Adenoepidermoid and adenosquamous carcinoma of the uterus A clinicopathologic

CONRAD

G.

NORMAN ALAN

JULIAN,

H.

DAIKOKU,

study of 118 cases

M.D. M.D.

GILLESPIE

Baltimore,

Maryland

‘4 wries oj’ 118 ca.ses cf adenoepidevmoid carcinoma arzd adenosquamous tumors g the uterus is presented. The results indicate that cerzkal tumors are frequently occult and art’ often not diagnosed until late in the course of the disease. Stage for .stuge, theJive-year .curuiz~al rate is poorer than the usual results for cev?&xl malignancy. Endometrial tumors also had a poor&~-year suroiual rate, with a high incidence oj’ vrtyovnetrial ~~xtension. The incidence oJ myometrial inzlasion and suruiualjgurrs were similar to those for

poorly

differentiated

endometrial

cancer.

(AM.

J. OBSTET.

GYNECOL.

128:

’

106. 1977.)

FROM THE third National Cancer Survey on the 1969 to 1970 morbidity from cancers of the female genital tract reveal that there are certain significant changes in the comparative incidences of gynecologic malignancy.’ Endometrial carcinoma is now the most frequent of invasive gynecologic tumors and comprises approximately 38 per cent of the total. Cervical cancer is still the most frequent genital malignancy in the black female population, but it comprises only about 30 per cent of the population at large. Ng and associates* believe that the increasing frequency of endometrial cancer might be related to the emergence of mixed adenosquamous carcinoma, previously an uncommon histologic type. In 1956, Glucksmann and Cherry3 presented a series of 175 cases of a so-called mixed variety of adenocarcinema and squamous carcinoma of the cervix. They believed that these tumors arose within the endocervix, were frequently associated with pregnancy, and had a

relatively poor prognosis when treated with irradiation. In view of recent changing concepts in the histopathologic variants of cervical and endometrial malignancy, this study explores some factors related to the appearance, behavior, and prognosis of these “mixed” tumors of the cervix and endometrium.

DATA

From Johns

the Department of Obstetrics Hopkins University School

and Gynecology,

of Med&ine.

Materlal and methads All cases of adenocarcinoma of the endometrium at The Johns Hopkins Division of Gynecologic Pathology between the years of 1950 and 1970 were reviewed in an attempt to locate “adenosquamous” or “aclenoepidermoid” tumors. For the purpose of clarity, it is important to define our terms. The term adenoacanthoma refers to adenocarcinoma of the endometrium with benign squamous metaplasia. Such cases are not included. The remainder of the cases are divided into two groups. They are referred to as either adenoepidermoid or adenosqyamous carcinomas. The term adenoepidermoid carcinoma refers to a mixed tumor of both epithelial elements in wrhich the epidermoid eiement is relatively undifferentiated. The cells are smali, are usually rounded. and have a relatively basophilic cytoplasm. At times, they appear to be lifting the malignant secretory epithelium toward the cenEer of a glandlike space (Figs. I. 2. and 3), much in the same fashion that the transitional epithelium does in

The

Presented by invitation at the Eighty-seventh Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, September 9-11~ 1976. Reprint requests: Dr. Conrad G. Julian, Department Obstetrics and Gynecology, Unilrersity of Vanderbilt of Medirine, Nashville, Tenwwec 3 7232.

of School

106

Volume Number

Adenoepidermoid

128 1

and adenosquamous

carcinoma of uterus

107

Fig. 1. Adenoepidermoid carcinoma of the cervix. Solid arrow designates area of adenocarcinoma; open arrow designates area of epidermoid carcinoma. (Hematoxylin and eosin. x90.) cystitis glandularis. There is little or no keratin or pearl formation. On the other hand, the adenosquamous tumor has squamous cells which are much more mature. Frequently, the cells are large with esinophilic cytoplasm, and keratin and pearl formation is common (Figs. 4 and 5). The cases of mixed tumors of the cervix were obtained in much the same fashion as described above, and the terminology that is used is identical. Approximately 120 cases were reviewed, and 360 sections were examined. The hospital unit histories as well as the private physicians’ charts, when they were available, were examined. The entire series represents 118 cases of adenoepidermoid and adenosquamous carcinoma of the. uterus. Thirty-two cases qualified as adenoepidermoid carcinoma of the cervix, and it is interesting to note that there was not one case of adenosquamous carcinoma of the cervix. There is only one case in the laboratory, and it does not appear in the series. So it seems that this particular pathologic entity is reasonably rare. Of the fundal tumors, 48 cases were adenoepidermoid and 31 were adenosquamous. There were seven cases in which both the cervix and the fundus were involved to such an extent that the tumor could not be assigned to either a cervical of fundal primary. Of the cervical tumors, 22 of 32, or 68.75 per cent

