2) undue penetrativeness of the trophoblastic elements, including the villi, into the depths 01 the uterine wall, extending into the peritoneum or into the adjacent parainetrium or vaginal vault. Such moles can therefore be locally invasive, but, they have little tendency to the distant metastasis which cha,racterizes choriocarcinoma, though there are certainly exceptions tco this. We shall not here again go into details as to the microscopic differentiat,ions of such moles from either the frankly benign ones or from the frankly malignant choriocarcinomas. As cont,rasted with the former, chorioadenoma destruens shows usually large fields of trophoblast, but even very benign moles with very little trophoblast may show the extreme penetrativeness which constitutes the other criterion of this lesion. As contrasted with choriocarcinoma, we have laid great stress on the fact that chorioadenoma shows a well-preserved vill.ous pattern, and that with rare exceptions choriocarcinorna shows a complete absence of the villi from which the malignant tumor had its source. In only 1 of our 74 cases were a few villi found. In some cases the diagnosis of chorioadenoma destruens cannot be made until after hysterectomy, but in a good many it can be made presumptively or at least suspected by the occurrence of intra-abclominal hemorrhage or by the findings by palpation of parametrial invasion or the demonstration of vaginal extension. Such clinical features, combined with cnrettings showing benign moles, with or without trophoblastic overgrowth, but with well-preserved villi, make it almost certain that the lesion is a chorioadenoma destruens rather than a choriocarcinoma, which might ot,herwise be neglected. Honnon.e Tests in Chorioadenoma Destruen.s.-Of the 34 cases of chorionclrnoma destruens only 13 had any sort of hormone follow-up.
In 9 cases (C.R. 51, 67, 97, 116, 126, 149, 170, 213, 255) the pregnancy test was negative within two months after hysterectomy. In 2 cases (C.R. 64 and 65) the pregnancy tests did not become negative until three months after hysterectomy.
quently excessive trophoblastic proliferation shown by these lesions near or in the uterine wall. However, we must stress that in t,hese two lesions welll)reserved villi are also present, and their presence even with fairly large c~ollections of trophoblastic cells should always make one lean away from the diagnosis of choriocarcinoma.
NO. REGISTRY
TOTAL
Benign mole Ryncytixl cndometritis Cllorioxdcnonla drstrums Ahortion Normal deridua of caxly Degenerating tissue (no Total
ovum trophohlast
)
120 Or 3; 5 1 1 188
IN
X0. OF WRONG IIIARNOSES
46 19 15 3 1 1 85
One must also remember that in any one section it is possible to obtain a tangential cut of the trophoblastic covering of the villi in such a way as to show only large clumps of trophoblastic cells without any villi. One should not, therefore, jump to a diagnosis of choriocarcinoma, but should examine several other sections to exclude this possibility. As we have stated in our previous paper, well-formed villi are almost always absent in cases of choriocarcinoma. We noted a few villi among large masses of trophoblastic cells in only 1 of our 74 cases of choriocarcinoma. Another source of error is the tendency to rely too much upon the socalled anaplastic changes in the trophoblast. For reasons we have already mentioned we have found this factor to be of very little help in gauging the benign or malignant nature of the lesion. The presence of hemorrhagic or trophoblastic nodes in t,he uterine wdl has also apparently been thought by some to be characteristic of choriocarcinoma. In the 49 cases of benign mole in which hysterectomies were performed. no less than 26 of the uteri contain one or more of these nodes. On microscopic examination these nodes were seen to consist of benign residual molar tissue with a variable quant,ity of old blood. At times, however, these nodes will contain only blood clots and a few scattered atrophic trophohlastic cells. Only when these nodes contain the characteristic large masses of wellpreserved t,rophoblast with no villi can one be justified in calling the lesion choriocarcinoma. The presence of these hemorrhagic nodes in the vagina in cases of chorioatlenoma destruens has also been assumed by some to be indicative of chorioc~arcinoma. One must remember that this local vaginal invasion occurs in (dases of chorioadenoma destruens, as well as in cases of choriocarcinoma, but that in the former villi will often be present in the vaginal lesion as well as in the primary lesion in the uterus. As we can see in Table VII no less than 19 of our 29 cases of syncytial endometritis were misdiagnosed as choriocarcinoma. We believe that this was because t,he pathologists concerned confused the infiltration of small clumps or narrow columns of syncytial cells characteristic of syncytial endometritis
one s11011ld rt’lll~~llll)t~t~. the trophololastic invasion of choriocal~cilloltla. t,hat in the c?ho~ioearcinoma the invasion is by bulky Inasses 01 t,rophohlastic cells with usually considerable hemorrhage at~tl llc~c~rosis. III syncytial endometritis there is no Iie(*rcbsis uf the snrromidin~ rllllsc~lr ;Intl III) \vt’ INLanghans cells arc prest>nt. .rf these tlift’rl.t~litidionrss are reinrnll)t~l*vfl licve this confusion will IW c~lea~tl 111)14I a great est,ent. with
however,
Summary 1. This is a report of 120 casts III’ I)ellig:lr hydatitiiform moit~, :S eases 01’ chorioadenoma destraens, and 37 01’ syllcytial elldometritis in the Mathicu Memorial Chorionepithelioma Registr>.. 2. The gross and microscol)ic aJ)t)(‘i~t’iIlI(~t~S of these two lesions are I’c’viewed. 3. Contrary to the findings of some authors, we have heen ~mahle IO derive mnch help from the gross ant1 micarosc*opic appearanc:e 0.C CVHcuat et1 molar tissue in predicting whether a given mole will or will llot later develop malignant histologic or clinical characteristics. i. The lesion called syncytia.1 endometritis is a rcsithnurl c~f norll)a I pregnaney, abortion, or hydntidifornl nlolc. ant1 not, an atypical variet.\- of’ c*lioriocarcinoma. Our follow-up of these ~ase’s suppol-ts this viewpoint. 5. Once again WC stress t,he freqnency with which cases of hptlat,idifornl mole, chorioadenoma destruens, a~(1 syncytiwl endomet,ritis are mistliagnosc~tl as ehoriocarcinoma. The ~‘ommon sonrces of error are diacnsscil antI we h:tyr tried to show how most of these pitfalls Iuxy 1~ avoidetl. References E.: Ah1. J. OBST. $ GYNEC. 15: 694, l!M. Ewing, J.: Surg., Gynec?. 85 OhYt‘. 10: :mi. 1910. Arch. Path 30: 2Ml, t9411, Hertig, A. T., and Edmonds, H. W.: Hertig, A. T., and Sheldon, W. H.: 91~1. .J. OHST: & (:Yh-EC.53: 1, 1947. Monatsehr. f. Geburtsh. u. UynLik. 1: 419, 513, 1895. Marchand, F.: Internat. Abstr. Surg. 68: 52, 181, 1939; in Surg., Gynw. Mathieu, A.: & Feb., 1939. J. A. M A. 78: 1771, 1932. Novak, E.: AM. J. &ST. & GYNEC. 59: 15, 1950. Novak, E.: Novak, E., and Seah, C. S.: AXC. .J. OBST. & (:YNE('. 67: $1::::. l!lii-&. Park, W. W., and Lees, J. C.: Arch. Path. 49: 73, 205, 1950. Ahr. J. OHHT. & GYMW. 56: 584, l!L48. Reis, R. A., and DeCosta, E. J.:
1. illlen,
2. 3. 4. 5. 6. 7.
8. 9. IO. 11.
6i Obst.,
Jan.