Management of stage I adenocarcinoma of the endometrium

Management

of Stage I adenocarcinoma

of

the endometrium EDWARD

H.

MISAK Boston,

COPENHAVER.

BARSAMIAN.

M

D

M.D.*

Massachusetts

Preoperative staging indicated confinement of the tumor to the uterus in 203 of 246 patients with endometrial adenocarcinoma; the accuracy of staging was 91 per cent. The absolute 5 year rate of cure uIa.p 76 per cent. Considerable uterine enlargement and undifferentiated tumor significantly reduced this rate. Although growing evidence indicates a reduction in vaginal recurrences with irradiation, its ‘necessity in achieving this goal and its role in prolonging survival are questioned. Our current management includes restricting surgical manipulation to a minimum; resorting to operation alone for the early, well-differentiated lesion, blocking the cervical canal effectively; and subjecting the total pelvis to preoperative irradiation when the lesion is more advanced or undifferentiated.

P R o G R E s s in the cure of all cancer has, for the most part, followed its early detection. This early detection is reflected in the fact that of 246 cases of endometrial adenocarcinoma studied at the Lahey Clinic from 1926 to 1960, 83 per cent were classified as International Classification Stage I. Therefore it is appropriate that we concentrate our efforts upon the clinical management of this group of patients. Classification

and

survival

are to compare and analyze results reported in the literature. The editorial boards of specialty publications are in a position to seek cooperation in the use of an acceptable system of classification; yet we find a variety of classifications in recent literature. The original classification at the Lahey Clinic]’ was based on pathology: Stage I lesions were those limited to the endometrium or superficial invasion of the myometrium, and Stage II lesions involved deep invasion of the myometrium. In deference to the new International Classification, all csxs were restaged. For many years Kottmeier”’ and the annual reports from Stockholm have divided their Stage I cases into two groups: operable cases and inoperable cases. The new International Classification is to be initiated with the next annual report. Bouts&s and his associates” used the same classification. The staging employed by ‘Beck, Latour, and Bourne’ is consistent with that based on operability. Unfortunately, it is impossible to compare such results with those classified as the present International Classification Stage I. “Stage 0 and Stage I” in the classification

rates

We have revised staging to conform with that outlined by the Cancer Committee of the International Federation of Obstetrics and Gynecology in September, 1961. A Stage I lesion is one confined to the corpus uteri as clinically diagnosed prior to treatment.? While we recognize and respect disagreement in classification, it is important that we have coordination and cooperation if we From Lahey *Former Present

the Department of Gynecology, Clinic Foundation. Resident in Gynecology, address: Beirut, Lebanon.

fThe TNM Classification of the American Joint Committee for refiorting cancer staging and end results is compatible with the International Classification. a64

Volume Number

9s 6

Management

employed by Renning and Javert14 are equivalent to International Classification Stage I. Therefore, it could be concluded that Renning and Javert found a 5 year survival rate of 70 per cent in 380 cases of International Classification Stage I. Most of these patients were treated by primary hysterectomy. Sixtytwo per cent of all their cases of adenocarcinorna of the endometrium would fall into International Classification Stage I. Gusberg and Yannopoulos” placed patients with a well-differentiated tumor and a normal-sized uterus in their Stage I. Therefore selected International Classification only Stage I cases may be compared with their series. The reported 5 year survival rate of these investigators was 81 per cent for 69 patients who were operated on and 87 per cent for 45 patients receiving both operation and irradiation. When allowances were made for deaths from intercurrent disease, the cure rates were 84 per cent and 98 per cent, thereby favoring preoperative irradiation, but this group of cases is small. Randall and GoddardI would classify 329 cases as International Classification Stage I representing 62 per cent of their reported cases (531)) wit.h a 5 year cure rate of 71 per cent. Present

study

Two hundred and three International Classification Stage I cases of adenocarcinema of the endometrium seen at the Lahey Clinic from 1926 to 1960 were reviewed. The accuracy of pretherapy staging was 91 per cent. If the staging were revised after therapy, it would be as follows: Stage I, 18!j cases; Stage II (extension to cervix), 2 cases; Stage 111 (extension outside the uterus), 13 cases; and Stage IV (extension outside the true pelvis or to the bladder or rectal mucosa), 3 cases. Table I summarizes the follow-up status. Among the 5 year “cures,” there were 6 patients who later died of recurrent adenocarcinoma and 2 still living with viable tumor. Table II relates the method of treatment

of endometrial

adenocarcinoma

865

Table I. Stage I adenocarcinoma of the endometrium-summary of follow-up status (203 cases) No.

