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Lymph node metastasis of ovarian cancer: A preliminary survey of 74 cases of lymphadenectomy
Lymph node metastasis of ovarian cancer: A preliminary survey of 74 cases of lymphadenectomy Pao-Chen Wu, M.D., Jing-Yi Qu, M.D., Jing·He Lang, M.D., Rong-Li Huang, M.D., Min-Yi Tang, M.D., and Li-Juan Lian, M.D.
Beijing, China Retroperitoneal lymph node dissection was performed in 74 cases of various types of ovarian malignancies. Fifty-three (71.6%) were histologically confirmed as cancer of epithelial origin and 19 (25.7%) as germ cell tumors. The results indicate that lymphatic metastasis is an exceedingly important route of spreading of this group of malignant diseases. The overall incidence of retroperitoneal positive nodes was 56.8% (42/74). In 49 cases undergoing systemic lymphadenectomy 32 were found to have glandular involvement, of which both aortic and pelvic nodes were positive in 17 cases (53.1%), aortic nodes positive but pelvic negative in six (18.8%), and pelvic nodes positive but aortic negative in nine (28.1%). In 32 cases with primary cancer that originated from the left ovary, 17 (53.1%) were found to have positive pelvic nodes, whereas in 19 cases with cancer arising from the right ovary, only one (5.3%) hlid metastasis of ipsilateral pelvic nodes. The routes of lymphatic spreading and the significance of lymphadenectomy in ovarian cancer are discussed. (AM J OSSTET GVNECOL 1986;155:1103-8.)
Key words: Ovary, cancer, lymph node metastasis
It is universally recognized that the spread of ovarian cancer is manifested by extensive intraperitoneal implantation and local invasion to adjacent tissues and/or organs. Little attention has been paid to another important but relatively inconspicuous route of metastasis-retroperitoneal spread through lymphatic pathways. In 1974 Knapp and Friedman' first reported their experience with aortic lymph node metastasis in patients with early ovarian cancer treated by lymphadenectomy. Thereafter, other articles have appeared in the literature.!" Beginning in 1982 retroperitoneal lymph node dissection has been carried out at the Peking Union Medical College Hospital as a routine operative procedure in addition to the cytoreductive surgery for most patients with ovarian malignancies. The purpose of this report is to present our preliminary prospective study on the incidence of pelvic and paraaortic node metastasis in order to assess the role of lymphadenectomy in the management of ovarian cancer.
Material and methode Subject of study. From June 1982 through August 1985 retroperitoneal lymph node dissection was performed during cytoreductive surgery in 74 cases of From the Department of Obstetrics and Gynecology, Peking Union Medical College. ReceivedforpublicationDecember 27,1985; revisedJune 16,1986; accepted July 7, 1986. Reprints request: Pao-ChenWu, M.D., the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
ovarian cancer. Primary operation was performed in 45 and operation for recurrent or incompletely resected tumors in the remaining 29. The histologic types and stage of the patients are shown in Table I. Ovarian cancer of epithelial origin constituted the majority of the cases, of which 35 (66.0%) were of serous type. The clinical staging was assessed during laparotomy with use of International Federation of Gynecology and Obstetrics (FIGO) criteria without considering the pathologic findings of the nodes. It can be clearly seen that the majority of the patients represented advanced cases, and Stage I disease accounted for only 13.5% of the total series. Surgical methods (Table II) Cytoreductive surgery. In addition to the traditional procedures of total hysterectomy, bilateral salpingooophorectomy, partial omenectomy, and appendectomy, all the tumor-bearing tissues including pelvic and abdominal peritoneum, serosa of small bowel, colon, and rectum were resected to the best of the surgeon's skill whenever the condition of the patients during operation permitted. Partial resection of intestine with anastomosis or colostomy was performed when the intestinal wall was deeply invaded. All excised tissues were labeled according to the sites and put into separate vessels for pathologic examination. If there should be a discrepancy between gross appearance and microscopic examination, the evaluation of staging would be revised on the basis of pathologic findings. Retroperitoneal lymphadenectomy. Lymph node dissection was usually carried out at the end of the cytoreductive surgical procedure for the intraperitoneal tu1103
1104 Wu et al.
November 1986 Am J Obstet Gynecol
Table II. Surgical methods in 74 cases of ovarian cancer No. of
\J
cases
1--
43.1%(25/58)
17.5%
25.8%--(16/6.2)
65% (4/62 )
~-(;;/::: 27. 8
Yo
(15/Sil)
Fig. 1. Incidence of metastasis in different groups of lymph
nodes. The groups of lymph nodes shown from abovedownward and from lateral to medialare para-aortic,commoniliac, external iliac, obturator, and internal iliac. The incidence of presacral nodes is indicated under the bifurcation of aorta. Table I. Subjects of study (n = 74) _ _ _ _ _1
Histologic type Epithelial Germ cell tumor Sex cord stromal Staging (FIGO)
IV
74 49 25*
*Aortic nodes not removed in 16.
( 11/63)
13 7'% (7/51 )
I II III
Cytoreductive surgery Retroperitoneal lymphadenectomy Systemic lymphadenectomy Selective sampling
No.
