Relation of Endometriosis to Carcinoma of the Ovary: '

Report of Seven Cases and Literature Review

LAMAN A. GRAY, M.D., MALCOLM L. BARNES, M.D.

From the Department of Obstetrics and Gynecology and Pathology, University ofLouisville School of Medicine and Norton Memorial Infirmary,

Louisville, Kentucky

IN 1925, Sampson 27 presented a lengthyreport entitled "Endometrial Carcinoma ofthe Ovary, Arising in Endometrial Tissueof that Organ." At that time, it was gen-erally accepted that the majority of benignand malignant epithelial tumors of theovary arose from the germinal epithelium.Sampson stated that many ovarian cystshave linings which resemble the epitheliumof the fallopian tubes, the endometrium,and even the endocervix, and that adeno-carcinoma of the ovary often has the samehistologic structure as that of the tubes anduterus. Sampson, however, believed thatadult endometrial tissue never arose fromdifferentiation of the germinal epithelium,but instead resulted from implantation ofbits of uterine mucosa carried by a back-flow of menstrual blood through the tubesinto the peritoneal cavity and, occasion-ally, from detached portions of tubal mu-cosa. He further theorized that menstrualblood escaping into the peritoneal cavitymay cause two groups of lesions-those aris-ing from the growth of implanted endo-metrial tissue, known today as "endometrio-sis," and those developing from metaplasiaof peritoneal mesothelium and surface epi-thelium of the ovary, due to stimulation bysome irritating substance in the menstrualblood. He thought the metaplasias at timesresembled endometrial epithelium, evenwith gland-like inclusions.

* Presented before the Southern Surgical Asso-ciation, Hot Springs, Virginia, December 7-9, 1965.

That carcinoma of the ovary may arisefrom endometrial cysts seemed logical toSampson because endometrial implants inthe ovary occur commonly and becauseectopic endometrium responds to hormonestimulation as does endometrium in theuterus and moreso than tubal mucosa. Henoted that many carcinomas of the ovaryare similar in microscopic appearance tothose found in the endometrial cavity, andthat the incidence of patients with ovariancancers, according to age, corresponds withthat of cancer of the endometrium. In orderto be reasonably certain that a particularcarcinoma develops in endometriosis in theovary, Sampson indicated that microscopiccontinuity must exist between cancer andbenign endometrial tissue in the sameovary, the two bearing the same histologicrelation to each other that cancer of theendometrium bears to the non-malignantportions of the endometrium in the uterus,and that the carcinoma arises in the tissueunder study and does not represent metas-tasis or invasion from some other source.

In Sampson's seven cases of carcinomawhich he attributed to an origin in endo-metriosis, four were in chocolate cysts ofthe ovary. Three of the seven were papil-lary carcinomas, and four were adenocarci-nomas suggestive of those seen in the endo-metrial cavity. He did not believe that allmalignant epithelial tumors of the ovaryare of endometrial origin, but that some

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are and possibly the percentage of these islarge.

"This is in accord both with the frequency ofmisplaced endometrial tissue in this organand, also, with the endometrial type of manyovarian carcinomas. A very important sugges-tion presents itself, namely, that malignantchanges possibly occur witlh greater frequencyin ectopic endometrial tissuie in the ovary thanin ectopic endometrial tisstue in other struc-ttures of the pelvis, and even with greater fre-quency than in the mtucosa of the body of thetiterus." ( 1925 )

Review of Literature

Following Sampson's original report in1925 of carcinomas arising in endometriosis,confirmation was slow and surprisingly fewcases are found in the literature.Vogt reported a case with carcinoma

in the posterior cul-de-sac possibly arisingin endometriosis, and Hanser ]3 had a simi-lar case. Tuthill '2 described a carcinosar-coma of the ovary arising in endometriosis,the only one of its kind.Teilum 3 reported adenocarcinoma aris-

ing in endometriosis, while MIcCullough,Froats and Falk 19 found an epidermoidcarcinoma in an endometrial cyst, never re-ported since. Miller, Grayzel, Shiffer andRosenblatt,2" in 1947, found adenocarci-noma arising in an endometrial cyst. In thesame year, Novak 22 carefully described asimilar instance, as did Rauramo.26 Kuzma 18reported two cases with adenoacanthoma inthe ovary with coincidental endometriosis.One had a microscopic carcinoma in theendometrial cavity. Apparently, Kuzma wasfirst to describe the association of adeno-acanthoma with endometriosis. In the verynext year, 1948, Moss and Runals 21 de-scribed adenoacanthoma with other ma-lignant patterns in an endometrial cyst.