I Five-year cure

156 (76%) 4

Follow-up less than 5 years Death Recurrent tumor Operative Intercurrent disease Unknown cause

22 8 12 1

Table II. Stage I adenocarcinoma of the endometrium-methods of treatment (203 cases)

No.

Five-year cure

Vaginal 7ecu7rences

141

112 (79%)

14 (10%)

irradiation Partial abdominal

43

33 (77%)

hysterectomy Partial abdominal hysterectomy and irradiation Irradiation alone No treatment

11

6

0

1 5 2

1 2 1

0 0 0

Method Total abdominal hysterectomy Total abdominal hysterectomy

and 2 ( 5%)

to the rates of survival and vaginal recurrence. The irradiation took varying forms of preoperative or postoperative therapy. Vaginal recurrences in only 2 of 43 irradiated patients are suggestive of benefit from irradiation, but the numbers are too small to allow valid conclusions to be drawn. The prognosis was not altered by the presence of squamous metaplasia and classification as adenoacanthoma. A relationship has been proved between the depth of myometrial invasion and prognosis. Depth of invasion has been omitted here since it cannot be defined either by clinical staging or by inspection of the uterus at operation. Table III analyzes the 141 patients treated in a uniform manner by total abdominal hysterectomy without irradiation. The addition of irradiation did not alter the results except for the small reduction in vaginal

866

Copenhaver

and

Barsamian

TabIe III. Stage I adenocarcinoma of thr endometrium treated by total abdominal hysterectomy only----relation of microscopic status and uterine size to survi\,al and vaginal recurrence I I ~

hysterectong instances

; Vagintll / recurren cc

5 year ~ cure

I Per ’ Per ) No. ) No. I cent I No. I cent Microscopic

status

Differentiated Undifferentiated (Unknown, 6 cases-~2 vaginal recurrences) Uterine sire Normal

Slightly enlarged Considerably enlarged with leiomyomas Considerably enlarged without leiomyomas

(Unknown. Selective scopic

100 3.5

83 23

83 66

In 2

10 ti

86 27

i0 22

01 81

II

13

10

9

!7

1

‘I

9n

1

10

II)

59

I

6

93

79

83

10

11

46

:Jl

67

2

‘f

1 case)

sire and status

micro-

Normal and differentiated*

Enlarged

and/or

undifferentiated? (Unknown, 2 cases,

both with vaginal recurrences) and

*Normal also includes with l&myomas.

the

uterus

+Enlarged refers to those patients sidelably enlarged without l&myomas.

with with

slight the

enlargement uterus

con-

recurrences cited in Table II. Each of the authors reviewed all microscopic sections to achieve objective grading. Grades I and II with complete differentiation of tumor into glandular patterns are labeled “differentiated.” When the tumor is undifferentiated. the prognosis is consistently poor. This is true whether the undifferentiated tumor appears as a few scattered islands of cells or completely dominates the microscopic picture. Considerable enlargement of the uterus from adenocarcinoma is associated with a more advanced stage of the disease and is reflected in a poor rate of cure. An analysis of recurrences among the 141 patients treated only by total abdominal

I\ of

~ntwr~tuq.

