GYNECOLOGIC

ONCOLOGY

3, 3.54-360 (1975)

Pretreatment Carcinoma

Lymphangiography in of the Uterine Cervix’

MILTON H. LEMAN,~ JR., LTC, MC, U.S.A., FACOG, ROBERT C. PARK, COL, MC, U.S.A., FACOG, ED D. BARHAM, LTC, MC, U.S.A., STANLEY E. CHISM, MAJ, MC, U.S.A., WILLIAM M. PETTY, MAJ, MC, U.S.A., FACOG, AND WARREN E. PATOW, COL, MC, U.S.A., FACOG Department

of Obstetrics

and Gynecology, Walter. Reed Army Wushington, D.C. 20012

Medical

Center,

Received July 15, 1975 Pretreatment diagnosis of lymphatic involvement and evaluation of its extent are important in patients with carcinoma of the uterine cervix. From April 1973 to December 1974 all Stage I and II patients with histologically confirmed carcinoma of the cervix al Walter Reed Army Medical Center who were good operative risks underwent pretreatment lymphangiography. A total of 60 patients was studied. Clinical Stage 1 patients with negative nodes underwent Wertheim-Taussig hysterectomy. Stage II patients with negative lymphangiograms received radiation therapy. All patients with positive lymphangiograms underwent exploratory laparotomy providing histologic correlation and received appropriate postoperative radiotherapy. Histologic correlation with negative lymphangiograms was found in 94.1% of cases. All nodal metastases 1 cm or greater were identified radiologically, thus permitting a more rational selection of patients for sut-gical staging and enabling the precise direction of therapy. The results of this study suggest a definite role for lymphangiography as an adjunct in diagnosis and planning therapy in patients with carcinoma of the uterine cervix. It would appear especially useful in the selection of those patients who might benefit from removal of bulky metastases and extended field irradiation.

Pretreatment diagnosis of lymphatic spread in early carcinoma of the uterine cervix is important if survival rates are to be improved. Survival of patients with lymphatic metastases is approximately one-half that of patients without lymphatic metastases [ 1, 21. In a significant number of patients with early clinical disease, regional lymphatic metastases cannot be detected by the usual diagnostic methods [3-6, 16, 211. In recent years, several authors have indicated that pedal lymphangiography is a reliable procedure for identification of lymphatic spread in cervical cancer I The opinions or assertations contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. This paper was presented at the Sixth Annual Meeting of the Society of Gynecologic Oncologists, Key Biscayne, Florida, January 1975. 2 Requests for reprints should be addressed to: Dr. Milton H. Leman. Lt. Colonel, Medical Corps, Department of Obstetrics and Gynecology, Brooke Army Medical Center, Ft Sam Houston, Texas 78234. 354 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.

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[7-l 11. Most of the studies reported have been in patients with advanced stages of disease. This report is of an ongoing study to determine the value of lymphangiography as an adjunct in the diagnosis and therapy of patients with Stage I and II carcinoma of the uterine cervix. MATERIALS

AND METHODS

Since April 1973, all clinical Stage I and II patients with a diagnosis of epidermoid or adenocarcinoma of the uterine cervix who are good operative risks receive pretreatment pedal lymphangiography. Through November 1974, 65 patients met the criteria for entrance into the study. Three patients refused the procedure, one was allergic to iodine, and one patient who had a positive lymphangiogram was excluded because of inability to cross-match blood. Sixty patients have been evaluated in the study as of this report. Histopathological confirmation of invasive epidermoid or adenocarcinoma of the cervix was made both by staff pathologists, Department of Pathology, Walter Reed Army Medical Center, and the Breast and Gynecology Branch, Armed Forces Institute of Pathology. Clinical staging was accomplished jointly by staff radiotherapists and gynecologic oncologists according to F.I.G.O. criteria. Pretreatment evaluation included a complete hemogram, chest X ray, intravenous pyelogram, cystoscopy, and barium enema. Other studies were accomplished as indicated. Lymphangiogram interpretations were not considered in evaluation prior to staging. LYMPHANGIOGRAMS

Bilateral pedal lymphangiograms were performed on each patient according to the technique of Kinmonth, Taylor, and Harper [ 121. Evans blue dye was injected into the first and second web spaces of each foot to localize the lymphatic channels and 10 ml of Ethiodol was injected directly into a lymphatic channel on the dorsum of each foot over a 1 to 2-hr period. X-ray films of the abdomen were taken immediately following completion of injection, and multiple views were taken 24 hr later. The lymphangiograms were evaluated and nodal defects were measured by a staff radiologist without knowledge of the patient’s clinical stage. Criteria for positivity were: (a) filling defects (other than those due to the lymph node hilum) in nodes cephalad to the iliac spines, (b) deviation of the normal lymph vessels around a mass (whether or not the mass fills with contrast medium), (c) obstruction of lymph flow as evidenced by failure to fill more cephalad nodes associated with collateral llow. All studies that were not clearly positive but were suspicious were regarded as negative. THERAPEUTIC