Corner, Hu and Hertig,3 in 1950, re-ported six cases of carcinoma of the ovarywhich appeared possibly to arise in endo-metriosis. Four were papillary cystadeno-

Annals of SurgeryMay 1966

carcinomas, one adenoacanthoma and onemucinous cystadenocarcinoma. In two ofthese cases, the authors believed there wasdirect transition of benign endometriuminto carcinoma. Their six cases were foundamong 265 ovarian cancers of which a totalof 16 had associated endometriosis. Theseauthors suggested that endometriosis mayarise from polydifferentiation of the origi-nal germinal epithelium. In nine other caseswith endometriosis without malignancy,they found germinal epithelium differenti-ated as mucinous, endocervical and tubalforms. In four, the endometriosis was pres-ent in adenofibromas. An area of mucinousepithelium was found in a benign endo-metrial cyst. These histologic findings sug-gested to Corner, Hu and Hertig that otherthan endometrial type malignancies mayarise witlhin primarily endometrial cysts.

In 1951, Bacher and Hertzog ' concludedthere were only 11 acceptable cases in theliterature which demonstrated carcinomadeveloping in or from endometriosis, andadded one case with carcinoma in smallendometrial cysts in each ovary. Kistnerand Hertig,15 in 1952, reviewed the litera-ture on primary adenoacanthomas of theovary and added five cases; three were con-sidered to have arisen in endometriosis.Frederikson 7 reported three cases with co-existing endometriosis and carcinoma ofthe ovary. Two were adenocarcinomas andone was a papillary carcinoma of question-able relationship. In the same year, Ols-son 24 had one case with endometrioid ade-nocarcinoma within an endometrial cyst.The other ovary contained benign endo-metriosis. Scott 2S found 12 ovarian carci-nomas in the literature which, in his opin-ion, conformed to Sampson's criteria. Hereported two new cases of ovarian adeno-carcinomas in endometrial cysts, and onewith both ovarian carcinoma and adeno-carcinoma in cul-de-sac endometriosis.

In 1954, Dockerty4 presented forty casesof adenoacanthoma of the ovary, twenty-seven apparently metastatic from endome-

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trium, while thirteen appeared primary. Intwo, the adenoacanthoma was traced to anarea of endometriosis as a point of origin.Hunter and Klein 14 described two caseswith cancer in endometrial cysts, adeno-acanthoma and adenocarcinoma.

Olesen and Jensen,2' Postoloff and Ro-denberg,25 and Kumar, Anderson and VanWyck 17 each had single cases of adeno-carcinoma in endometrial cysts. WVeinrod,Bagg and Sharnoff 34 found adenoacan-thoma in ovarian endometriosis in one case.Four years later, both benign and malig-nant endometriosis of the bowel was dis-covered. The intestinal adenoacanthoma ap-pears to be the first reported.

In 1957, Thompson :`r reported thirteencases of primary adenoacanthoma from1,337 records in the Ovarian Tumor Reg-istry and added four cases. He stated thatof 30 reported in the literature, ten arosefrom endometriosis. Of the seventeen hereported, seven developed in endometrio-sis, three probably did, one had endo-metriosis nearby and two had endometriosiselsewhere in the pelvis. No endometriosiswas found in four of the 17 cases. It washis opinion that primary adenoacanthomasin the ovary must arise in endometriosis.Because of the relatively low-grade malig-nancy, he advised conservative operations.Greene and Enterline 12 reported two casesin the same year, one adenoacanthoma andone adenocarcinoma which developed inendometriosis. Ferreira and Clayton 6 de-scribed three instances in which carcinomaarose in endometriosis, one in the ovaryand two in the rectovaginal septum. Onecase with adenocarcinoma probably devel-oping in an endometrial cyst was reportedby Sterns.9

Nine cases wTith carcinoma thought tohave arisen in endometriosis were describedby Dockerty.5 Tw0o were in adenomyosis ofthe uterus, tvo in the rectovaginal septumand five in endometrial cysts of the ovary.Of the latter, twTo were papillary adeno-carcinomas, twvo adenocarcinomas and one

TO CARCINOMA OF THE OVARY 715adenoacanthoma. Concannon, Veprovskyand Garrow 2 reported one case with bi-lateral adenoacanthoma of the ovary aris-ing in endometriosis, while Koss,16 in 1963,found adenoacanthoma in a small endo-metrial cyst in an obturator lymph node.

Case ReportsIn this paper, seven cases of carcinoma

of the ovary are reported which developedwithin endometrial cysts (the first 5 havebeen described recently)," with considera-tion of the types of carcinomas and rela-tions to other Mfullerian epithelium. Thedifficulty in discerning associated endo-metriosis in extensive carcinoma and thefinding of associated endometriosis in 141ovarian carcinomas under study are dis-cussed.