%
53
71.6
19 2
25.7 2.7
10
13.5
8
10.8
49 7
66.2
9.5
mors but before resection of the intestine if the latter procedure was indicated. Systemic lymphadenectomy denotes complete lymph node dissection covering all pelvic groups of nodes together with a segment of paraaortic lymphatic tissue about 4 to 5 cm in length from the bifurcation of the aorta up to the level of the inferior mesenteric artery. This was done in 49 cases. In the remaining 25 cases only selective sampling of lymph nodes was performed, and in 16 of these cases paraaortic nodes were not removed. The resected lymphatic tissue was grouped and labeled as para-aortic, presacral, left and right common iliac, external iliac, internal iliac, and obturator and was subjected to histologic examination individually.
Results Positive nodes were found in 42 of 74 cases studied, providing an overall incidence of retroperitoneal lymph node metastasis of 56.8%. The incidence of positive pelvic nodes was 48.7% (36174) and that of para-
aortic nodes was 43.1 % (25/58). The metastatic rates of different groups of lymph nodes are shown in Fig. 1, indicating that ovarian cancer may spread to any group of the pelvic nodes. Results of the study include the following: 1. Exploratory findings and microscopic examination of lymph nodes. In order to assess the accuracy of evaluation during surgical exploration, the gorss appearance of the lymph nodes documented at operation was correlated with the pathologic examination in Table III. In 32 cases with suspicious nodes, 28 (87.5%) were proved to be positive histologically. Of 42 cases in which the nodes were grossly normal, 33.3% were found to be microscopically positive. 2. Pelvic node and para-aortic node metastasis. In this series there were 49 cases with systemic lymphadenectomy, in which a complete set of pelvic nodes together with para-aortic nodes from the same patients were available for comparison (Table IV). Among 32 cases with lymph node metastasis, both pelvic and paraaortic nodes were positive in 17 (53.1 %), aortic nodes positive but pelvic nodes negative in six (18.8%), and pelvic nodes positive but aortic nodes negative in nine (28.1 %). 3. Histologic type and lymph node metastasis. The incidence of lymph node metastasis in different histologic types of tumors is shown in Table V. Positive nodes were found in 11 of 19 cases of germ cell tumor (57.9%), and in 24 of 35 cases of serous epithelial cancer (68.6%). Dysgerminoma seemed to have a tendency to metastasize to the para-aortic nodes, and positive nodes were found in both of the two cases of malignant Brenner tumor and none of the two cases of granulosa cell tumor. However, because too few cases were seen for these subtypes of cancer, the incidence thus obtained may not be meaningful. 4. Clinical staging and lymph node metastasis (Table VI). Among 10 patients with Stage I disease, two (both had dysgerminoma) were found to have positive nodes, an incidence of 20.0%, indicating that lymph node metastasis may occur even in very early cases of ovarian cancer. There was no apparent difference of lymph node metastasis among Stages II, III, and IV patients, and the incidence of positive nodes of
Lymph node metastasis of ovarian cancer
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1105
Table III. Correlation of exploratory findings and pathologic examination of nodes Pathologic findings Negative
Positive Gross appearance
No. of cases
No.
Suspicious Normal
32
28
42
14
Total
74
42
Stage III cases, which accounted for the majority of the series, was similar in patients with epithelial cancer and germ cell tumor. 5. Histologic grading and lymph node metastasis. Among 53 cases of epithelial cancer the primary tumor was available for histologic grading in 50. The relationship between histologic grading and node metastasis is shown in Table VII. No positive nodes were found in four patients with borderline tumors. In 36 cases with moderate to poorly differentiated tumors, 25 had positive nodes, giving a metastasis rate of 69.4%. 6. Site of the primary cancer and lymph node metastasis. As shown in Table VIII, in 32 cases in which the primary cancer originated in the left ovary, 17 (53.1 %) were found to have positive pelvic nodes, and chances of spread to the lymph nodes of the left and right pelvic walls were equal. However, for 17 cases with primary cancer arising in the right ovary, only one had metastasis of the ipsilateral pelvic nodes. The difference is statistically highly significant (p < 0.01), although the mechanism remains to be clarified. The same tendency of pelvic node metastasis from cancer of the left ovary was also demonstrated when patients with epithelial cancer and those with germ cell tumor were analyzed separately. There was no marked difference of incidence of para-aortic node involvement between cancer originating in left and right ovaries. 7. Primary or secondary operation in relation to lymph node metastasis (Table IX). In 45 cases the lymphadenectomy was carried out during the primary operation, and 57.8% were found to have positive nodes; in the remaining 29 cases the operation was performed as a secondary surgical procedure for recurrent or incompletely resected tumors, and the incidence of lymph node metastasis was 55.2%. 8. Lymph node metastasis and outcome of the patients. The outcome of patients in the present series followed for at least 8 months until April 1986 is shown in Table X. The rates of complete remission (patients remaining free of detectable disease) for those with and without lymph node involvement were quite similar (52.4% versus 50.0%). However, because of the briefness of period of follow-up, the result is far from conclusive.
I
%
No.