were found in black patients and the remainder in Caucasians. The mean age of the group was 45.4 years, with a range of 27 to 66 years. The mean parity was 4.7, with a range of 0 to 18. Nulliparity was 6.25 per cent. None of the patients was noted to be diabetic or to have an abnormal glucose tolerance test. Only one patient was pregnant or recently postpartum at the time of diagnosis, in contrast to the Glucksmann and Cherry3 series. Many of the patients had endophytic lesions. As many as seven of 17 patients with Stage I disease had very little in the way of an apparent lesion, despite the fact that five of the seven were described as barrel lesions. The staging and five-year survival rates are presented here. Six patients had in situ lesions. All patients in this category were treated with simple hysterectomy, and all were living and well five years later, except for one patient who died from another disease. Two patients had microinvasive disease and were treated with total abdominal hysterectomy. Both are living and well. Fifteen patients with stage IB lesions were treated, and only six were living and well at the end of five years. Consequently, this group had a five-year survival rate of only 40 per cent. Five of these patients had exploratory operation with the expectation that a radical hysterectomy would have to be performed. One patient had one parametrium involved. Two patients had gross involvement of the pelvic nodes, and one had pelvic nodes microscopically

08 Julian, Daikoku, and Gillespie

Fig. 2. Adenoepidermoid differentiated epidermoid (Hematoxylin and eosin.

carcinoma carcinoma. x 100.)

of the endometrium. Central area represents mostly poorly Upper porrion and right lower corner show adenocarcinoma.

Fig. 3. Adenoepidermoid carcinoma of the endometrium. The plug of epithelium demonstrates poor differentiation at the periphery. It is impossible to state whether this is epidermoid or adenomatous. Toward the center there is definite differentiation toward glandular epithelium. (Hematoxvlin and eosin. x250.)

Volume Number

Adenoepidermoid

1‘28 1

and adenosquamous

Fig. 4. Adenosquamous carcinoma of the endometrium. Closed arrow designates squamous epithelium. Just to the right of the arrow there is a definite attempt Open arrow in left lower quadrant of the picture points to an area of fairly adenocarcinoma. (Hematoxylin and eosin. x 100.)

Fig. 5. Adenosquamous squamous epithelium portion of the figure.

carcinoma of the endometrium. in right upper corner of figure. (Hematoxylin and eosin. x 100.)

carcinoma

an area of mature at pearl formation. well-differentiated

Large well-differentiated, Adenocarcinoma is present

eosinophilic in the central

of uterus

109

110

Table

Julian, Daikoku, and Gillespie

I. Survival

No. of Stagr

May I, 1977 Am. ,J. Obstet. Gynecol.

data for adenoepidermoid Living

and

carcinoma

well

patients

0’0.)

Died of cancer

I II II1 IV

28 10 9 1

19 5 -

6 4 9 1

Total

48

24

20

infiltrated with tumor but no apparent evidence of gross involvement. Three patients with Stage IB disease were treated with radical hysterectomy, as was one patient with Stage IIA. The remainder were treated with conventional total pelvic irradiation (standard Manchester central irradiation and external Cobalt 60 telo therapy). The five-year survival figure for those with Stage IB disease was 40 per cent. There were only two cases of Stage IIA tumor, and these showed very early vaginal extension. Certainly, a five-year survival rate of 100 per cent in this very small group is not meaningful. If the Stage IB and IIA figures are combined, the survival rate is 47.1 per cent. The over-all survival rate for the entire group is 46.7 per cent. If the in situ cases are deleted, it is 38.5 per cent for those patients with invasive disease. In seven cases, it was impossible to determine whether the primary tumor was cervical or endometrial. This group was treated with total pelvic irradiation, followed by a simple hysterectomy four to six weeks later. The tumor was apparently confined to the uterus in all cases, and at exploration there was no overt evidence that the disease had spread to other pelvic or extrapelvic tissues. However, only two of the seven patients were living and well at the end of five years. There were 79 cases of definitive primary endometrial carcinoma, 48 of which were adenoepidermoid and 3 1 were adenosquamous. In the adenoepidermoid the mean age of the patients was 64.3 years, group, with a range of 33 to 89 years. Five of the 48 patients were less than 55 years of age at diagnosis. The mean parity was 2.7 with a range of 0 to 14. The incidence of nulliparity was nine of 43, or 21 per cent. Obesity, as defined by the Metropolitan Insurance Company tabIes, ivas present in 37.5 per cent of the cases. IIypertension, defined as a blood pressure reading of 140/90 resting and repeated after six hours, was present in 43.8 per cent of the cases. Diabetes, both overt and in patients with just abnormal glucose tolerance, was noted in 16.7 per cent of the group. The average age of the last normal menstrual period was 48.2 years. The staging and survival data are summarized in Table I. It will be noted that the subdivision of IA and IB has been deleted. It was our experience that uterine enlarge-

of the endometrium Died of other disease

Living with Cancer

1 1

Lost to follow-up

Lizjing

and ~11 (5%)