Case 1. Bilateral adenoacanthoma in endo-metrial cysts of the ovary; atypical endometrialhyperplasia of uterus. Patient D. S., NS 61-3609,NS 61-3713, age 29 years, complained of pro-longed menstruation, dysmenorrhea and pain inthe right side for several months. An adherentcystic mass was palpable in the right adnexal re-gion. There was no induration in the cul-de-sacAfter observation for two months, operation re-vealed an apparent endometrial cyst 8 cm. in di-ameter in the right ovary. Chocolate fluid wasspilled during excision of the tube and ovary. Theleft ovary showed only filmy adhesions. Pathologicexamination showed a soft meaty growth 5 cm. indiameter growing from the lining of the cyst.microscopically endometrial glands, stroma andtransition to adenoacanthoma, grade II (Fig. 1).

In view of the size of the tumor and spillageof cyst contents, a second operation wa.s per-formed seven days later; the uiterus and left tubeand ovary were excised. Within the left ovary wasa small endometrial cyst 2 cm. in diameter withcharacteristic endometrial lining and transition toadenoacanthoma. This appearance in a second en-dometrial cyst suggested not metastasis but simul-taneous development of the same type of tumoras in the right ovary (Fig. 2). The endometriumwithin the uterus contained areas of atypical endo-metrial hyperplasia with closely packed adeno-matous glands. Some of the cells within theseglands were large with mitotic nuclei, and onearea had large secretory glands. While the latterwas not carcinoma, this was a definite atypicality(Fig. 3). This patient was given deep irradiation

GRAY AND BARNES Annals of SurgeryMay 1966

FIG. 1. Case 1. Adenoacanthoma in endometrial FIG. 2. Case 1. Adenoacanthoma in endometrialcyst, right ovary. cyst, left ovary.

therapy becatise of rtupture of the original cyst.Five years later, after a long period of intermittentdiarrhea, partial intestinal obstruction developed.A stricture of the terminal ileum was resected. Atthat time, there was no evidence of cancer withinthe abdomen.

Comment. This patient had bilateral en-

dometrial cysts of the ovary, rather large on

the right and quite small on the left. Ineach, there was transition into adenoacan-thoma, grade II. Atypical endometrial hy-perplasia in the endometrial cavity, withareas suggesting Arias-Stella reaction, sug-gested abnormal stimulation. In this case,it appears that both ovaries were stimulatedby a simultaneous tumor stimulus; at thesame time an incomplete malignant stimulusappeared in the endometrium within theuterus.

Case 2. Clear cell adenocarcinoma in an endo-metrial cyst of the left ovary; endometriosis in the

right ovary. This patient, L. MI., NS 59-3838, age

60 years, had an enlarging pelvic mass for severalmonths without pain. Her menopause was at 48years with no postmenopausal bleeding. A largesolid tumor, 12 by 15 cm., almost completely filleda cystic space and arose from the left ovary. Thecyst wall suggested endometrium; the lining con-

sisted of cuboidal, nonsecretory epithelium withstromal arrangement beneath the surface cells(Fig. 4). This lining epithelium blended in withpapillary and acinar type glands with large cellshaving pale cytoplasm, vesicular nuclei, and vary-

ing degrees of mitotic activity (Fig. 5). In theright ovary, endometriosis was found with quiteactive glands and stroma. This contrasted with theatrophic endometrium in the uterus. Because theleft ovarian tumor was adherent, deep therapy withradioactive cobalt was administered. Six years later,the patient is well and has no complaints.

Comment. This patient had a clear cell,secretory adenocarcinoma developing in an

endometrial cyst with active endometriosisin the opposite ovary. The endometrium in

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FIG. 3. Case 1. Small area secretory glands withlarge swollen cells in otherwise nonsecretory endo-metrium with atypical hyperplasia. This stuggestsArias-Stella reaction. Patient never pregnant.

the uterus was atrophic. Both a benign andmalignant tumor stimulus seemed to bepresent.

