Precursors of corpus cancer. II

PRECURSORS OF CORPUS CANCER. II A Clinical and Pathological Study of Adenomatous Hyperplasia':' S. B.

GusBERG, M.D., DAVID

B.

MooRE, M.D., AND :B'REDERICK MARTIN, M.D.,

NEW YORK,

N. Y.

(From the Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University and the Sloane Hospital for Women)

HE surge of renewed interest in early detection of uterine cancer in the past decade has brought a twofold benefit: It has helped uncover many such lesions in the early stages of malignancy when one can offer the patient a very high probability of cure with therapeutic techniques now available, and has therefore encouraged both the physician and the patient in the hope for conquest of these disorders; and in addition these studies have led to a concept of the developmental nature of uterine cancer which has in turn enabled us to define certain cancer precursors in the uterus. It is less important for us now, in our imperfert state of knowledge concerning these cancer precursors, to attempt a final evaluation of the precise relation of preclinical and clinical cancer in this area than it is to offer the obstetrician and gynecologist, who has always taken a keen interest in the preventive-medicine aspects of his regional surgery. a reliable guide to the problems of management of abnormal uterine bleeding. Study of the intraepithelial cancer of the cervix has begun to fill this need to a considerable extent in tumors of this area though its frequently asymptomatic nature has sometimes made it seem a blessing of some mixture in young, asymptomatie, healthy women. That this knowledge is of importance no one can dispute, and there is no doubt that it will makt:' an important contribution to the solution of the problem of l:er'viral cancer. In a similar fashion in rerent years studies of menopausal bleeding and endometrial hyperplasia of nwnopausal and postmenopausal patients have lP
T

*Presented in part at a meeting- of the American College of SurgeonB. Chicago. Ill., October, 1953.

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cancer precursor, however, the latter report fractionated this group into those called adenomatou.s and those called cancer in situ. Inasmuch as many welldefined endometrial adenocarcinomas tend to remain intramucosal for long periods of time, and such a geographic designation is difficult to assay biologically, we have preferred the coneept that Rdenomatous hyperplasia is a precursor of possible later adenoma malignum rather than true but surface cancer. Since the publication of these initial reports Speert6 and Te Linde, Jones, and Galvin 7 have also reported on this abnormality and it has become increasingly accepted and used as a working gynecologic concept.

Fig. !.-Pale-staining hyperplastic gland with early budding. This pallor is eosinophilic in contrast to more basophilic stain of surrounding epi thelium. (X 250; reduced II,.)

'N e became interested in such studies approximately ten years ago because they offered a possible explanation for the question raised by our studies of menopausal bleeding and the background of endometrial cancer with a suggested relationship between them. In addition, the endometrium offers such an endless variation of facets of endogenous and exogenous endocrine stimulation that we were attracted to this site as the most logical one for the study of a developmental end point of pathologic physiology of the reproductive tract that might possibly lead to malignancy. The concept of adenomatous hyperplasia as distinguished from cystic glandular hyperplasia has become extremely useful to our laboratory of gynecologic pathology and our gynecologic clinic and we now wish to report a study of 100 such cases collected from our hospital in an effort to clarify further the histologic picture, describe its clinical pattern, and define its cancer significance.

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GUSBERG, MOORE, AND MARTIN

Am. ,). Obst.

&

Gyne,·.

December. !9q

The 100 cases of adenomatous hyp('rplasia reported here have be<>n regi.'ltered in the files of the pathology lahoratory of the Sloane Hospital fot' Women. All specimens were obtained either by curettage or hystereet.omy \Vith the exeeptiou of one that was dh;eovcred with endometrial hi.opsy.