1

2 -

67.85 50.00 0.0 0.0

1

2

.50

-

ment, as measured by a uterine sounding of greater than 8 cm., was more frequently found on the basis of benign pathology than malignant disease. In grading the adenocarcinoma, 46 of 48 cases were grade 3 or greater, and only two patients had changes of grade 2 or less. Twenty-eight of 48 patients, or 58 per cent, were Stage I. The five-year survival figures for Stage I and Stage II disease were 67.9 and 50 per cent, respectively. In Stage I disease, treatment was almost entirely by central irradiation, followed in four to six weeks by total abdominal hysterectomy-bilateral salpingo-oophorectomy. Stage 11 was managed by total pelvic irradiation followed by total abdominal hysterectomy-bilateral salpingo-oophorectomy. Stage III disease was handled in a similar fashion. The one case of Stage IV disease was treated with progestational therapy, without response. Recurrences were mainly outside the pelvis, with lung and para-aortic nodal tissue being the most common sites. The liver and peritoneum were the next most common sites, and the pelvic tissues, including the vagina, were the least common. Among those patients in whom it was possible to establish the histologic character of the metastasis, eight of 12 were adenoepidermoid, two were adenocarcinoma, and two were indeterminate. Myometrial invasion proved to be the most significant prognostic factor. Twenty-eight of 48 patients, or 58.3 per cent, had at least some degree of myometrial extension. Deep myometrial invasion (greater than 50 per cent) was noted in 12 of 28 cases, or 42.9 per cent. Superficial invasion (25 per cent or less) was present in 11 of 28 cases, or 39.3 per cent. In most instances, patients with deep myometrial extension had disease more advanced than Stage 1. Only four cases with 50 per cent myometrial extension or greater were Stage I. There were only six cases with 100 per cent myometrial invasion, and these were all Stage II or greater. Myometrial invasion of 50 per cent or greater was associated with a mortality rate of nine of 12, or 75 per cent. Invasion of less than 50 per cent produced a mortality rate of eight of 16, or 50 per cent. Only three of 20 patients with no myometrial invasion died as a result of the tumor. In many respects, findings for adenosquamous neoplasia were very similar.‘The mean age of the patients

Volume Number

Adenoepidermoid

128 1

Fig. 6. Adenosquamous carcinoma of the endometrium toxylin and eosin. x 100.) Table Stage I II III IV Total

II. Survival

I

No. of patients 18 9 3

data for adenosquamous Living

and well 0’0.)

8 4 0

carcinoma

Died of cancer

and adenosquamous

carcinoma of uterus

with deep myometrial extension. (Hema-

of the endometrium Died of other disease

Living with cancer

Lost to follow-up

7 5 3

2 0 0

0 0 0

0 0

1

Living

and well m

44.4 44.4 0

1

0

1

0

0

0

0

31

12

16

2

0

1

38.7

was 66.5 years. The average parity was 2.7 with a range of 0 to 7. The incidence of nulliparity was eight of 27 cases, or 30 per cent. Fifty-five per cent of the patients were obese. by the criteria described above and 62 per cent were hypertensive. Five of 21 patients, or 23.8 per cent, had some degree of abnormality in glucose tolerance. The average age at the last normal menstrual period was 48.4 years. Four of 31 patients, or 12.9 per cent, were under 55 years of age at the time of diagnosis. Staging and five-year survival figures are noted in Table II. Eighteen of 31 cases, or 58.5 per cent, were Stage I. Again, it was noted that grading of the adenocarcinoma usually showed lack of differentiation. Thirty of 31 were grade 3 or greater. The fiveyear survival rate for Stage I was only 44.4 per cent, but the difference appears to be related to myometrial invasion (Fig. 6). Fourteen of 18 patients with Stage I disease had some degree of myometrial invasion, and