Case 3. Papillary adenocarcinoma, grade I, inendometrial cyst of the ovary, bilateral; malignantadenomyosis, grade II; adenocarcinoma cervix.grade III. This patient, D. J., NS 52-1431, age 43years, complained of low abdominal pain and in-termenstrual bleeding for one year. Examinationrevealed an enlarged, firm and irregular bleedingcervix. The uterus was enlarged, and there were

bilateral adherent masses in the pelvis. Biopsy ofthe cervix showed adenocarcinoma of the endo-cervix, grade III. Because of obvious extension ofthe tumor, the patient was given deep x-ray

therapy, a tumor of 5,000 r to the entire pelvis.There was little shrinkage in the cervix or ab-dominal masses. At operation there were bilaterallarge chocolate cysts of the ovaries, 12 cm. in di-ameter, and an enlarged uterus three times nonnalsize. The ovarian masses and supracervical portionof the uterus were excised. The cervix could not

FIG. 4. Case 2. Wall endometrioid cyst from whichcarcinoma arose.

be removed because of extension of tumor to thewalls of the pelvis. Microscopic sections showedadenocarcinoma extending through the wall of theuterus, with deeply staining glands (Fig. 6). Areasof endometrial type of stroma were seen aroundportions of carcinoma which suggested malignantchange in adenomyosis. The endometrium itselfwas atrophic. Both fallopian tubes were enlargedand thick-walled with apparent marked endome-triosis within the lining of each tube. Old bloodwas present in the lumens. Each ovary containedlow-grade papillary serous cystadenocarcinoma,largely filling the cystic spaces. The walls of thecysts suggested compressed endometrial tissue. Thepatient died after one year.

Comment. The multiple forms of carci-noma within this pelvis included adeno-carcinoma of the cervix, adenocarcinoma in

apparent adenomyosis of the uterus, endo-metriosis of the fallopian tubes, and largechocolate cysts of the ovaries suggestive of

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718 GRAY AND BARNES

Fic. 5. Case 2. Papillary and acinar secretoryadlenocarcinoma arising in endometrial cyst.

endometriosis filled the papillary serotuscystadenocarcinoma. These findings sug-

gested an extraordinary tumor stimuluswith production of multiple cancers inMiullerian epithelium.

Case 4. Papillary adenocarcinoma of secretorytype in endometrial cyst of the left ovary; bilateralovarian endometriosis. This patient, L. P., KS 61-4620, age 42 years, complained of pelvic pain forsix months. Examination revealed a large cysticmass in the left side of the pelvis. At operation,an unuistually large chocolate cyst, 15 by 10 cm. indiameter, was found. The interior of the cyst con-

taine(l chocolate material and a papillary growth1- to 2-cm. thick. The right ovary contained twosmall clhocolate cysts 2 cm. in diameter. The lin-ings of the cysts in each ovary were characteristicof endometriosis, consisting of tubal-like epitheliumwhile the stroma was characteristic of that foundin the endometrium. In the left ovary a transitionbetween benign epithelium and papillary secretoryadenocarcinoma, grade I, suggested malignantchange seen in the uterine mucosa (Fig. 7). The

Annals of SurgeryMlay 1966

FIG. 6. Case 3. Adenocarcinoma in myometrium.Sections from ovaries revealed low-grade papillaryadenocarcinoma in endometrial cysts.

endometrium within the utertus represented endo-m11etrial hyperplasia (Fig. 8). No follow Up wasavailable.

Comment. In this instance, endometriosisin each ovary, transition to a secretory typeof adenocarcinoma in the left ovary, andendometrial hyperplasia in the uterus sug-gested multiple stimulating effects on Miil-lerian epithelium.

Case 5. Small papillary adenocarcinoma devel-oping in endometrial cyst of the ovary; adenomyo-sis of the uterus; endometrial hyperplasia withatypical polypoid adenoma. This patient, L. M.,JS .53-971, age 46 years, complained of menor-rhagia and dysmenorrhea. A symmetrically en-larged uiterus and small cystic ovaries were ex-cised. The endometrium showed benign cystichyperplasia and an atypical polypoid adenoma.Adenomyosis was present in the uterus and a smallchocolate cyst in the left ovary demonstrated tran-sition from endometriosis into papillary adenocar-cinoma, grade II (Fig. 9). This patient was lostto follow up.

RELATION OF ENDOMETRIOSIS TO CARCINOMlA OF THE OVARYr

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FIG. 7. Case 4. Papillary secretory adenocarcinoma,arising in wall endometrial cysts.

Comment. The Mullerian and Mullerian-oriented epithelium seemed to have receivedmultiple stimulations in this case, xvithendometriosis in the ovary which pro-

gressed to carcinoma, and hyperplasia ofthe endometrium which progressed to pre-

malignant atypical hyperplasia

Case 6. Clear cell adenocarcinoma developingin endometrial cyst of the right ovary; atypicalchanges in benign endometrial cyst in left ovary.

