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Retroperitoneal metastatic spread of ovarian cancer
GYNECOLOGIC
ONCOLOGY
6,
447-450
Retroperitoneal
(1978)
Metastatic
of Ovarian
Cancer
T. CREASMAN, M.D.,FACOG,l SAMIRABU-GHAZALEH, JFACOG, AND H. J. SCHMIDT, M.D., FACOG
WILLIAM
Division
of Gynecologic Duke University
patients
with
M.D.,
Oncology, Department of Obstetrics and Gynecology, Medical Center, Durham, North Carolina 27710 Received
Four
Spread
ovarian
December
cancer,
after
7, 1977
chemotherapy
or
combined
immunochemo-
therapy, were found to have retroperitoneal disease at the time laparotomy, even though there was no evidence of intra-abdominal cancer can metastasize to both the pelvic and para-aortic lymph
of second-look exploratory residual cancer. Ovarian nodes, and therefore these
areas with
extent
must ovarian
be evaluated cancer.
in order
to assess
appropriately
the true
of disease
in patients
Ovarian cancer is the third most common female genital malignancy, yet the number of women dying from this disease is equal to the combined deaths from carcinoma of the corpus and cervix, the number one and two most frequent pelvic cancers [I]. There are several reasons to account for this poor prognosis. No early detection mechanism is yet available in ovarian cancer; in fact, two thirds of all patients diagnosed with this malignancy have Stage III or IV disease at the time of exploratory laparotomy. As a result, surgery is of limited benefit except in early disease or when considerable debulking can be performed. Radiation of large abdominal-pelvic masses has not proved effective. Single agent chemotherapy, to date, appears to be as effective as multiple agents without the latter’s toxicity; unfortunately, only 50% of patients receiving a single agent chemotherapy will have an objective response and some patients respond only for a few months [2, 31. Therefore, the lack of early diagnosis and apparent capability of the tumor to resist current therapy account for the poor prognosis in ovarian cancer. There are some patients treated with chemotherapy who will have a dramatic clinical response with complete disappearance of ascites and masses and who may come to a second-look laparotomy to determine the true effect of the chemotherapy and the possibility of stopping the drug. It is important to discontinue the drug if disease is not demonstrated, as there are reports of secondary malignancies in patients who have been on long-term alkylating agents [41. A very thorough evaluation of the abdominal cavity must be made to determine lack of residual disease in this type of patient. If no ascites is present, peritoneal ’ Author
to whom
requests
for
reprints
should
be sent.
447 0090-8258/78/0065-0447$01.00/O Copyright Q 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
448
CREASMAN,
ABU-GHAZALEH,
AND
SCHMIDT
cytology on first entering the peritoneal cavity should be obtained from the pelvis as well as the lateral abdomina1 gutters. Prognostically, peritoneal cytology appears to be extremely important [5]. Evaluation of the diaphragms is critical, as this is the lymphatic exit of the peritoneal cavity. Any nodules in these areas should be biopsied. The omentum, if not previously removed, should be evaluated and partial omentectomy should be performed. The omentum is rich in macrophages and can phagocytize foreign (malignant) particles within the abdominal cavity. A nidus of malignant cells may be present microscopically which could enlarge if the omentum were left in situ. The bowel and its mesentery must be thoroughly evaluated and any suspicious area must be biopsied. Multiple peritoneal biopsies should be obtained, particularly in the pelvis, of any irregular areas or at adhesion sites. Recently, retroperitoneal spaces and lymph node evaluation have been carried out as part of the second-look procedure. The findings of four patients within 3 months with no gross disease intraperitoneally, with negative peritoneal cytology, and with metastasis to the retroperitoneal spaces, particularly in the lymph nodes, prompted this report. MATERIALS
AND METHODS
At the time of the second-look laparotomy, the retroperitoneal nodal area is sampled after thorough evaluation of the peritoneal cavity as noted above. This is done on all patients without demonstrable disease within the abdominal cavity but also in those patients with resectable residual disease. The small intestines are displaced to the upper abdomen and the peritoneum over the bifurcation of the aorta is incised. The lymph node fatpad over the upper common iliacs, vena cava, and aorta is removed in toto up to the vicinity of the renal vessels. The pelvic nodes are also sampled. The retroperitoneal pelvic areas are opened and the pararectal and paravesical spaces are entered. The main vessels are outlined. The lymphatic tissue from the lower common iliacs is removed along with the nodal tissue from the external iliacs down to the inguinal ligament. The lymphatic tissue from the obturator fossa superior to the obturator nerve is removed. There is no attempt to do a thorough lymphadenectomy as it is done in the surgical management of early invasive carcinoma fof the cervix. Any enlarged nodes are removed separately and submitted for pathological evaluation. Any extranodal enlarged tissue in the