87.5 33.3
28
I
% 12.5 66.7
4
32
Table IV. Pelvic node versus para-aortic node metastasis in 49 cases with systemic lymphadenectomy Lymph node Pelvic Positive Negative Positive Negative Total
I
Aortic
No. of cases
%
Negative Positive Positive Negative
9 6 17 17
12.2 34.7 34.7
49
100.0
18.4
Comment Ovarian cancer has become increasingly important in recent years and now ranks as the leading cause of death among all gynecologic malignancies. While clinicians are studying the behavior of ovarian cancer and searching for better therapeutic modalities, it is quite inconceivable that little attention has been paid to an important route of spread-lymphatic metastasis-in this group of diseases. There may be two possible explanations. First, the metastasis along the lymphatic pathway has been overshadowed by the outstanding extensive intraperitoneal implantation of ovarian cancer, which diverts the attention of most gynecologists. Second, according to the traditional conception of anatomy, the lymphatics of an organ run constantly parallel to the blood vessels. Therefore the lymphatics of ovary should take a course identical with the ovarian veins in the infundibulopelvic ligament to the abdominal aorta and inferior vena cava along the psoas muscle. Thus a misguided impression has resulted, which leads the clinicians to believe that once retroperitoneal lymphatic metastasis of ovarian cancer happens, the first group of lymph nodes involved will always be the para-aortic nodes, which are situated high above the pelvis and far beyond the reach of regular surgical and radiation therapy. Although a high incidence of involvement of pelvic nodes in patients with ovarian cancer was reported in the 1960s based on the findings of autopsies," it had been generally regarded as a phenomenon occurring only in very late cases, resulting from a retrograde flow of tumor cells to the pelvic lymphatic channels because
1106 Wu et al.
November 1986 Am J Obstet Gynecol
Table V. Histologic type and lymph node metastasis Pam-aortic node Histologic type
No. of cases
Epithelial cancer Serous Mixed type Clear cell Endometrioid Brenner Mixed mesodermal Germ cell tumor Endodermal sinus tumor Teratoma Dysgerminoma Mixed type Sex cord stromal tumor Total
I
No. positive
I
Total
Pelvic node
% positive
No. of cases
I
No. positive
I
% positive
No. of cases
I
No. positive
I
% positive
23 2 10 1 2 1
12 0 3 0 2 0
52.2 0 30.0 0 100.0 0
35 2 10 3 2 1
23 0 4 1 2 0
65.7 0 40.0 33.3 100.0 0
35 2 10 3 2 1
24 0 4 1 2 0
62.9 0 40.0 33.3 100.0 0
9
4
44.4
9
2
22.2
9
4
44.4
6 2
2 2
33.3 100.0
2
0
0
7 2 1 2
4 0 0 0
57.1 0 0 0
7 2 1 2
5 2 0 0
71.4 100.0 0 0
58
25
43.1
74
36
48.6
74
42
56.8
Table VI. Clinical staging and lymph node metastasis Epithelial cancer Stage
No. of cases
I
No. positive
Germ celltumor
I
positive
No. of cases
%
I
No. positive
I
% positive
I II III IV
5 7 39 2
0 3 26 2
0 42.9 66.7 100.0
4 1 9 5
2 1 6 2
50.0 100.0 66.7 40.0
Total
53
31
58.5
19
11
57.9
Table VII. Histologic grading and lymph node metastasis in epithelial cancer % positive
Histologic grading
o
o
Borderline Highly differentiated Moderately differentiated Poorly differentiated
4 10 30 6
5 22 3
50.0 73.3 50.0
Total
50
30
60.0
of the blockage of the lumbar lymph chain by tumor emboli, and bearing little clinical significance. In a monograph Plentl and Friedman" pointed out that in addition to the classical lymphatic pathway there are lymph trunks from the ovary coursing within the folds of broad ligaments and reaching the pelvic wall to terminate directly in the iliac nodes. This statement has recently been proved by a report of Chen and Lee' in which nine of 61 cases of epithelial carcinoma of ovary were found to have positive pelvic nodes only without concomitant para-aortic node metastasis. Burghardt et al.," based on the results of lymphadenectomy in 48 cases of ovarian cancer, thought that pelvic nodes were
involved earlier than the para-aortic nodes and even suggested that aortic nodes were involved only in cases of positive pelvic nodes. However, because some of their cases were documented as having aortic node metastasis only through palpation, the conclusion should be considered with some reservation. The results of the present study clearly demonstrate the importance of lymphatic metastasis in ovarian cancer. In 49 cases with systemic lymphadenectomy, the incidence of positive para-aortic nodes was 46.9% and that of positive pelvic nodes was 53.1 %, indicating that malignant tumors of the ovary may have an equal chance to metastasize along the lymphatic pathways to aortic and pelvic nodes. Particularly interesting is the fact that in 32 cases with positive nodes, six (18.8%) had only para-aortic node involvement and nine (28.1 %) had only pelvic node involvement, giving further confirmation of Plentl and Friedman's statement that the lymphatic drainage from the ovary may carry the tumor cells directly to nodes on the pelvic wall without traversing the para-aortic nodes. Regardless of the efforts in using newer and more sophisticated surgical, radiotherapeutic, and chemotherapeutic modalities of treatment, the survival rate
Lymph node metastasis of ovarian cancer
Volume 155 Number 5
1107
Table VIII. Site of primary cancer and pelvic node metastasis Positive lymph node Site of primary cancer
Left ovary Right ovary Bilateral
Total Tumor type
No. of cases
Left
Right
Bilateral
No.