This patient, M. S., NS 59-4195, age 46 years, was

treated for migratory phlebitis and pulmonary in-farct for three montlhs before a mass was felt inthe lower abdomen. Operation revealed a cysticovarian tumor on the right, 10 cm. in diameter,which weighed 295 Gm. Within the cyst was a

friable greyish-yellow tumor, sturrounded by a

(ltiantity of amber colored fluid. The left ovaryformed a characteristic chocolate cyst 4.5 cm. indiameter. The ttumor in the larger ovary coIn-sisted of a clear adenocarcinoma, with large, palecells and rather vesicular nuclei arranged inpapillary and acinar forms (Fig. 10). In the wallof the cyst adjacent to the ttumor, the lining was

Fic. 8. Case 4. Endometrial hyperplasia in uterus,somewhat atypical.

composed of tall, broad epithelial cells in a singlelayer with slight stroma.

In the left ovary, the endometrial lining withinthe chocolate cyst contained both glands andstroma. In one area in this cyst, the cells were

swollen, irregular in outline, and had larger nuiclei.Some abnormal stimnuilus appeared to have affectedthe epitheliuim in this otherwise benign en-

dometrial cyst. The endometrium within theuiterus revealed cystic endomiietrial hyperplasia.After complete operation, the patient has been

well six years.

Comment. This patient had a clear cellpapillary adenocarcinoma within a cystsuggestive of endometriosis in one ovary.

In the opposite ovary, an endometrial cysthad an area of atypical cells in the liningepithelitum. This suggested that the tumorstimulus caused a true malignant tumor inthe right ovary, atypical changes in a

benign endometrial cyst in the left ovary,and endometrial hyperplasia within theuterus.

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Annals of SurgeryMay 1966

GRAY AND BARNES

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FIG. 9. Case 5. Low-grade papillary adenocarinomaarising in endometrial cyst.

Case 7. Clear cell adenocarcinoma in endo-metrial cyst of ovary; benign endometrial cyst ofopposite ovary. This patient, E. R., NS 60-1303,age 58 years, complained of swelling and pressure

in the abdomen. Operation revealed a large choco-

late cyst of the right ovary, 14 cm. in diameter,and a smaller chocolate cyst in the left ovary,

5 cm. in diameter. Microscopic examination showedclear cell adenocarcinoma of papillary and acinartype with quite large cells with clear cytoplasm,rather vesicular nuclei and varying degrees ofmitotic activity (Fig. 11). The tumor blended inwith characteristic endometrial tissue in the liningof the cystic cavity. The left ovary contained a cystwith typical endometrial lining. Patient has beenwell for five years.

Comment. The patient had bilateral en-

dometrial cysts in the ovaries. WVithin one

was a relatively large clear cell secretoryadenocarcinoma with transition from theendometrial lining of the cyst. The uteruswas not available for study. The tumorstimulus may have produced bilateral

FIG. 10. Case 6. Clear cell adenocarcinoma arisingin endometrial cyst.

ovarian endometriosis which progressed toform carcinoma in one.

Summary of Reported Cases

Of 70 cases of carcinoma apparently de-veloping in endometriosis of the ovary re-

ported in the literature, including our 7cases, 52 have been described since 1950.One may prefer to exclude certain cases

because the photomicrographs are not con-

clusive or the description does not clearlyindicate transition from benign to malig-nant growth. The identity of an endo-metrial cyst from a photomicrograph isdifficult. There is sufficient evidence how-

ever to accept all these cases for likelyassociation.

Twenty-six were adenocarcinomas (in-cluding 4 clear cell secretory adenocarcino-mas reported by us), 24 adenoacanthomas,

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-t7glt 8 :;\'SF TABLE 1. Carcinoma-Endometrial Cysts.,P ~[& p !;:m.'..i'AjUx 74

FIG. 11. Case 7. Clear cell adenocarcinoma ofovaries in papillary type arising in endometrialcyst.

13 papillary serous cystadenocarcinomas,and one mucinous carcinoma. Two unusualcases were described as epidermoid carci-noma and carcinosarcoma. Novak pointedout that all adenoacanthomas of the ovary

must be considered as arising in endo-metriosis, though a large number of car-

cinomas developing in ovarian endometrio-sis have been reported as endometrioid or

solid adenocarcinomas. Ninteen per centwere papillary serous or mucinous tumors.From a review of the 70 cases, it is evi-

dent that any of the forms of Mullerian-oriented carcinomas, as suggested by Cor-ner, Hu and Hertig, may arise in endo-metrial cysts, though the pure endometrioidtumors are more common. The lattertumors resemble carcinomas usually foundin the endometrial cavity, both secretory andnonsecretory, and adenoacanthomas. Since

Case Age Type Stage Results

1. 29 Adenoacanthoma II Well 5 -rs.2. 60 Clear cell adenoca I Well 6 vrs.3. 43 Papillary adenoca II Dead 1 yr.4. 42 Secretory adenoca I No follow-up5. 46 Papillary adenoca I No follow-up6. 46 Clear cell adenoca I Well 6 vrs.7. 58 Clear cell adenoca I W'ell 5 yrs.