111

six of 18 had deep (greater than 50 per cent) myometrial involvement. Of the entire group, 20 had myometrial involvement, and 10 had extension greater than 50 per cent. Seven of 3 1 had full myometrial involvement, and all of these but one were Stage II or greater. The over-ail survival rate for the entire group was 38.7 per cent. In this group myometrial invasion continued to be associated with a poor prognosis. Only one of 10 patients with deep myometrial invasion survived for five years; the remainder died of cancer. All patients with full-thickness myometrial involvement died of carcinoma. Only one patient with tumor invasion of less than 50 per cent died of the disease. The microscopic appearance of the metastasis was adenosquamous in eight of 10 patients and adenocarcinoma in the remaining two patients. Recurrences confined to the pelvis were rare. Most recurrences represented pulmonary and para-aortic nodal involvement, plus or minus pelvic disease. There were only two cases of solitary pelvic

112 Julian, Daikoku, and Gillespie

Table III. Survival

data for adenoepidermoid

No. of Stage

May 1, 1977 Am. J. Obstet. Gynecol.

Living

patients

and well (No.)

and adenosquamous

carcinoma

Died of other disease

Died of cancer

of the endometrium

Living with cancer

Lost to follow-up

Living

a-rtd well (%j

I II III IV

46 19 12 2

27 9 0 0

13 9 12 2

2 1 0 0

1 0 0 0

3 0 0 0

58.7 47.4 0 0

Total

79

36

36

3

1

3

45.6

Table IV. Trends

in endometrial

Adenocarcinoma

Adenoepidermaid

1969

22

1970 1971 1972 1973 1974 1975

45 43 63 66 71 53

4 3 2 6 6 8 22

Year

carcinoma

Adenosquumous

Admoefkimmoid and adenosquamous (%)

0 0 0 1 3 2 4

15 6 4 10 12 12 32

though it is our impression that the incidence of these pathologic entities is greater, it is difficult to find a denominator for the data. The hospital serves as a referral center both for patients and for pathologic specimens, and this fact makes it impossible to define the population. As for adenoepidermoid carcinoma of the cervix, there seems to be no noticeable trend in our laboratory. These observations are summarized in Table V.

.

Comment Table V. Trends Year

Epiderm&d

1969 1970 1971 1972 1973 1974 1975

36 44 58 55 60 88 83

in carcinoma Adenocarcinoma 2 6 6 17 if 16

of the cervix

Adenoepidennoid 5 12 6 9 12 13 18

Adenoepidermoid (%) 12 19 9 11 14 11 15

recurrences, and these occurred in the vagina. Table III summarizes the survival data for the combined group, i.e., both adenoepidermoid and adenosquamous carcinoma of the endometrium. The fiveyear survival figures are 58.7 per cent for Stage I disease, 47.4 per cent for Stage II, and 0 for Stages III and IV. The over-all survival rate is 45.6 per cent. Insufficient data are available in this series to establish any relationship between either adenoepidermoid or adenosquamous carcinoma of the endoemtrium and exogenous estrogen. We do know that at least 16 of the combined group used some variety of systemic estrogen, but information on the remaining patients is either lacking or incomplete. Because of Reagan’s* suggestion that there might be changing trends in the microscopic appearance of endometrial neoplasia, an attempt was made to tabulate the number of times the pathologic disgnosis of adenoepidermoid and adenosquamous carcinoma of the endometrium was made in the Division of Gynecologic Pathology between the years 1969 and 1975. These data are summarized in Table IV. Al-

In recent years, the interest in adenoepidermoid carcinoma of the cervix has centered around the differences in the histopathologic appearance of this tumor from that of the traditional epidermoid and adenocarcinema, the apparent frequency of this disease associated with pregnancy, and the poor prognosis when managed with the usual radiotherapeutic techniques.3’5 Several findings in our material are worth noting. It is of significant interest that six of 32 patients, or 18.8 per cent, had in situ carcinomas. One makes the pathologic diagnosis of an in situ adenocarcinoma or of a tumor with an adenocarcinomatous component with great trepidation. Adenocarcinomas frequently metastasize as whole glands, and it becomes exceedingly difficult to establish what represents contiguous invasive disease and what is intraepithelial change. The mean age of 45.4 years and the mean parity of 4.7 are certainly comparable to those of epidermoid cancer of the cervix and do not distinguish adenoepidermoid carcinoma in any way from this entity. We were struck by the rather poor five-year survival rate when compared with the usual rate for epidermoid carcinoma. This is in keeping with the findings of Giucksmann and Cherry3 and Wheeless and his colleagues.5 Wheeless and associates presented a five-year survival figure of 53 per cent for 29 Stage I patients, as compared with our figure of 40 percent. The few patients who underwent exploratory operation for possible radical pelvic operation demonstrated a high incidence of disease beyond the cervix. The tumor appears to arise high in the endtiervicat canal, as suggested by other investigators, and to give rise to a large number of occult and “barrel” lesions. Fre-