Age and Menopausal Relationship The peak incidence of our cases occurred in the fifth decade of life with 46 patients being seen in this age group. Our youngest patient was 26 years of age and our oldest 71 years of age. 'rhree categories of patients were established with respect to the menopause: (A) The pre-menopausal age group included those under 45 years of age who had never noted amenorrhea or secondary menopausal symptoms and those over 45 who, until the onset of the present illness, had had perfectly regular and normal menses without signs of impending menopause; we noted 47 per cent in this group. (B) The menopausal group consisted of patients usually over 45 years of age who had noted progressively irregular menses with loss of rhythm and frequently change in flow accompanied by mild to moderate secondary menopausal symptoms (vasomotor) or brief periods of amenorrhea; 20 per cent fell into this category. (C) The postmenopausal group were those who had had at least six months of consecutive amenorrhoa combined with either objective or subjective findings; 33 per cent of our patients were found to be in this classification. It is important to emphash~f' that such a classification of patients with respect to this menopausal faetor may be an extremely difficult one to define clearly. Prior Menstrual Pattern In an attempt to evaluate the endocrine status of the patient as evidenced by her menstrual pattern before the onset of this disease we studied the recorded menstrual data but found this to be insufficiently precise to permit us any significant conclusion. We found 4 patients whose menses had been grossly irregular before the onset of their present illness, 5 to be abnormally profuse, while 2 of the 33 postmenopausal patients were recorded as having had a bloody menopause. We are dubious of the accuracy of these figures for they are lower than that to be expected for the general female population. The necessity for making a decision concerning the line between past history and present illness in such patients makes this factor difficult exc:ept in the course of a specific continuing study. Race and Economic Status Eighty-eight per cent of our patients were found to be white and 12 per cent Negro but this figure must be examined in the light of the fact that 54 per cent of these patients were private rather than ward and this would bring this group into line with the expected 35 to 40 per cent of Negro patients that we customarily see on our ward service. Thus, both the racial incidence and economic level strongly approximate that of our gynecologic service as a whole. Relation to Fertility In this study 14 per cent were single, 60 per cent married, 11 per cent divorced, and 14 per cent widowed, with 1 per cent of undetermined marital status. In the 60 married patients 19 had never conceived and, in addition, 4 others were relatively infertile in that one had been pregnant but not carried through pregnancy successfully beyond the twenty-eighth week, and 3 others had had a child but complained specifically of later infertility. Of the total

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group then 31 per cent had never been pregnant, 4 per cent had expressed infertility problems of varying degrees, while in the married group 31.6 per cent had not conceived and 6.6 per cent had relative infertility. One might compare this with the general population where it is said 10 per cent of marriages are involuntarily infertile. Fig. 2.

Fig.~-

Fig. 2.-Area of crowding and pseudostratification of glan,Jular epithelium. reduced 1,4.) Fig. 3.-Crowding and marked pseudostratification of glandular epithelium. reduced ';4.)

(X 251J; ( X250;

] -1-76

lHii::\BEl:W, MOORE, AND MAR'l'I!'\

Arn

& GyJtrc. }Jeremher. l!J~ I

J. Obst.

Body Habitus and Endocrine Disorders As this study progressed we were impressed with the considerable number of obese patients who were observed. Thirty-four per cent of otu· patient~ were recorded as being distinctly obese while ::2 per eent were noted to he of normal weight, 4 per cent thin, and in 30 per rent body configuration was not commented upon. ·whether or not this has any endocrine significan<'r onP cannot state, but included in this series were 3 patients with diabetes mellitus, 5 with a history of thyroid disturbanre, 2 with liver disease, and :: with unrelated major chronic disease.

Symptoms The composite patient in this group had been having abnormal vaginal bleeding for approximately 16 months before she reached treatment. Frequently these patients noted both metrorrhagia and mrnorrhagia with this group constituting 38 per cent of the total. Sixteen of the entire group had suffered metrorrhagia only with relatively normal menses, and 10 per cent noted menorrhagia alone without m1y intermenstrual bleeding. In the entire group of cases it was noted that hemorrhage was profuse in 17 per cent, for these patients suffered a reduction in hemoglobin below 11 Gm. and several values of 6 and 7 Gm. were noted. Of 33 patients with this disease who were postmenopausal, 29 had postmenopausal bleeding as a symptom.