Epithelial Germ cell Epithelial Germ cell Epithelial Germ cell
19 13 II 6 23 0
2 3 0 0 3 0
3 2
6
I
11 6
I
0 0 14 0
0 18 0
from ovarian cancer has shown little improvement in the last decades. The difficulty in irradicating the widely disseminated intraperitoneal lesions has probably accounted for the main reason of failure of the efforts of gynecologists, but the menace of the silent spreading of the tumor through the lymphatic channels retroperitoneally should not be overlooked. According to the results of this preliminary study, it is suggested that retroperitoneal lymphadenectomy during routine cytoreductive surgery for ovarian cancer may be an ideal choice for both staging evaluation and therapeutic purpose, provided the condition of the patient permits. Since the revision of the FlGO staging classification for ovarian cancer in 1975," positive retroperitoneal lymph nodes have been included in the criteria of Stage III disease. Whenever the retroperitoneal nodes are involved, the patient should be categorized as Stage III instead of I even though the primary cancer appears to be confined to the ovary. This revision requires a reevaluation of the traditional methods in assessing the stage of patients with ovarian cancer. Although a thorough surgical exploration during the initial operation is very important in accurately assessing the extent of intraperitoneal tumor, evaluation of lymph node involvement by palpation according to our data is not adequately reliable. Lymphangiography may be considered a very useful part of detecting lymph node involvement, but difficulties in interpreting the lymphographic manifestations on account oflack of studies correlating radiologic with histologic abnormalities limit the popularization of this technique. Therefore the most reliable method in assessing lymph node involvement in ovarian cancer is to subject the resected lymphatic tissue to pathologic examination. In this series, six (35.3%) of 18 cases categorized as Stage I or II during surgical exploration were found to have positive nodes after histologic study of the removed lymphatic tissue and should be reclassified as Stage III. From the therapeutic point of view, the current policy is for surgeons to do their best to remove all the primary and metastatic tumors in the peritoneal cavity. According to the results of the present series and others," 5 the incidence of retroperitoneal nodal involvement is
0 1 0
I
I
% 57.9 46.2 9.1 78.3
Table IX. Primary or secondary operation in relation to lymph node metastasis % positive
Operation
No. of cases
Primary Secondary Total
45 29
26 16
57.8 55.2
74
42
56.8
around 50%. Therefore all attempts in improving the prognosis of ovarian cancer by emphasizing only the thoroughness of resection of intraperitoneal tumors will be futile if the presence of this important route of metastasis which may transport cancer cells to any part of the body is neglected. Retroperitoneal lymphadenectomy will not only lessen the tumor burden by removing the cancer-bearing nodes but also may provide a guideline for further treatment. If positive pelvic nodes and negative para-aortic nodes are found on pathologic examination, simple lymphadenectomy will be sufficient. If positive para-aortic nodes are found, postoperative irradiation of the lumbar lymph chain up to the level of the diaphragm may be necessary in irradicating the upward-spreading tumor cells. Burghardt et al.' compared the actuarial survival rates after operative treatment in Stage III ovarian cancer patients with and without lymphadenectomy. In 21 cases with lymphadenectomy the survival rate at 2 years was 95.1 %, whereas in 10 cases without lymphadenectomy the survival rate was only 40%. Although the comparability of the survival rates of these two groups of patients was limited because of the difference in postoperative chemotherapeutic regimens used, the results nevertheless indicate the possibility of improving the therapeutic results and prognosis of ovarian cancer through retroperitoneal lymphadenectomy.
REFERENCES 1. Knapp RC, Friedman EA. Aortic lymph node metastasis
in early ovarian cancer. AM J OBSTET GYNECOL 1974;119:1013.
2. DelgadoG, Chun B, Gaglar H, Bepko F.ParaaorticIymph-
1108 Wu at al.
November 1986 Am J Obstet Gynecol
Table X. Lymph node metastasis and outcome of patients No. of cases
No.
Yes No
42 32
Total
74
I
Death
Recurrence
Remission Lymph node metastasis
%
No.
22 16
52.4 50.0
38
51.4
2 5 7
adenectomy in gynecologic malignancies confined to the pelvis. Obstet Gynecol 1977;50:418. 3. Creasman WT, Abu-Ghazaleh S, Schmidt HJ. Retroperitoneal metastatic spread of ovarian cancer. Gynecol Oncol 1978;6:447. 4. Chen SS, Lee L. Incidence of para-aortic and pelvic lymph node metastases in epithelial carcinoma of the ovary. GynecolOncol 1983;16:95. 5. Burghardt E, Pickel H, Stettner H. Management of
I
I
%
%
No.
4.8 15.6
18 11
42.8 34.4
9.4
29
39.2
advanced ovarian cancer. Eur J Gynaecol Oncol 1984; 3:155. 6. Bergman F. Carcinoma of the ovary: a clinicopathological study of 86 autopsied cases with special reference to mode of spread. Acta Obstet Gynecol Scand 1966;45:211. 7. Plentl AA, Friedman EA. Lymphatic system of the female genitalia. Philadelphia: WB Saunders, 1971;170. 8. Day TG, Smith JP. Diagnosis and staging of ovarian cancer. Semin Oncol 1975;2:217.