Volume Number

128 1

quently, this condition presents as a late form of Stage I disease at the time of diagnosis, and any form of therapy might be expected to yield less than the usual fiveyear survival rate. That these tumors arise from an undifferentiated epithelial cell with the potentiality for either epidermoid or adenomatous differentiation is axiomatic. It was the impression of Ng and associates* that the mixed adenosquamous endometrial tumors were associated with a short symptomatic prelude, had less well-differentiated glandular components, were more advanced at the time of diagnosis, and had over-all five-year survival rates that were considerably lower than those obtained with the ordinary variety of adenocarcinoma of the endometrium. Our data confirm much of this. In the context of Ng and associates, the term adenosquamous included what we have defined as adenoepidermoid carcinoma, as well as what we have called adenosquamous tumors. It is apparent from the mean age, parity, incidence of obesity and hypertension, and abnormal glucose tolerance that both adenoepidermoid and adenosquamous carcinoma arise in a population very similar to that associated with ordinary adenocarcinoma of the endometrium. We separated the adenosquamous from the adenoepidermoid tumors because our thesis, prior to accumulation of our data, was that there might be a difference in the manner in which they behaved biologically or responded to therapy. However, there was very little difference between the two groups in regard to age, parity, abnormal glucose tolerance, hypertension, obesity, or average age at the last menstrual period. Although there was a sizable difference in the five-year survival rate in Stage I disease, this difference was not statistically significant enough to be unlikely to occur by chance. The two most significant findings were the high incidence of deep myometrial involvement and the poor differentiation of the adenomatous component. It must be recalled that adenocarcinoma of the endometrium is not a uniform pathologic change and that all variants of the picture, from benign hyperplasia to poorly differentiated adenocarcinoma, frequently prevail. This is also true of the adenomatous component in adenosquamous and adenoepidermoid endometrial tumors. The area of poorest differentiation is chosen to establish the grade of the tumor. The results here, then, are not really too different from those obtained from patients with poorly differentiated adenocarcinoma of the endometrium. In 1969, Cheon6 noted that 46 per cent of 79 patients with poorly differentiated carcinoma of the endometrium had deep myometrial infiltration with tumor. The five-year survival rate for poorly differentiated ade-

Adenoepidermoid

and adenosquamous

carcinoma of uterus

113

nocarcinoma was 50 per cent when Jones’ compiled 15 series from the literature in his review article. Depth of myometrial invasion has been a valuable index, perhaps the most valuable, of prognosis in adenocarcinoma of the endometrium.5r ’ This could possibly be related to the associated high incidence of pelvic lymph node involvement.’ Pelvic nodal invasion seems to be negligible if there is no myometrial involvement or only superficial infiltration. Among these patients who had positive pelvic nodes and who were treated by radical operation and pelvic lymphadenectomy, the five-year survival rate was between 25 and 30 per cent. If one can extrapolate from adenocarcinoma of the endometrium to adenosquamous and adenoepidermoid carcinoma, relatively high probability of pelvic lymph node involvement would be expected. The dismal survival figures in this group suggest to the clinician that he would have to include in his treatment plan some provision for the management of the pelvic lymph nodes. Although a high likelihood of para-aortic nodal involvement in the presence of pelvic lymph node involvement is expected, we must assume that in at least 25 to 30 per cent of the cases the nodes above the pelvis were not involved. A physician can choose a number of alternative approaches when confronted with Stage I adenosquamous or adenoepidermoid carcinoma of the endometrium that appears to be confined to the uterus. He may choose to irradiate the entire pelvis, including the pelvic lymph node area, and follow this in a few days or in four to six weeks by simple extrafascial hysterectomy-bilateral salpingo-oophorectomy. Or he might choose to perform an exploratory laparotomy as a staging procedure. This could include peritoneal washings and para-aortic nodal sampling. If there was no overt disease outside the pelvis, he would proceed with simple hysterectomy-bilateral salpingooophorectomy. In those patients who had deep myometrial involvement or previously inapparent cervical extension, postoperative pelvic irradiation might be performed in addition to intracavitary vaginal irradiation. If there were superficial myometrial invasion or less, only vaginal irradiation need be considered. It is not within the scope of this study to suggest whether preoperative or postoperative irradiation is preferable in the management of Stage I endometrial carcinoma, but operative staging and postoperative irradiation do offer some theoretical advantage when dealing with a variant of endometrial malignancy that can be locally quite extensive at the time of diagnosis. As to the origin of the squamous cell in endometrial neoplasia, we agree with the precepts of Baggish and Woodruff.g Well-differentiated cells, either benign or malignant, do not give rise to a distinctly different cell

114 Julian, Daikoku, and Gillespie

line. It is most probable that an indifferent cell, capable of differentiation to either glandular or squamous epithelium, when subjected to some form of neoplastic induction, gives rise to adenocarcinoma, mixed adenosquamous or adenoepidermoid carcinoma, or, in

May 1, 1977 Am. J. Obstet. Gynecol.

very rare instances, squamous carcinoma of the endometrium. The same indifferent subepithelial cell can produce benign squamous metaplasia, with and without associated endometrial carcinoma.