r:*ctlrrent

~l‘htw tlirnw

: \,,*,yiria

were

I! i

alonc~

ti: vagina 11111sothrr- qitt’s. 8: .tnd other sitcbh without vaginal in\.oI\-~~nrrnt, 10. Of thy (1 patients witli focal vaginal involvtmrnt. ali were livirq at, 72, 98. 104, 139, 146, and 189 months.” Of thr 8 patients in wholli vaginal involvt3rient cvas onlv part of a nlorfh widespread recurrence. 6 died of recurrent cancer at 9, 9, 34, 62. 105. and 14-7 months. One was living at 141 months under palliative treatment. with prugestins. and one wah lost to folio\\--Ilp study- iit 1li months. All ifi ljatients who had rt’currt~nct~s without ILL,ginal invol\,emrnt died of (‘anc(*r. Since ottr prt5t:nt policy is to omit irradiation in thr ah~cnc(~ of undifferentiated tumor and significant uterinr eniargernent: it was beliebed appropriate to reanalyze tht: 10 vaginal recurrences for this group of 93 patients. The 6 patients with focal Lpaginal im~olvemcnt are described above. Of the It’maining 4. 2 died of cancer at 34 and 62 months. ant‘ is li\+q with cancer at 141 months, and ant* \VX lo\t to follow-up at 13 months. Comment Ilues curettage afl’ect the CLIW rate? Koberts and his co-workers” isolated cancer cells in blond samples drawn from 4 of 5 patients during curettage. Cole” has cautioned about the difficulty of distinguishing cancer cells in the blood and their importance in the dissemiqation of tumor. Some investigators have advocated proceeding with expectant treatment for all patients havin(r .> postmenopausal bleeding to avoid the trauma of curettage. This policy seems imprudent at present, for only 25 per cent of our patients with postmenopausal bleeding have endometrial adenocarcinoma. It would be logical, however, to do the least instrumentation necessary to make a diagnosis. Should the cervix be blocked at the titne of operation3 Of the 67 patients in whom the cervix was sutured before hysterectomy

Vohsx1e Number

99 6

was performed, the 5 year cure rate was 84 per cent, compared with 77 per cent for the 88 patients in whom the cervix was not sutured-an insignificant difference. In our experience closure of the external cervical OS by simple suture has not sealed the canal; indeed, thin secretions may be seen leaking from the uterine cavity through such a sutured 0s. The suturing of a flap of cervical or vaginal mucosa over the cervix is believed to be more effective. Since 1960 we have used the Sprattl’ cervical obturator preceded and followed by thorough cleansing of the vagina. We hope that effective blocking of the cervix will reduce or eliminate focal recurrences of tumor in the vagina. Pratt, Symmonds, and Welch12 supported this premise. They found complete absen.ce of vaginal recurrence after 100 vaginal hysterectomies without irradiation. They routinely packed and sutured the uterus or sutured a vaginal flap over the cervix. This procedure was followed by repreparing and re-draping of the surgical field. Is early ligation of the Fallopian tubes and -the ovarian and uterine blood supply beneficial? Some workers believe that access to the peritoneal cavity and the general vascular system should be blocked as quickly as possible after opening into the abdominal cavity. There are no results to support or reject such a procedure so we must base our choice upon logic. It would seem practical to emphasize use of gentle surgical technique to avoid pressing upon, pulling, or tearing of the uterus and adnexa. If the Fallopian tubes have been releasing viable cancer cells, irrigation of the pelvis and abdomen with a nitrogen mustard solution would seem an appropriate consideration. We have not employed early ligation or irrigation. Concerning the role of the long-acting progestins and clomiphene citrate in the treatment of early endometrial adenocarcinema, Kelly and Baker? observed regressions of metastatic tumor when a long-acting progestin was used systemically. This has been repeatedly confirmed. Kistner, Griffiths, and Craig8 found extensive surface necrosis and secretory effect in malignant en-

Management

of

endometrial

adenocarcinoma

867

dometrium when 3 ml. of medroxyprogesterone acetate was instilled into the uterine cavity. Wall, Franklin, and KaufmanIs reported that use of clomiphene citrate brought regression of well-differentiated adenocarcinoma in a patient who refused operation and who did not respond to 17ahydroxyprogesterone caproate. Dosage was 50 mg. four times daily. While such medications have produced objective palliation, their use as a preoperative measure for patients with International Classification Stage I adenocarcinoma should best be considered when the surgical procedure must be postponed for medical reasons. How extensive should surgical resection be? Should a large portion of the vagina be removed? Winterton?’ observed no recurrence of vaginal tumor when the procedure included meticulous packing of the vagina with a pack soaked in dilute mercury perchloride, radical hysterectomy, and removal of a generous vaginal cuff. In his series of patients who were not given supplementary irradiation, he witnessed only two vaginal recurrences of tumor, but in both a vaginal cuff had not been removed. On the inclusion of pelvic lymphadenectomy in the operation, Beck and Latour’ recently made indirect assessment of lymphadenectomy by use of clinical and necropsy material. From this they concluded that extrapelvic extension of tumor may be present in the large majority of patients with involved pelvic nodes; therefore, they question the value of lymphadenectomy. The reported survival rates, such as Parsons and Cesare’sll 81 per cent and Winterton’s” 79 per cent, show no decisive benefit from an extended operation. When irradiation alone was applied to patients with early lesions, a 5 year cure rate of 15 to 66 per cent was obtained for cases summarized in the Annual Report.‘O There is no question that an operation with or without irradiation is superior to irradiation alone. It is also apparent that the addition of intravaginal radium reduces the incidence of recurrent tumor in the vagina as noted by Kottmeierg (4 per cent in 347