Beijing, China Retroperitoneal lymph node dissection was performed in 74 cases of various types of ovarian malignancies. Fifty-three (71.6%) were histologically confirmed as cancer of epithelial origin and 19 (25.7%) as germ cell tumors. The results indicate that lymphatic metastasis is an exceedingly important route of spreading of this group of malignant diseases. The overall incidence of retroperitoneal positive nodes was 56.8% (42/74). In 49 cases undergoing systemic lymphadenectomy 32 were found to have glandular involvement, of which both aortic and pelvic nodes were positive in 17 cases (53.1%), aortic nodes positive but pelvic negative in six (18.8%), and pelvic nodes positive but aortic negative in nine (28.1%). In 32 cases with primary cancer that originated from the left ovary, 17 (53.1%) were found to have positive pelvic nodes, whereas in 19 cases with cancer arising from the right ovary, only one (5.3%) hlid metastasis of ipsilateral pelvic nodes. The routes of lymphatic spreading and the significance of lymphadenectomy in ovarian cancer are discussed. (AM J OSSTET GVNECOL 1986;155:1103-8.)
Key words: Ovary, cancer, lymph node metastasis
It is universally recognized that the spread of ovarian cancer is manifested by extensive intraperitoneal implantation and local invasion to adjacent tissues and/or organs. Little attention has been paid to another important but relatively inconspicuous route of metastasis-retroperitoneal spread through lymphatic pathways. In 1974 Knapp and Friedman' first reported their experience with aortic lymph node metastasis in patients with early ovarian cancer treated by lymphadenectomy. Thereafter, other articles have appeared in the literature.!" Beginning in 1982 retroperitoneal lymph node dissection has been carried out at the Peking Union Medical College Hospital as a routine operative procedure in addition to the cytoreductive surgery for most patients with ovarian malignancies. The purpose of this report is to present our preliminary prospective study on the incidence of pelvic and paraaortic node metastasis in order to assess the role of lymphadenectomy in the management of ovarian cancer.
Material and methode Subject of study. From June 1982 through August 1985 retroperitoneal lymph node dissection was performed during cytoreductive surgery in 74 cases of From the Department of Obstetrics and Gynecology, Peking Union Medical College. ReceivedforpublicationDecember 27,1985; revisedJune 16,1986; accepted July 7, 1986. Reprints request: Pao-ChenWu, M.D., the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
ovarian cancer. Primary operation was performed in 45 and operation for recurrent or incompletely resected tumors in the remaining 29. The histologic types and stage of the patients are shown in Table I. Ovarian cancer of epithelial origin constituted the majority of the cases, of which 35 (66.0%) were of serous type. The clinical staging was assessed during laparotomy with use of International Federation of Gynecology and Obstetrics (FIGO) criteria without considering the pathologic findings of the nodes. It can be clearly seen that the majority of the patients represented advanced cases, and Stage I disease accounted for only 13.5% of the total series. Surgical methods (Table II) Cytoreductive surgery. In addition to the traditional procedures of total hysterectomy, bilateral salpingooophorectomy, partial omenectomy, and appendectomy, all the tumor-bearing tissues including pelvic and abdominal peritoneum, serosa of small bowel, colon, and rectum were resected to the best of the surgeon's skill whenever the condition of the patients during operation permitted. Partial resection of intestine with anastomosis or colostomy was performed when the intestinal wall was deeply invaded. All excised tissues were labeled according to the sites and put into separate vessels for pathologic examination. If there should be a discrepancy between gross appearance and microscopic examination, the evaluation of staging would be revised on the basis of pathologic findings. Retroperitoneal lymphadenectomy. Lymph node dissection was usually carried out at the end of the cytoreductive surgical procedure for the intraperitoneal tu1103
1104 Wu et al.
November 1986 Am J Obstet Gynecol
Table II. Surgical methods in 74 cases of ovarian cancer No. of
\J
cases
1--
43.1%(25/58)
17.5%
25.8%--(16/6.2)
65% (4/62 )
~-(;;/::: 27. 8
Yo
(15/Sil)
Fig. 1. Incidence of metastasis in different groups of lymph
nodes. The groups of lymph nodes shown from abovedownward and from lateral to medialare para-aortic,commoniliac, external iliac, obturator, and internal iliac. The incidence of presacral nodes is indicated under the bifurcation of aorta. Table I. Subjects of study (n = 74) _ _ _ _ _1
Histologic type Epithelial Germ cell tumor Sex cord stromal Staging (FIGO)
IV
74 49 25*
*Aortic nodes not removed in 16.
( 11/63)
13 7'% (7/51 )
I II III
Cytoreductive surgery Retroperitoneal lymphadenectomy Systemic lymphadenectomy Selective sampling
No.