PLAN

Clinical Stage I patients underwent exploratory laparotomy. If frozen sections of selected lymph nodes were negative, complete Wertheim-Taussig hysterectomy was performed. If these nodes were positive, appropriate radiation therapy was accomplished. Clinical Stage II patients with negative lymphangiograms were not explored and received appropriate radiation therapy. Those Stage II

356

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ET AL.

patients with lymphangiographic evidence of positive lymph nodes underwent exploratory laparotomy and selective lymphadenectomy with removal of all radiographically positive lymph nodes and/or any nodes that were clinically suspicious of containing metastatic tumor. Intraoperative X ray was used to guide lymph node removal in all instances. If frozen sections of these nodes confirmed the radiographic findings, appropriate postoperative radiotherapy was accomplished. Radiotherapy was tailored to the individual patient and lesion and included extended para-aortic fields where indicated and intracavitary radiation using the Fletcher colpostats and tandem if geometrically feasible. RESULTS

Of the 60 evaluable patients in the study, 48 underwent exploratory laparotomy providing histologic correlation (Table 1). Lymphangiograms were interpreted as negative in 34 of the 48 explored patients, with histologically negative nodes in 32, giving a 94.1% accuracy. (The two false negative lymphangiograms were in Stage IB patients, in whom there were microscopic metastases.) There were 14 patients with positive lymphangiograms. Eight of the 14 had histologically positive lymph nodes and six had negative nodes, for an accuracy of 57.1%. One patient had a positive lymphangiogram, and biopsy revealed only granulomatous disease with no evidence of tumor. She was subsequently treated with radiation and antitubercular drugs. In the other five no specific abnormality was reported. In four of the five patients, review of the lymphangiograms indicated the criteria for positivity had not been fully met. The fifth patient had a definite semilunar defect, less than 1 cm in diameter, in a right external iliac node; however, serial sections revealed no evidence of tumor. In all cases where defects suspicious of nodal metastasis were 1 cm or greater, a subsequent biopsy was positive, giving a correlation of 100%. Ten patients in this series had histologically proven nodal metastases, and eight were suspected by pretreatment lymphangiogram (Table 2). Five of the biopsy proven positive nodes were in patients who were in clinical Stage IB. One patient had adenocarcinoma of the endocervix with a single 3-cm node in the lower left para-aortic area without histologically proven pelvic extension. Intraoperative X rays invariably revealed the radiographically positive nodes to have been excised. The afferent and efferent lymphatic channels of the positive nodes were ligated and marked with silver clips for identification of the TABLE CORRELATION

Lymphangiogram

OF LYMPHANGIOGRAM PATIENTS WHO Histology

Negative Negative

Negative Positive

Positive Positive

Positive Negative

1 AND HISTOLOGY WERE EXPLORED Number

IN STAGE

of cases

32 2 34 (total) 8 6

14 (total)

I AND

II

Accuracy

94.1

57.1

(%)

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LYMPHANGIOGRAPHY

TABLE 2 CORRELATION OF HISTOLOGY AND LYMPHANGIOGRAM

Histology

Lymphangiogram

Number of cases

Accuracy (%)

Positive Positive

Positive Negative

8 2 10 (total)

80.0

nodal beds and reduction of lymphatic drainage. There were five unilateral technical failures. Three were in patients who were explored and found to have negative nodes, and two were not explored. No major complications occurred as a result of the lymphangiography. Transient fever (101°F) occurred in two patients and in each case resolved without treatment. No complications occurred that could be attributed to the combined surgery and radiation. Complications were only those encountered with the Wertheim-Taussig hysterectomy at our institution and have been previously reported [ 131. The onset of radiation therapy was delayed approximately 7 days by surgical exploration and in no case more than 10 days. Three patients in the group receiving only radiation therapy were clinical Stage IB. All three had negative lymphangiograms and were treated in a manner similar to patients with Stage II lesions. The incidence of positive nodes could not be accurately determined histologically since not all patients were explored. However, nodal involvement was histologically demonstrated in five of 43 Stage I patients and five of 17 Stage II patients, giving a minimum positive node incidence of 11.6 and 29.4%, respectively (Table 3). These figures are comparable to the incidence of positive nodes reported [2-6, 131 and imply that nodal metastases are not being missed in a significant number of unexplored patients with negative lymphangiograms. DISCUSSION

Survival rates in patients with early carcinoma of the cervix can be improved only if the full extent of disease is known. This cannot be accomplished by palpation alone [8,21]. Our study suggests that lymphangiography can be used in a meaningful way to attain this end. The accuracy of this procedure has varied considerably in various reports. Two recent papers suggest that a high degree of accuracy is attainable with lymphangiography in predicting nodal metastases if specific criteria are strictly interpreted [7, 81. Certain limitations are inherent in the procedure: (a) nodal metastases less TABLE 3 POSITIVE NODE INCIDENCE FOR ALL STAGE I AND II PATIENTS

Stage I Stage II

5143” 5/17*

* Includes three patients with negative lymphangiograms, not explored. b Includes nine patients with negative lymphangiograms, not explored.