Estrogenic Therapy in Relation to Induction of Adenomatous Hyperplasia Of the entire group, 22 per cent were noted to have received estrogenic preparations of one kind or another before the onset of vaginal bleeding. Of these, 8 patients had received hormonal therapy less than one year, 5 patients were treated for one to three years, and in 9 patients the length of administration was unknown. The development of adenomatous hyperplasia by longterm administration of estrogenir hormones in postmenopausal patients has been observed by us on several occasions and we have also noted such changes to occur in the uteri of somr postmenopausal patients with functioning ovarian tumors.

Pathology

Gross.-In this series the uterus was described as normal in size in 50 patients. In 28, fibromyomas of the uterus were present, while 17 uteri contained endometrial polyps. It is of interest to note that 23 of the entire group had uteri which were distinctly and diffusely enlarged without obvious cause and an additional 4 were larger than could be explained by the small fibromyomas present. This incidence of 27 idiopathically enlarged uteri with adenomatous hyperplasia is an observation which seems significant; such uterine enlargement may also be noted with cystic glandular hyperplasia. Microscopic.-In our previous report concerning adenomatous hyperplasia a description of the important microscopic findings was presented. It is important to note that adenomatous hyperplasia is frequently focal, occurring in areas otherwise having cystic glandular hyperplastic endometrium, though orcasionally the adenomatous pattern may prevail throughout the endometrium. The stroma varies in its activity, sometimrs being' aetive, as may be seen with cystic glandular hyperplasia, but at other times, in postmenopausal uteri, one can note this activity of the epithelium with a completely quiescent stroma. The pale eosinophilic-staining quality of some of the glands in adenomatous hyperplasia and the intense activity of the glandular epithelium with pseudo-

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stratification, crowding of glands, and frequent budding into the lumen are well-known characteristics and may be noted in the accompanying photomicrographs (Figs. 1 to 10). Table I presents the percentile incidence of these various characteristics to illustrate their greatt>r or lt>sser presence in Fig. 4.

Fig. 5. F'lg. 4.-Marked crowding with Intense reduplicati on of glands replacing stroma in this a rea. (X 250; reduced 1,4.) Fig. 6.-Redupllcatlon of glands completely replacing stroma in several foci. The diagnosis of carcinoma in situ could be entertained. (X 260; reduced 1,4.)

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GUSBERG, MOORE, AND MARTIN

Am.

1. Obst. & Gynec. December, 1954

some specimens. It is well known to gynecologic pathologists that endometrial patterns may vary signifirantl)T from one area to another. This is geen i1: proliferative endometrium to some extent, and also seen in abnorma I endometrium of both the hyperplastic varieties and in frank malignancy. In faet, we have several examples in our laboratory of all three varieties of abnormal change in an endometrium whieh shows cystic glandular hyperplasia in one area, adenomatous hyperplasia in another, and undoubted adenocarcinoma in still another .

.Fig. 6.-G enera l pa ttern of early budding in a trophic strom a . TABLE

I.

(X 250 ; red uced 74 . l

MICROSCOPIC PATTERN OF ADENOMATOUS HYPERPLASIA

0

1%

3%

+ ++

24% 43% 28% 4%

16% 39% 41% 1%

+++ ++++ Adenomatous pattern:

focal general

= =

53% 47%

Treatment and Result In our study group 37 patients were treated by curettage only, while 26 received radium on x-ray sterilization following curettage, and ~fi were treated with hysterectomy. One patient whose lesion was discovered by endometrial biopsy received no other therapy.

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One can only evaluate the result of treatment in those patients who were followed for more than six months and did not have a hysterectomy performed as their treatment. Of patients treated with curetta-ge only, 24 -were considered cured (though only 13 were followed over six months), but 13 required further treatment. Of those who were treated with curettage followed Fig. 7.