TABLE 2. Type of Ovarian Carcinzoma-141 Cases,Miillerian-114 Cases

Serous 78 CasesMucinous 16 CasesSolid (endometrioid) 20 Cases

various forms may arise in endometriosis,perhaps many more common tumors dohave this origin. Of our 7 cases (Table 1),5 were Stage I (limited to one ovary) and2 were Stage II (both ovaries involved). Itis only in early cases, Stage I particularly,that ovarian tissue uninvolved in tumormay be available for study.

Present Clinical Experience

In 114 cases of carcinoma of the ovaryof Mullerian type (taken from 141 carci-nomas of the ovary of all types, Table 2).which are under continuous review (Grayand Barnes,s Gray,9 and Gray and Barnes 0l),32 were Stage IV with generalized carcino-matosis, where endometriosis never couldbe found; 27 were Stage III, with localextension through the pelvis, where endo-metriosis likely could not be found; and 14were Stage II (both ovaries involved),where endometriosis often could not bedistinguished. There were 41 cases in clin-ical Stage I (35.0 per cent), in which it wasreasonably possible to distinguish an orig-inal benign endometrial growth. Of StageI cases, 3 had carcinoma developing inendometrial cysts. Four had endometriosisin the opposite ovary, and one had endo-metriosis in the cul-de-sac. An additional 3cases had possible endometriosis of the

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TABLE 3. Association of Endometriosis According toClinical Stage of Ovarian Carcinomas 141 Cases,

Miillerian Tumors-114 Cases

Stage I II III IV

Serous 28 11 17 22Assoc. endo. 5 3 1 1

Mucinous 10 1 4 1Assoc. endo. 2

Solid 3 2 6 9Assoc. endo. 1Suggestive endo. 3

Total 114 cases (88.4%o)Total assoc. and suggestive endo. 16 (14.0%)

ovary, and 2 postmenopausal women hadpseudodeciduosis of one ovary. Thus inStage I cases, endometriosis was directlyor possibly involved in 13 of 41. Of 114Mullerian-oriented carcinomas of the ovary

of all Stages, endometriosis was directly or

possibly involved in 18, including 2 withpseudodeciduosis, (15.8 per cent). TwoStage II, one Stage III and one Stage IVhad definite endometriosis in a portion ofone ovary (Table 3). In cases with exten-sive ovarian carcinoma, one may postulateas Sampson did, that endometriosis may

precede carcinoma of the ovary more fre-quently than ordinarily considered.The 7 carcinomas found in endometrial

cysts reported in this paper (5 from our

own series, and 2 from local hospitals)apparently arose in endometrial cysts ofMiillerian origin. With the variety ofMiillerian tumors types found in our seriesand in the literature, it would seem thatthese carcinomas may have developed inpre-existing endometriosis. Thus in a broadsense "endometrioid" tumors may includenot only solid adenocarcinomas, papillaryadenocarcinomas and adenoacanthomas, allcommonly found in the endometrial cavity,but also may include the typical papillaryserous cystadenocarcinoma and mucinouscarcinoma (one of the latter reported byCorner, HIu and Hertig).

Annals of SurgeryMay 1966

TABLE 4. Assoc. Mfiillerian Stimuli in 7 Cases ofCarcinoma in Endometrial Cysts

Endo. hyperplasia 3Atyp. endo. hyper. 2Adenomyosis 1Malig. adenomyosis 1Adenoca. cervix 1Endometriosis tube 1Endomet. both ovaries 6Atyp. cells endo. cyst 1Uterus not excised 1