11.6% 29.4%

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ET AL.

than 3 mm do not cause radiographic or functional alterations in nodes, (b) nodes that are totally replaced by tumor may not be visible and can be missed unless there is associated lymphatic channel obstruction or collateral flow that can be identified, and (c) false positive interpretations may result from changes caused by fibrosis, inflammation, fatty degeneration, periadenitis, and also granulomatous disease as demonstrated in one of our patients [9, 221. Venography and lymph node scanning have been used alone and in combination with lymphangiography to improve the pretreatment diagnosis of nodal metastases [S, 15, 16, 25, 281. However, none of these methods has been shown to be more accurate than lymphangiography alone in early disease. Moreover, they lack the ability of the lymphangiogram to guide selective lymph node removal accurately and to assist in a more complete total lymphadenectomy [22]. Pelvic angiography has been used by some investigators [ 16, 241. In a recent study reported from our institution, a totally negative correlation was observed between angiography and histological extent of disease [ 241. The ability of radiotherapy to sterilize nodal metastases has been clearly demonstrated [ 14, 19-2 11. This curative potential exists even when the para-aortic nodes are involved, although gynecologists have in the past regarded para-aortic spread as evidence of incurability [ 14, 21, 231. If these nodal metastases are to be sterilized, they must be included in the radiation fields, making pretreatment localization imperative. Upper common iliac and para-aortic nodes are not included in the standard 15 X 15-cm pelvic portals [23]. Extended field techniques are now being employed by radiotherapists where higher nodal metastases are identified [ 8, 261. Efficacy of such treatment programs require further follow-up. In extrapolating data from radiation therapy of head and neck squamous cancer, Fletcher has suggested that bulky nodes, i.e., those greater than 2 cm in diameter, have a much reduced rate of sterilization than smaller nodes [ 181. This would favor removal of bulky nodes in order to enhance tumor kill by wellplaced radiation fields [ 291. Routine surgical staging has been suggested by some authors and is presently being studied in a cooperative effort by the Gynecologic Oncology Group. This method is undesirable because of limitations in operating time, personnel, and bed space as well as increased morbidity and protracted treatment time. For these reasons, identifying nodal involvement and selectively removing bulky nodes prior to radiation therapy is our current approach. This study demonstrates that lymphangiography can identify bulky nodal metastases with a high degree of accuracy in a significant number of Stage I and II patients with carcinoma of the cervix. In many instances these nodes are either larger than can be expected to be cured by radiation or are located outside the standard pelvic radiation field. CONCLUSIONS

1. Regional lymph node metastases that are not identified by usual diagnostic means occur in a significant number of patients with Stage I and II carcinoma of the cervix.