Fig. 8. Fig. 7.-Pseudostratitlcation and budding in focus of hyperplasia. ( X250; reduced 1,4.) Fig. 8.-Budding and eosinophilic pallor of epithelium in intensely active area of hyperplastic epithelium. ( X260; reduced "R..)

GUSBERG, :MOORE, AND MAR'l'lN

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\111 ,

r.

O b ~ t. &

G y11t:c

f >ccemher, I
by radiation sterilization, 23 were considered cured (only 10 were followed over six months), but 3 required further treatment. 'rhese groups certainly are small in number and probably statistically insignificant but thPy show HH·

Fic:-. 1 0.

Fig. 9.-Intense budding with complete replacem e nt of stroma in areas of hype rplasia. (X250; reduced Fig. 10.-Hyperpla.st!c epithelium with general pattern of budding and intraluminal activity. (X250; reduced

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trend in these patients of the need in a considerable percentage of more treatment than the simpler ones which are conventionally offered for menopausal bleeding. If one also adds the consideration of prophylaxis in the planning of such treatment it would appear that adenomatous hyperplasia might be a finding in a patient who is bleeding dysfunctionally at the menopause that would weigh the scale in favor of hysterectomy.

Carcinoma Significance It is again important to emphasize that the follow-up of these patients has been a relatively brief one to the present time and therefore one cannot make a complete evaluation of the final relationship of adenomatous hyperplasia to carcinoma. In addition to this, our series of 100 is shortened by the fact that 36 patients were treated by hysterectomy. In the entire group we noted 2 patients who later developed carcinoma of the endometrium. In addition to this there were 3 patients in whom frank adenocarcinoma coexisted with adenomatous hyperplasia, 5 others in whom there was coexisting adenoma malignum or low-grade adenocarcinoma which might be called cancer in situ by some, and 10 instances in which the coexistence of low-grade carcinoma or adenoma malignum was considered but a decision concerning the malignancy of the tissue in question could not be reached. These groups, then, in whom 10 per cent had coexistent cancer or developed cancer later, and another 10 per cent in whom coexisting cancer could not be excluded, make the syndrome of adenomatous hyperplasia a significantly dangerous lesion which must be considered a cancer precursor in this area (Table II). TABLE II. CARCINOMA SIGNIFICANCE OF ADENOli!ATOUS HYPERPLASIA Later development of cancer of endometrium Coexisting adenocarcinoma Coexisting adenoma malignum Coexisting lesion of borderline malignancy

2%

3% 5% 10%

Comment As we stated previously, the short period of follow-up and our tendency to treat probable uterine cancer precursors by hysterectomy does not permit us at this time to make a final analysis of the precise relationship of adenomatous hyperplasia to endometrial cancer. 'Ve can examine the significant number of adenocarcinomas in the same uterus with intermediary stages between them that makes such a relation probable; we have seen several later carcinomas which also suggest that we may think of adenomatous hyperplasia in a similar category to intraepithelial carcinoma of the cervix as a change which is not yet irrevocable, may not go on to active, frank malignancy, but must impress us with the necessity for serious consideration of this eventuality in planning treatment for such patients. References 1. 2. 3. 4. 5. 6. '1

lo

Gusberg, S. B.: AM. J. 0BST. & GYNEC. 54: 905, 1947. Novak, E., and Rutledge, F.: AM. J. 0BST. & GYNEC. 55: 4t), 1948. Herti2'. A. T .. and Sommers. S. C.: Cancer 2: 946. 1949. Hertig; A. T.; Sommers, S. C., and Bengloff, H.: Cancer 2: 964, 1949. Sommers, S. C., Hertig, A. T., and Bengloff, H.: Cancer 2: 957, 1949. Speert, H.: Cancer 5: 927, 1952. m,.. ..L.t:l

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