868

Copenhaver

and Barsamian

cases), Debbie” (2.4 per cent in 84 cases; Boutselis and his associates” ( 1.8 per cent in 208 cases), and Rutledge, Tan, and ( 1.5 per cent. in 139 cases). But Fletcher’” whether supplem,entary irradiation improw the .rurvival rate over hysterectomy alone remains a moot point. The solution of this

issue will reqrnre coordination of clnnral; rc search that has yet to r\&~Although Gusberg and Yannopoulos” wet-c on the brink of this solution (perhaps in favor of irradiation for all but the very early lesion), their unique classification and small numbers do not invite definite conclusions.

REFERENCES

1.

Beck, R. P., and Latour,

J. P.: AM. J. OBST. & GYNEC.~~: 307, 1963. 2. Beck, R. P., Latour, J. P., and Bourne, H. B.: AM. J. OBST. & GYNEC. 88: 178, 1964. 3. Boutselis, J. G., Bair, J. R., Vorys, N., and Ullery, J. C.: Ahn. J. OBST. & GYNEC. 85: 994, 1963. 4. Cole, W.: J. A. M. A. 181: 434, 1962. 5. Dobbie, B. N. W.: J. Obst. & Gynaec. Brit. Emp. 88: 702, 1953. 6. Gusberg, S. B., and Yannopoulos, D.: AM. J. OBST. & GYNEC. 88: 157, 1964. 7. Kelly, R. M., and Baker, W. H.: New England J. Med. 264: 216, 1961. 8. Kistner, R. W., Griffiths, C. T., and Craig, J. M.: Cancer 18: 1563, 1965. H. L.: AM. J. OBST. & GYNEC. 78: 9. Kottmeier, 1127, 1959. 10. Kottmeier, H. L., editor: Annual Report on the Results of Treatment In Carcinoma of the Uterus and Vagina. Statements of Results Obtained in 1948 to 1957, Inclusive (collated in 1963). Published under the patronage of the International Federation of

Il. 12. 13. 14. 15.

16. 17. 18. 19.

20.

Gynecology and Obstetrics, Stockholm, 1963. vol. XIII, pp. 370-372. Parsons, L., and Cesare, F.: Surg., Gynec. & Obst. 108: 582, 1959. Pratt, J. H., Symmonds, R. E., and Welch, 1. S.: AM. 1. OBST. & GYNEC. 88: 1063. 1964. Randall, J: H., and Goddard, W. B.:‘Surg., Gynec. & Obst. 103: 221, 1956. Renning, E. L., and Javert, C. T.: AM. J. OBST. & GYNEC. 88: 171, 1964. Roberts, S., Long, L., Jonasson, O., McGrath, R., McGrew, E., and Cole, W. H.: Surg., Gynec. & Obst. 111: 3, 1960. Rutledge, F. N., Tan, S. K., and Fletcher, G. H.: ARI. J. OBST. & GYNEC. 75: 167, 1958. Spratt, D. W.: Obst. & Gynec. 15: 526, 1960. Swinton, N. W., Schwyzer, H. C., and Sass, R. E.: S. Clin. North America 34: 791, 1954. Wall, J. A., Franklin, R. R., and Kaufman, R. H.: AM. J. OBST. & GYNEC. 88: 1072: 1964. Winterton, W. R.: Pror. Roy. Sot. Med. 57: 471. 1964.