Multiple effects of tumor stimulus werenoted in this series of 7 cases of carcinomain endometrial cysts (Table 4). One hadan adenocarcinoma of the cervix, adenocar-cinoma in the myometrium (which sug-gested malignant adenomyosis), endo-metriosis of the tubes, in addition tobilateral papillary serous carcinoma inbilateral endometrial cysts. In a secondcase, ovarian cancers were bilateral inendometrial cysts, which suggested notmetastases but simultaneous development.In a third patient, very atypical cells werefound in an opposite endometrial cyst. Ofthe 7 cases, 6 had bilateral ovarian endo-metriosis. Three had cystic glandular endo-metrial hyperplasia in the uterus, and 2others had atypical endometrial hyperplasiain the uterus, which suggested an incom-plete malignant stimulus. One of the lattersuggested an Arias-Stella reaction, previ-ously described in association with ectopicpregnancy.These multiple findings suggest the

tumor stimulus first may promote benignendometriosis, then atypical (premalignant)changes, and finally malignant disease,which may be bilateral in the ovary orinvolve other areas in the Mullerian tract(the tubes, uterus and endocervix). Atheory of developmental origin of endo-metriosis due to stimulus of unknown type,which may proceed to a malignant tumor,with associated stimulation of the variousMiillerian epithelia is supported by thefinding of these multiple effects of Miil-lerian epithelium. That endometrioid car-

Volume 163 RELATION OF ENDOMETRIOSIS TO CARCINOMA OF THE OVARY 723Number 5

cinomas may develop without the inter-mediate stage of adult endometriosis seemslikely from study of some early tumors.Benign stimulations of Mullerian-orientedepithelia to form polyps, hyperplasia andectopic endometrial growths on the one handand premalignant changes in the endo-metrium and endometrial cysts seems re-lated to malignant tumors of the ovary. Themalignant process may have intermediateforms or may develop directly from Mil-lerian and Mullerian-oriented epithelium.Only the histologic study of many earlycases of carcinoma of the ovary will clarifywhat remains suggestive at present.

Summary and Conclusions1. Seven cases with carcinoma of the

ovary are reported which were found inendometrial cysts. Four were secretoryadenocarcinomas, 2 were papillary adeno-carcinomas, and 1 was an adenoacanthoma.Of 70 reported cases 26 include adenocarci-nomas, 24 adenoacanthomas, 13 papillaryadenocarcinomas, and 1 mucinous carci-noma. These various forms of Mullerian-oriented carcinomas may arise from endo-metriosis. Since ovarian cancer commonlyis so widely dispersed as to obliterate nor-mal ovarian tissue and pelvic peritoneum,endometriosis may precede carcinoma morecommonly than ordinarily considered.

2. Endometrioid carcinomas may encom-pass all malignant Mullerian tumors of theovary. Certainly, patterns of endometrialcarcinomas are variable. These forms maydevelop indirectly from the intermediateadult stage of endometriosis or directlyfrom the endometrially Mullerian-orientedgerminal epithelium of the ovary.

3. Mullerian-oriented carcinomas maydevelop multicentrically from endometrialgrowths, not only in both ovaries but onthe pelvic peritoneum, or directly from cer-tain areas of potent celomic cells.

4. Multiple effects on Mullerian epi-thelium may follow when a tumor stimulusappears, coincident with the appearance of

an ovarian carcinoma. These include endo-metrial hyperplasia, atypical endometrialhyperplasia and very early carcinoma ofthe endometrium.

Acknowledgment: Photomicrographs preparedby Miss Lois Hofman, C.T., A.S.C.P.

References1. Bacher, W. C. and Hertzog, A. J.: Bilateral

Ovarian Carcinoma Arising in EndometrialCysts: Report of a Case. Amer. J. Clin. Path.,21:965, 1951.

2. Concannon, P. J., Veprovsky, E. C. and Gar-row, I.: Bilateral Adenoacanthoma of theOvary Arising in Endometriosis. Amer. J.Obstet. Gynec., 83:180, 1962.

3. Corner, G. W., Jr., Hu, C. Y. and Hertig,A. T.: Ovarian Carcinoma Arising in Endo-metriosis. Amer. J. Obstet. Gynec., 59:760,1950.

4. Dockerty, M. B.: Primary and SecondaryOvarian Adenoacanthoma. Surg. Gynec.Obstet., 99:392, 1954.

5. Dockerty, M. B.: Malignancy ComplicatingEndometriosis. Pathologic Features in NineCases. Amer. J. Obstet. Gynec., 83:175, 1962.

6. Ferreira, H. P. and Clayton, S. G.: ThreeCases of Malignant Change in Endometriosis,Including Two Cases Arising in the Recto-vaginal Septum. J. Obstet Gynec. Brit. Emp.,65:41, 1958.

7. Frederikson, H.: Coexisting Ovarian Endo-metriosis and Malignant Tumors: Report ofThree Cases. Acta Obstet. Gynec. Scand., 32:54, 1953.

8. Gray, L. A. and Barnes, M. L.: Carcinoma ofthe Ovary-A Report of 106 Cases: 1. AFurther Effort at Pathological Differentiation.Ann. Surg., 155:722, 1962.