REFERENCES

1. Cramer,

D. W., and Cutler, S. J.: AM. J. OBSTET. 118: 443, 1974. Ng., B. P., Reagan, J. W., Storaasli, J. P., and Wentz, W. B.: Am. J. Clin. Pathol. 59: 765, 1973. Glucksmann, A., and Cherry, C. P.: Cancer 9: 97 1, 1956. Reagan, J. W.: Gynecol. Oncol. 2: 144, 1974 Wheeless, C. R., Graham, R., and Graham, J. B.: Obstet. Gynecol. 35: 928, 1970. GYNECOL.

2. 3. 4. 5.

Discussion DR. GEORGE D. WI&BANKS, Chicago, Illinois. Dr. Julian and his co-authors have studied a large number of patients with what, in most institutions, is a rarely diagnosed malignancy of the cervix and endometrium. On the one hand, they have helped clarify some of the confusion about these malignant mixed tumors of the cervix and endometrium by careful pathologic description and prognostic implications. On the other hand, however, they have confused the issue, perhaps, by adding yet another subdivision to the varied nomenclature of these mixed carcinomas. In their review of the adenoepidermoid carcinomas of the cervix, the authors have confirmed the trend toward the increasing percentage of these mixed tumors in total carcinomas of the cervix that Ng and associates have suggested (Table I). They also showed the poorer prognosis for patients with these mixed tumors, as compared with those having squamous carcinomas and those with pure adenocarcinomas. It would be interesting to know whether to decrease in survival shown in this study is related as much to the differentiation of the malignancies as to the presence of both epithelial types as noted by Silverberg and associates’ in their series of mixed endometrial carcinomas. As the authors noted, the percentage of the mixed tumors of the cervix is probably higher than that in the average hospitai series because of the referral nature of the population. Since the numbers in the manuscript are a bit confusing, Dr. Julian could perhaps clarify this by listing the total cervical cases in the time period of the series reported in detail. The authors also found a poorer prognosis, stage for stage, in patients with this tumor as compared with that for patients with squamous cervical disease. Thus, the study suggests that Stage IB lesions of the mixed tumor seem to be larger and more “barrel-shaped” than the usual IB lesions. The authors found a higher incidence of extension of the lesions beyond the cervix in those five patients who underwent exploratory operation prior to radical operation. Of interest are the six patients

6. Cheon, H. K.: Obstet. Gynecol. 34: 680, 1969. 7. Jones, H. W., III: Obstet. Gynecol. Survey 30: 149, 1975. 8. Lewis, B., Stallworthy, J. A., and Cowdell, R.: BP. J. Ohstet. Gynaecol. 77: 343, 1970. 9. Baggish, M. S., and Woodruff, J. D.: Obstet. Gynecol. Survey 22: 69, 1967.

with in situ lesions and the two with microinvasion. None of these patients died of their tumors when treated by simple hysterectomy. In situ adenocarcinoma of the cervix is a difficult diagnosis to make, and this group of patients should probably be reported as a separate series. The authors carefully divide the mixed tumors of the endometrium into two categories: adenoepidermoid carcinoma, in which both elements are &aIignant and the squamous portion is “relatively -undifferentiated,” and adenosquamous carcinoma in which the malignant squamous element is more differentiated. The clinical features of this divison of patients show little difference in the two populations. No cases of adenosquamous carcinoma of the cervix were identified. Patients in both groups have a poorer prognosis than do patients with pure adenocarcinomas of the endometrium. Myometrial invasion was found to be more frequent and to extend deeper than comparable simple adenocarcinomas and, in both instances, it involved poorer survival outlooks. The adenocarcinomatous elements in the mixed tumors were more poorly differentiated than one would expect. Concomitantly, there was a higher incidence of positive pelvic nodes in those patients whose nodes were explored than in patients with pure adenocarcinomas. This paper kindled our interest in these mixed tumors, and consequently, we have started a review of our patients with adenocarcinoma of the endometrium. To date we have identified 280 patients with endometrial carinoma from 1965 to 1974. There were no diagnoses of a mixed malignant tumor. In reviewing 20 cases diagnosed as a adenoacanthoma, we have found four which fit Dr. Julian’s criteria for adenosquamous carcinoma and no lesions consistent with adenoepidermoid carcinoma. Notiever, the study is only in the preliminary phase. In their study of mixed endometrial carcinomas, Silverberg and associates’ found an interesting correlation in that the survival rate of patients with mixed tumors was comparable to the lower survival rate