%
53
71.6
19 2
25.7 2.7
10
13.5
8
10.8
49 7
66.2
9.5
mors but before resection of the intestine if the latter procedure was indicated. Systemic lymphadenectomy denotes complete lymph node dissection covering all pelvic groups of nodes together with a segment of paraaortic lymphatic tissue about 4 to 5 cm in length from the bifurcation of the aorta up to the level of the inferior mesenteric artery. This was done in 49 cases. In the remaining 25 cases only selective sampling of lymph nodes was performed, and in 16 of these cases paraaortic nodes were not removed. The resected lymphatic tissue was grouped and labeled as para-aortic, presacral, left and right common iliac, external iliac, internal iliac, and obturator and was subjected to histologic examination individually.
Results Positive nodes were found in 42 of 74 cases studied, providing an overall incidence of retroperitoneal lymph node metastasis of 56.8%. The incidence of positive pelvic nodes was 48.7% (36174) and that of para-
aortic nodes was 43.1 % (25/58). The metastatic rates of different groups of lymph nodes are shown in Fig. 1, indicating that ovarian cancer may spread to any group of the pelvic nodes. Results of the study include the following: 1. Exploratory findings and microscopic examination of lymph nodes. In order to assess the accuracy of evaluation during surgical exploration, the gorss appearance of the lymph nodes documented at operation was correlated with the pathologic examination in Table III. In 32 cases with suspicious nodes, 28 (87.5%) were proved to be positive histologically. Of 42 cases in which the nodes were grossly normal, 33.3% were found to be microscopically positive. 2. Pelvic node and para-aortic node metastasis. In this series there were 49 cases with systemic lymphadenectomy, in which a complete set of pelvic nodes together with para-aortic nodes from the same patients were available for comparison (Table IV). Among 32 cases with lymph node metastasis, both pelvic and paraaortic nodes were positive in 17 (53.1 %), aortic nodes positive but pelvic nodes negative in six (18.8%), and pelvic nodes positive but aortic nodes negative in nine (28.1 %). 3. Histologic type and lymph node metastasis. The incidence of lymph node metastasis in different histologic types of tumors is shown in Table V. Positive nodes were found in 11 of 19 cases of germ cell tumor (57.9%), and in 24 of 35 cases of serous epithelial cancer (68.6%). Dysgerminoma seemed to have a tendency to metastasize to the para-aortic nodes, and positive nodes were found in both of the two cases of malignant Brenner tumor and none of the two cases of granulosa cell tumor. However, because too few cases were seen for these subtypes of cancer, the incidence thus obtained may not be meaningful. 4. Clinical staging and lymph node metastasis (Table VI). Among 10 patients with Stage I disease, two (both had dysgerminoma) were found to have positive nodes, an incidence of 20.0%, indicating that lymph node metastasis may occur even in very early cases of ovarian cancer. There was no apparent difference of lymph node metastasis among Stages II, III, and IV patients, and the incidence of positive nodes of
Lymph node metastasis of ovarian cancer
Volume 155 Number 5
1105
Table III. Correlation of exploratory findings and pathologic examination of nodes Pathologic findings Negative
Positive Gross appearance
No. of cases
No.
Suspicious Normal
32
28
42
14
Total
74
42
Stage III cases, which accounted for the majority of the series, was similar in patients with epithelial cancer and germ cell tumor. 5. Histologic grading and lymph node metastasis. Among 53 cases of epithelial cancer the primary tumor was available for histologic grading in 50. The relationship between histologic grading and node metastasis is shown in Table VII. No positive nodes were found in four patients with borderline tumors. In 36 cases with moderate to poorly differentiated tumors, 25 had positive nodes, giving a metastasis rate of 69.4%. 6. Site of the primary cancer and lymph node metastasis. As shown in Table VIII, in 32 cases in which the primary cancer originated in the left ovary, 17 (53.1 %) were found to have positive pelvic nodes, and chances of spread to the lymph nodes of the left and right pelvic walls were equal. However, for 17 cases with primary cancer arising in the right ovary, only one had metastasis of the ipsilateral pelvic nodes. The difference is statistically highly significant (p < 0.01), although the mechanism remains to be clarified. The same tendency of pelvic node metastasis from cancer of the left ovary was also demonstrated when patients with epithelial cancer and those with germ cell tumor were analyzed separately. There was no marked difference of incidence of para-aortic node involvement between cancer originating in left and right ovaries. 7. Primary or secondary operation in relation to lymph node metastasis (Table IX). In 45 cases the lymphadenectomy was carried out during the primary operation, and 57.8% were found to have positive nodes; in the remaining 29 cases the operation was performed as a secondary surgical procedure for recurrent or incompletely resected tumors, and the incidence of lymph node metastasis was 55.2%. 8. Lymph node metastasis and outcome of the patients. The outcome of patients in the present series followed for at least 8 months until April 1986 is shown in Table X. The rates of complete remission (patients remaining free of detectable disease) for those with and without lymph node involvement were quite similar (52.4% versus 50.0%). However, because of the briefness of period of follow-up, the result is far from conclusive.
I
%
No.