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2. Bilateral pedal lymphangiography can accurately diagnose and localize bulky nodal metastases, obviating the necessity to evaluate all patients surgically. 3. More selective surgical staging can be accomplished with the aid of lymphangiography. 4. Selective removal of bulky nodes and marking nodal beds, allowing for a better design and individualization of radiation fields, may be a more rational approach to therapy and improve survival in early carcinoma of the cervix. REFERENCES 1. Gusberg, S. B., Yannopoulos, K., and Cohen, C. J. Virulence indices and lymph nodes in cancer of the cervix, Amer. J. Roentgenok 111, 273-277 (197 1). 2. Pilleron, J. P., Dunard, J. P., and Lenoble, J. G. Carcinoma of the uterine cervix stages I and II treated radiation therapy and extensive surgery, Cancer 29, 593-596 (1972). 3. Brunschwig, A., and Daniel, W. W. Surgery of pelvic lymph node metastases from carcinoma of the cervix, Amer. 1. Obstet. Gynecol. 83, 389-392 (1962). 4. Claibome, H. A., Thornton, W. N., and Wilson L. A. Pelvic lymphadenectomy for carcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 80, 672-682 (1960). 5. Henriksen, E. Distribution of metastases in Stage I carcinoma of the cervix: A study of 66 autopsied cases, Amer. J. Obstet. Gynecol. 80, 919-932 (1960). 6. Henriksen, E. Lymphatic spread of carcinoma of the cervix and of the body of the uterus: A study of 420 necropsies, Amer. J. Obstet. Gynecol. 58,924-942 (1949). 7. Terry, L. N., Jr., Piver, M. S., and Hanks, G. E. The value of lymphangiography in malignant disease of the uterine cervix, Radiology 103, 175-177 (1972). 8. Piver, M. S., Wallace, S., and Castro, J. R. The accuracy of lymphangiography in carcinoma of the uterine cervix, Amer. J. Roentgenol. 111, 278-283 (197 1). 9. Piver, M. S., and Barlow, J. J. Para-aortic lymphadenectomy, aortic node biopsy and aortic lymphangiography in staging patients with advanced cervical cancer, Cancer 32, 367-370 (1973). 10. Averette, H. E., LeMaire, W. J., Lecart, C. J., and Ferguson, J. H. Lymphography in the preoperative detection of lymphatic metastasis, Obstet. Gynecol. 27, 122-129 (1966). 11. Nelson, J. H., Jr., Masterson, J. G., Herman, P. G., and Benninghoff, D. L. Anatomy of the female pelvic and aortic lymphatic systems demonstrated by lymphangiography, Amer. J. Obstet. Gynecol. 88, 460-469 (1964). 12. Kinmonth, J. B., Taylor, G. W., and Harper, R. K. Lymphangiography: a technique for its clinical use in the lower limb, Bit. Med. J. 1, 940-942 (1955). 13. Park, R. C., Patow, W. E., Rogers, R. E., and Zimmerman, E. A. Treatment of stage I carcinoma of the cervix, Obstet. Gynecol. 41, 117-122 (1973). 14. Silberstein, A. B., Aron, B. S., and Alexander, L. L. Para-aortic lymph node irradiation in cervical carcinoma, Radiology 95, 181-184 (1970). 15. Lee, K. F., Greening, R., Kramer, S., Hahn, G. A., Kuroda, K., Lin, S., and Koslow, W. W. The value of pelvic venography and lymphography in the clinical staging of carcinoma of the uterine cervix: Analysis of 105 proven cases by surgery, Amer. J. Roentgenol. 111, 278-283 (1971). 16. Averette, H. E., LeMaire, W. J., and LePage, J. R. Lymphography, Gynecologie 12 (2), 372-397 (1972). 17. Averette, H. E., Dudou, R. C., and Jord, J. H., Jr. Exploratory celiotomy for surgical staging of cervical cancer, Amer. J. Obstet. Gynecol. 113, 1090-1096 (1972). 18. Fletcher, G. H. Clinical dose-response curves of human malignant epithelial tumors, Brit. J. Rndiol. 46, 1-12 (1973). 19. Rutledge, F. N., and Fletcher, G. H. Transperitoneal pelvic lymphadenectomy following supervoltage irradiation for squamous cell carcinoma of the cervix, Amer. J. Obstet. Gynecol. 76, 321-334 (1958). 20. Morton, D. G., Lagasse, L. D., Moore, J. G., Jacobs, M., and Amromin, G. D. Pelvic lympha-

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denectomy following radiation in cervical carcinoma, Amer. J. Obstet. Gynecol. 88, 932-943 (1964). Buchsbaum, H. J. Para-aortic lymph node involvement in cervical carcinoma, Amer. J. Obstet. Gynecol. 113, 942-947 (1972). Lecart, C., and Lenfant, P. Critical appraisal of lymphangiography in cancer of the female genital tract, Lymphology 4, lOO- 108 (197 1). Tawil, E., and Belanger, R. Prognostic value of the lymphangiogram in carcinoma of the uterine cervix, Radiology 109, 597-599 (1973). Petty, W. M., Teaford, A. K., Park, R. C., and Patow, W. E. Angiographic evaluation of early carcinoma of the cervix, Gynecol. Oncol. 1, 2 11-2 19 (1973). Littman, P., Davis, L. W., and Lepanto, P. Evaluation of nodal metastases in patients with cervical carcinoma, Cancer 31, 1307- 1311 (1973). Fletcher, G. H., and Rutledge, F. N. Extended field technique in management of cancers of the uterine cervix, Amer. J. Roentgenol. 114, 116-122 (1972). Ucmakle, A., and Bonney, W. A. Exploratory laparotomy as routine pretreatment investigation in carcinoma of the cervix, Radiology 104, 371-377 (1972). Mortel, R., Lewis, G. C., Jr., and Brady, L. W. Evaluation of abdominal lymph scanning in gynecologic cancer, Gynecol. Oncol. 1, 36-43 (1972). Fletcher, G. H. Cancer of the uterine cervix, Amer. J. Roentgenol. 111, 225-242, (1971).

Pretreatment lymphangiography in carcinoma of the uterine cervix.

GYNECOLOGIC ONCOLOGY 3, 3.54-360 (1975) Pretreatment Carcinoma Lymphangiography in of the Uterine Cervix’ MILTON H. LEMAN,~ JR., LTC, MC, U.S.A.,...
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