Volume 128 Number

Adenoepidermoid

and adenosquamous

carcinoma of uterus

115

1

Table I. Mixed

carcinoma

of the cervix

and endometrium Cervical

Al&t?WrS

Skinner and McDonald, 1940 Glucksmann and Cherry, 1956 Wheeless and associates, 1970 Silverberg and associates, 1972 Ng and associates, 1973 Julian and associates, 1976 Wilbanks and associates, 1976

Time span

1915-1938 1942-1971 1969-1975 1965-1974

Mixed

(total)

2,489 588 1,048 424

1:;

(8%) 58 (10%))

168 (;6%)t 160 (38%)

Endometrial [total)

148 542 363 280

Mired

11 (l%*) 26 (18%) 68 (13%) 79 (17%) 4 (1%)

*Both cervical and endometrial mixed tumors were one per cent of all uterine malignancies. ?A11 cervical carcinomas with glandular components. among patients with poorly differentiated adenocarcinemas. He also noted a similar improved survival rate in patients with well-differentiated adenocarcinemas when compared to those with adenoacanthomas (adenocarcinomas with benign squamous metaplasis). The origins of these squamous elements as discussed by the authors are interesting and bear further thought and study. Baggish and Woodruff have an extensive discussion of current theories. In summary, the authors confirmed and clarified the conclusions of earlier studies that there is a trend toward an increased percentage of mixed carcinomas of the cervix and uterus which contain both malignant glandular and malignant squamous elements. These tumors seem to be more virulent, extending beyond expected limits and responding more poorly to conventional therapy. It is important to make careful histologic studies of patients with both cervical and endometrial carcinomas so that more aggressive treatment can be considered. It seems a little premature to suggest histologic subdivisions of these tumors, since pathologists and gynecologists still need to recognize and understand the primary differences between adenocarcinomas, adenocarcinomas with squamous metaplasia (benign squamous elements), and true mixed tumors, with both malignant glandular and squamous elements. In each category, there will be degrees of differentation. It is suggested that those gynecologic pathologists interested in this malignancy decided on simple and common terminology and diagnostic criteria. REFERENCE 1. Silverberg, S. G., Bolin, M. G., and DeGiorgi, L. S.: Adenocanthoma and mixed adenosquamous carcinoma of the endomeu-ium, Cancer 30: 1307, 1972. DR. HAROLD M. M. TOYELL, New York, New York. The authors have presented an in depth, retrosepctive clinical pathologic study of 118 cases of mixed epithelial cancers of the uterus, of which 32 arose in the cervix, 79 arose in the endometrium, and seven originated in both the cervix and the endometrium. Be-

cause of the referred nature of both the clinical and pathologic material at the institution, no true or valid incidence of these mixed epithelial tumors could be ascertained. However, after reviewing the pathologic records of cervical cancers over the past seven years, adenoepidermoid carcinoma of the cervix was diagnosed in 13 per cent of the cases, adenocarcinoma was diagnosed in 14 per cent, and pure epidermoid carcinomas was diagnosed in 73 per cent. Only one case of adenosquamous carcinoma of the cervix was seen. Perhaps Dr. Julian might comment on why this histologic type of tumor is seen so rarely in the cervix. There was no apparent change in the frequency of these diagnoses over the past seven years. Regarding endometrial carcinomas, the incidence of mixed epithelial carcinoma was found to be 16 per cent. Laboratory records did appear to show an increasing incidence of the diagnosis of these two histologic types of endometrial cancer. Indeed, in the last year alone, 32 per cent of all endometrial cancers seen in the laboratory were of the mixed epithelial type. The authors stress two points: (1) That these particular histologic types of uterine cancers are more difficult to cure with conventional methods of therapy than are the pure epithelial cancers, and (2) that there appears to be an increasing frequency in the diagnosis of mixed epithelial tumors of the endometrium but not of the cervix. There were 26 patients with invasive adenoepidermoid carcinoma of the cervix (Stage I, 17; Stage II, six; and Stage III, three). Ten of these patients or 38.5 per cent, were alive and well after five years. A review of the results of treatment for all invasive cancers of the cervix from 1954 through 1963, as reported by the essayist from his institution in the fifteenth volume of the Annual Reports, indicates a 47.9 per cent cure rate. This IO per cent difference in cure rate does suggest that there is a lower cure rate in patients with invasive adenoepidermoid cervical cancers. It was observed that these tumors tend to arise high in the canal, are occult and often present as so-called “barrel” lesions. In our experience, such tumors de-