87.5 33.3
28
I
% 12.5 66.7
4
32
Table IV. Pelvic node versus para-aortic node metastasis in 49 cases with systemic lymphadenectomy Lymph node Pelvic Positive Negative Positive Negative Total
I
Aortic
No. of cases
%
Negative Positive Positive Negative
9 6 17 17
12.2 34.7 34.7
49
100.0
18.4
Comment Ovarian cancer has become increasingly important in recent years and now ranks as the leading cause of death among all gynecologic malignancies. While clinicians are studying the behavior of ovarian cancer and searching for better therapeutic modalities, it is quite inconceivable that little attention has been paid to an important route of spread-lymphatic metastasis-in this group of diseases. There may be two possible explanations. First, the metastasis along the lymphatic pathway has been overshadowed by the outstanding extensive intraperitoneal implantation of ovarian cancer, which diverts the attention of most gynecologists. Second, according to the traditional conception of anatomy, the lymphatics of an organ run constantly parallel to the blood vessels. Therefore the lymphatics of ovary should take a course identical with the ovarian veins in the infundibulopelvic ligament to the abdominal aorta and inferior vena cava along the psoas muscle. Thus a misguided impression has resulted, which leads the clinicians to believe that once retroperitoneal lymphatic metastasis of ovarian cancer happens, the first group of lymph nodes involved will always be the para-aortic nodes, which are situated high above the pelvis and far beyond the reach of regular surgical and radiation therapy. Although a high incidence of involvement of pelvic nodes in patients with ovarian cancer was reported in the 1960s based on the findings of autopsies," it had been generally regarded as a phenomenon occurring only in very late cases, resulting from a retrograde flow of tumor cells to the pelvic lymphatic channels because
1106 Wu et al.
November 1986 Am J Obstet Gynecol
Table V. Histologic type and lymph node metastasis Pam-aortic node Histologic type
No. of cases
Epithelial cancer Serous Mixed type Clear cell Endometrioid Brenner Mixed mesodermal Germ cell tumor Endodermal sinus tumor Teratoma Dysgerminoma Mixed type Sex cord stromal tumor Total
I
No. positive
I
Total
Pelvic node
% positive
No. of cases
I
No. positive
I
% positive
No. of cases
I
No. positive
I
% positive
23 2 10 1 2 1
12 0 3 0 2 0
52.2 0 30.0 0 100.0 0
35 2 10 3 2 1
23 0 4 1 2 0
65.7 0 40.0 33.3 100.0 0
35 2 10 3 2 1
24 0 4 1 2 0
62.9 0 40.0 33.3 100.0 0
9
4
44.4
9
2
22.2
9
4
44.4
6 2
2 2
33.3 100.0
2
0
0
7 2 1 2
4 0 0 0
57.1 0 0 0
7 2 1 2
5 2 0 0
71.4 100.0 0 0
58
25
43.1
74
36
48.6
74
42
56.8
Table VI. Clinical staging and lymph node metastasis Epithelial cancer Stage
No. of cases
I
No. positive
Germ celltumor
I
positive
No. of cases
%
I
No. positive
I
% positive
I II III IV
5 7 39 2
0 3 26 2
0 42.9 66.7 100.0
4 1 9 5
2 1 6 2
50.0 100.0 66.7 40.0
Total
53
31
58.5
19
11
57.9
Table VII. Histologic grading and lymph node metastasis in epithelial cancer % positive
Histologic grading
o
o
Borderline Highly differentiated Moderately differentiated Poorly differentiated
4 10 30 6
5 22 3
50.0 73.3 50.0
Total
50
30
60.0
of the blockage of the lumbar lymph chain by tumor emboli, and bearing little clinical significance. In a monograph Plentl and Friedman" pointed out that in addition to the classical lymphatic pathway there are lymph trunks from the ovary coursing within the folds of broad ligaments and reaching the pelvic wall to terminate directly in the iliac nodes. This statement has recently been proved by a report of Chen and Lee' in which nine of 61 cases of epithelial carcinoma of ovary were found to have positive pelvic nodes only without concomitant para-aortic node metastasis. Burghardt et al.," based on the results of lymphadenectomy in 48 cases of ovarian cancer, thought that pelvic nodes were
involved earlier than the para-aortic nodes and even suggested that aortic nodes were involved only in cases of positive pelvic nodes. However, because some of their cases were documented as having aortic node metastasis only through palpation, the conclusion should be considered with some reservation. The results of the present study clearly demonstrate the importance of lymphatic metastasis in ovarian cancer. In 49 cases with systemic lymphadenectomy, the incidence of positive para-aortic nodes was 46.9% and that of positive pelvic nodes was 53.1 %, indicating that malignant tumors of the ovary may have an equal chance to metastasize along the lymphatic pathways to aortic and pelvic nodes. Particularly interesting is the fact that in 32 cases with positive nodes, six (18.8%) had only para-aortic node involvement and nine (28.1 %) had only pelvic node involvement, giving further confirmation of Plentl and Friedman's statement that the lymphatic drainage from the ovary may carry the tumor cells directly to nodes on the pelvic wall without traversing the para-aortic nodes. Regardless of the efforts in using newer and more sophisticated surgical, radiotherapeutic, and chemotherapeutic modalities of treatment, the survival rate
Lymph node metastasis of ovarian cancer
Volume 155 Number 5
1107
Table VIII. Site of primary cancer and pelvic node metastasis Positive lymph node Site of primary cancer
Left ovary Right ovary Bilateral
Total Tumor type
No. of cases
Left
Right
Bilateral
No.