9. Gray, L. A.: Histogenesis of Ovarian Carci-noma. Prog. in Gynec., J. V. Meigs, Edit.,Greene & Stratton, IV:465, 1963.

10. Gray, L. A. and Barnes, M. L.: Carcinoma ofthe Ovary-Report of 106 Cases: 2. Pathol-ogy, Clinical Course, Treatment. Ann. Surg.,159:279, 1964.

11. Gray, L. A. and Barnes, M. L.: Relation ofEndometriosis to Carcinoma. Amer. Surg.,31:798, 1965.

12. Greene, J. W., Jr. and Enterline, H. T.:Carcinoma Arising in Endometriosis. Obstet.Gynec., 9:417, 1957.

13. Hanser, R.: Karcinoma auf der basis aus-gedehnter endometriose. Z. Krebsforsch., 43:306, 1936.

14. Hunter, R. and Klein, J.: Carcinoma of theOvary Arising from an Endometrial Cyst.Amer. J. Obstet. Gynec., 67:1127, 1954.

15. Kistner, R. W. and Hertig, A. T.: PrimaryAdenoacanthoma of the Ovary. Cancer, 5:1134, 1952.

16. Koss, L. G.: Minature Adenoacanthoma Arisingin an Endometriotic Cyst in an ObturatorLymph Node. Report of a First Case. Cancer,16:1369, 1963.

724GRAY AND BARNES Annals of Surgery724 GRAY AND BARNMay 1966

17. Kumar, D., Anderson, W. and Van Wyck, D.:Ovarian Carcinoma Arising in an Endo-metrial Cyst. J. Obstet. Gynec. Brit. Emp.,62:375, 1955.

18. Kuzma, J. F.: Ovarian Adenoacathoma As-sociated with Endometriosis of the Ovary.Am. J. Obstet. Gynec., 53:245, 1947.

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DISCUSSION

DR. JOSEPH H. PRATT (Rochester, Minn.): Dr.Gray has certainly presented us this evening withan intriguing aspect of endometriosis. It is ex-tremely difficult to prove just how many malignantlesions really arise from areas of external endo-metriosis. The overgrowth of the tumor tissue maypreclude entirely the possibility of utilizing anyof Sampson's criteria.

Our own incidence of endometrioid carcinomaswhich may arise in areas of endometriosis is about15 to 20%. This is similar to Dr. Gray's figures,and also to those of Dr. Doward Taylor, whoshowed 20 such cases in 120 cases of carcinoma ofthe ovary.

We recently have seen three cases that seemedto fit into this general category. [Dockerty, Mal-comb B.: Malignancy Complicating Endometriosis.Am. J. Obst. & Gynec. 83:175-179 (Jan.) 1962.]They are interesting because practically in thesame sections we see benign and malignant tissue:

(Slide) This is the uterus of a 66-year-oldlady who had been bleeding for 6 years. A D&Cwas done. It was not remarkable except for pro-liferation of endometrium, and the uterus wasremoved. (Slide) On a microscopic section there isbenign adenomyosis and adenocarcinoma in thesame field, and the entire wall of the uterus wascomposed of similar tissues. (Slide) The secondcase was a 34-year-old woman who had had inter-mittent abdominal pains for a year, associated withher menses. She was explored as a semi-emergency

for abdominal pain of 2 or 3 days. A left ovariancyst was found to be a ruptured endometrioma. AsDr. Gray mentioned in his talk, this woman hadbilateral endometriomas. In the lower left portionof the cyst there are several nodular areas thatmicroscopically show a benign endometrial wallof the cyst and a papillary adenocarcinoma, GradeI, from one of the little nodular areas.

(Slide) This is another 34-year-old patientwith bilateral endometriomas: a large, 5-inch or soin diameter endometrioma has a smaller area ofadenocarcinoma in it. In the same section is be-nign endometrium beginning to pile up, and prac-tically in situ malignancy. This lady was alive andwell 5 years later.

In any case, our 5-year survival in such endo-metrioid types of tumor seems to be distinctlybetter than those of the papillary of the mucinousserocystadenocarcinomas. However, the very choiceof cases would determine the statistical values ofsuch a series; in other words, if we take onlythose cases that are demonstrably in endometrialcysts or closely associated with one, we will bepicking early lesions that should have a goodprognosis, and the prognosis will depend on howmany questionable cases we are willing to include.

This problem certainly needs more study andmore elucidation. In the past we have all con-sidered endometriosis primarily a benign disease.If we are going to agree that 20% of ovarianmalignancies may arise in areas of endometriosis,certainly our viewpoint needs a little revision.