1 I6

Julian, Daikoku, and Gillespie

mand the utmost respect, because they frequently involve a much greater extent of disease than is appreciated on pelvic examination. Findings (Jn the 79 patients with mixed epithelial tunlors of the endometrium indicate that there were no significant clinical differences found in these patients with respect to the usual clinical parameters associated with adenocarcinoma of the endometrium. Howcser, it is important to note that 76 of the 79 mixed epithelial tumors, or 96 per cent, were associated with a poorly differentiated or a highly undifferentiated adenocarcinomatous component. As might be expected, tr\o of three of theses tumors invaded the myomrtrium and over 40 per cent had deeply invaded the m~ometrium. h’o &rmation regarding lymph node metastases is available from this study. It would not be unreasonable to rxpect a higher incidence of involved lymph nodes, and, ccmsequently, the cure rates might not be as good with conventional therapy, when compared, stage for stage, with cases of pure endometrial carcinoma. Wr do not have a group of pure adenocarcinomas of of the end rethe cndometrium, s,, that comparison sults of treatment with those for mixed endometrial carcinomas, either as a total group or stage for stage, is not possible. Such a clinical pathologic study should quickly confirm or refute the poorer prognosis that we believe exists with these mixed epithelial tumors. ‘l‘he authors are to be commended for furthering our clinical knowledge on the behavior and nature of these histologic types of uterine cancers. Personally, 0111‘ laboratory does not distinguish these forms of cervical or endometrial carcinomas in their reports, probably because of a lack of awareness of the clinical and therapeutic impact of these carcinomas over and above that of the pure epithelial carcinomas of the uterus. 1 have two questions: (1) To what extent did the squamous component of mixed epithelial endometrial cancers, with its varying degrees of differentiation, predominate over the glandular component of the tumor.3 Reagan has reported that the epidermal component was dominant in 40 per cent of his material. I perscmally find this percentage to be somewhat high. (2) What would the author suggest as an appropriate means of treating an otherwise healthy 65-year-old paticnl with a Stage IA or IB mixed epithelial carcinoma of thr endometrium? DR. JULIAN (Closing). The purpose of making any subdivision pathologically is only to ascertain if the tumors in the categories behave differently in terms of their biological behavior or their response to therapy.

May I, 1977 Am. J. Obstet. Gynecol.

We were unable to point out. any real difference, in a statistically meaningful fashion. between the adcnosquamous and the adenoepidermoid tumors of the endometrium. As to the trends, it was difficult to establish anything in this regard. Because we are now more aware of the tumor, we make the diagnosis a little more frequently. In addition, more people know we are interested in the tumor and send us pathologic specimens. There really is no denominator for this figure, and I hesitate to make any other extrapolations from the infOrmati(Jn. There is little prognostic difference between very poorly differentiated endometrial cancer, adenotpidermoid carcinoma, or adenosquamous carcinoma of the endometrium. They have the same yariety of five-year survival rates and the same index of myometrial extension, and they seem to respond in the same way to therapy. Perhaps that is one of the messages that we should extract from the paper. I believe that the management of Stage I endometrial carcinomas should be primarily operative. In other words, primary total abdominal hysterectomy-hilateral salpingo-oophorectomy. with subsequent radiation dependent 011 the operative findings and pathology. I would suggest external radiation to the whole pelvis in addition to vaginal radiation for those patients with deep myometrial invasion. For those patients with superficial myometrial invasion, only vaginal radiation need be considered. No postoperative radiation should be given in grade 1 disease without myometrial invasion. Dr. Tovall asked why the adenosquamous component of the cervix was infrequent. I really do not know. As far as the difference between our 1954 to 1963 survival figures, from the annual report of cervical lesions, versus the survival rates for these cervical lesions, I think that the over-all survival rates were not that much different. When the rates are compared stage for stage, there was a really significant difference between Stage 1 and Stage II disease, and these types of carcinoma had a much poorer prognosis. To what extent the squamous or epidermoid component predominated can be answered in the following manner. It varied a great deal. In many areas it was moderately predominant; in others it was not predominant. II also varied from section to section. This study included only those patients who had predominantly adenoepidermoid or adenosquamous tumors, and it excluded those cases in which there were small foci of adenoepidermoid or adenosquamous pathology.