Epithelial Germ cell Epithelial Germ cell Epithelial Germ cell
19 13 II 6 23 0
2 3 0 0 3 0
3 2
6
I
11 6
I
0 0 14 0
0 18 0
from ovarian cancer has shown little improvement in the last decades. The difficulty in irradicating the widely disseminated intraperitoneal lesions has probably accounted for the main reason of failure of the efforts of gynecologists, but the menace of the silent spreading of the tumor through the lymphatic channels retroperitoneally should not be overlooked. According to the results of this preliminary study, it is suggested that retroperitoneal lymphadenectomy during routine cytoreductive surgery for ovarian cancer may be an ideal choice for both staging evaluation and therapeutic purpose, provided the condition of the patient permits. Since the revision of the FlGO staging classification for ovarian cancer in 1975," positive retroperitoneal lymph nodes have been included in the criteria of Stage III disease. Whenever the retroperitoneal nodes are involved, the patient should be categorized as Stage III instead of I even though the primary cancer appears to be confined to the ovary. This revision requires a reevaluation of the traditional methods in assessing the stage of patients with ovarian cancer. Although a thorough surgical exploration during the initial operation is very important in accurately assessing the extent of intraperitoneal tumor, evaluation of lymph node involvement by palpation according to our data is not adequately reliable. Lymphangiography may be considered a very useful part of detecting lymph node involvement, but difficulties in interpreting the lymphographic manifestations on account oflack of studies correlating radiologic with histologic abnormalities limit the popularization of this technique. Therefore the most reliable method in assessing lymph node involvement in ovarian cancer is to subject the resected lymphatic tissue to pathologic examination. In this series, six (35.3%) of 18 cases categorized as Stage I or II during surgical exploration were found to have positive nodes after histologic study of the removed lymphatic tissue and should be reclassified as Stage III. From the therapeutic point of view, the current policy is for surgeons to do their best to remove all the primary and metastatic tumors in the peritoneal cavity. According to the results of the present series and others," 5 the incidence of retroperitoneal nodal involvement is
0 1 0
I
I
% 57.9 46.2 9.1 78.3
Table IX. Primary or secondary operation in relation to lymph node metastasis % positive
Operation
No. of cases
Primary Secondary Total
45 29
26 16
57.8 55.2
74
42
56.8
around 50%. Therefore all attempts in improving the prognosis of ovarian cancer by emphasizing only the thoroughness of resection of intraperitoneal tumors will be futile if the presence of this important route of metastasis which may transport cancer cells to any part of the body is neglected. Retroperitoneal lymphadenectomy will not only lessen the tumor burden by removing the cancer-bearing nodes but also may provide a guideline for further treatment. If positive pelvic nodes and negative para-aortic nodes are found on pathologic examination, simple lymphadenectomy will be sufficient. If positive para-aortic nodes are found, postoperative irradiation of the lumbar lymph chain up to the level of the diaphragm may be necessary in irradicating the upward-spreading tumor cells. Burghardt et al.' compared the actuarial survival rates after operative treatment in Stage III ovarian cancer patients with and without lymphadenectomy. In 21 cases with lymphadenectomy the survival rate at 2 years was 95.1 %, whereas in 10 cases without lymphadenectomy the survival rate was only 40%. Although the comparability of the survival rates of these two groups of patients was limited because of the difference in postoperative chemotherapeutic regimens used, the results nevertheless indicate the possibility of improving the therapeutic results and prognosis of ovarian cancer through retroperitoneal lymphadenectomy.
REFERENCES 1. Knapp RC, Friedman EA. Aortic lymph node metastasis
in early ovarian cancer. AM J OBSTET GYNECOL 1974;119:1013.
2. DelgadoG, Chun B, Gaglar H, Bepko F.ParaaorticIymph-
1108 Wu at al.
November 1986 Am J Obstet Gynecol
Table X. Lymph node metastasis and outcome of patients No. of cases
No.
Yes No
42 32
Total
74
I
Death
Recurrence
Remission Lymph node metastasis
%
No.
22 16
52.4 50.0
38
51.4
2 5 7
adenectomy in gynecologic malignancies confined to the pelvis. Obstet Gynecol 1977;50:418. 3. Creasman WT, Abu-Ghazaleh S, Schmidt HJ. Retroperitoneal metastatic spread of ovarian cancer. Gynecol Oncol 1978;6:447. 4. Chen SS, Lee L. Incidence of para-aortic and pelvic lymph node metastases in epithelial carcinoma of the ovary. GynecolOncol 1983;16:95. 5. Burghardt E, Pickel H, Stettner H. Management of
I
I
%
%
No.
4.8 15.6
18 11
42.8 34.4
9.4
29
39.2
advanced ovarian cancer. Eur J Gynaecol Oncol 1984; 3:155. 6. Bergman F. Carcinoma of the ovary: a clinicopathological study of 86 autopsied cases with special reference to mode of spread. Acta Obstet Gynecol Scand 1966;45:211. 7. Plentl AA, Friedman EA. Lymphatic system of the female genitalia. Philadelphia: WB Saunders, 1971;170. 8. Day TG, Smith JP. Diagnosis and staging of ovarian cancer. Semin Oncol 1975;2:217.