retroperitoneal space is also removed if feasible. Biopsy of only enlarged clinically positive nodes is inadequate as microscopic disease may be in other nodes and not appreciated with the palpating finger. Hemovacs are placed in the retroperitoneal spaces for proper drainage. Three patients, after initial surgery, received a year of combined chemotherapy-immunotherapy (Alkeranlcornybacterium parvum). No clinical evidence of disease was present at the end of 1 year in two patients; however, some small nodules were present just above the cuff in the third patient, but these had been stable for a period of time. A second-look exploratory laparotomy was performed. No intraperitoneal disease was present and all peritoneal cytology was negative for malignant cells in these three patients. One patient had metastatic disease in the pelvic lymph nodes involving only the right obturator fossa with
METASTATIC
SPREAD OF OVARIAN
CANCER
449
multiple other nodes in both the pelvic and para-aortic regions negative. One patient had disease in the para-aortic area with the pelvic regions free of metastasis. In the third patient the pelvic and para-aortic lymph nodes were negative for metastasis but tumor was present above the vaginal cuff in the retroperitoneal area. One additional patient was found to have Stage IC ovarian carcinoma treated with a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy in 1975. She was placed on chlorambucil. Eighteen months later a right inguinal node was appreciated. Biopsies showed metastatic disease. On referral, no clinical abdominal or pelvic disease was noted and a second-look procedure was performed. No intraperitoneal disease was present and peritoneal cytology was negative for tumor cells. Metastatic disease was present in the right external iliac nodal area with all other lymph nodes being negative (Table 1). All four of these patients have received external irradiation to the appropriate area. COMMENT
Ovarian cancer can and does spread to the retroperitoneal lymphatics. Knapp and Friedman [6] found metastasis in the para-aortic lymph nodes in 5 of 26 patients with clinical Stage I carcinomas of the ovary. Nine patients had pelvic node biopsies, all of which were negative for metastatic disease, even though three of these patients had tumor in the para-aortic nodes. Lymphangiograms have identified metastatic disease in both the pelvic and para-aortic nodes although metastases in these patients were not confirmed histologically [7]. Smith and associates [8] reported four patients, with negative intraperitoneal “secondlook” operation, who succumbed after chemotherapy was stopped. One of the four patients had a positive para-aortic node found at surgery. Autopsy studies, although biased because of end stage disease evaluation, nevertheless note a high incidence of nodal disease both in the pelvic and para-aortic regions [93. The knowledge that ovarian cancer can metastasize to the lymph nodes is well known although evaluation of para-aortic and pelvic lymph nodes is not routine in the primary therapy of this disease. In part, this is due to the extensive abdominal carcinomatosis present in many patients at the time of the primary surgery. In early stage disease or when considerable debulking can be carried out, it may be worthwhile to sample the pelvic and para-aortic nodes at the time of initial surgery. In patients who come to second-look laparotomy after chemotherapy, these areas must be evaluated to determine the true extent of residual disease. These four patients add evidence that metastatic disease to the retroperitoneal areas may be much higher than previously thought. Retroperitoneal node metasTABLE
I
Stage
Drug therapy
Positive second-look findings
IC IIC IIC III
Chlorambucil AlkeraniC. parvum AlkeraniC. parvum Alkeran/C. parvum
Right external iliac lymph node Perivaginal retroperitoneal nodule Para-aortic lymph node Right obturator lymph node
CREASMAN,
450
ABU-GHAZALEH,
AND SCHMIDT
tasis helps to explain why patients with negative second-look operations later develop recurrences and die. The use of radiotherapy in patients with only retroperitoneal disease seems logical since this type of therapy has proven beneficial in patients with nodal disease in both cervical and endometrial malignancies [ 10, 111. We have used radiation therapy in the treatment of an additional patient with ovarian cancer that had residual disease only in the retroperitoneal area and she is without evidence of disease now approaching 5 years. On the other hand, the use of radiation therapy in patients with significant intra-abdominal disease has not been beneficial. It would appear from the previous reports as well as the present report that patients with ovarian cancer should have both the pelvic and para-aortic nodes sampled at the time of primary operative therapy or at second-look. Metastasis in the lymph nodes in early ovarian cancer may be another reason why survival is poor. Nore odded in proof. Since the submission of this report an additional patient has been seen with only nodal metastasis present at time of second look operation. Initially she had Stage III disease treated with surgery followed by one year of Alkeran-C. ptrr\wm combined chemoimmunotherapy and then the second look.
REFERENCES 1. Silberberg, E. Cancer statistics, 1977, Ca-A Cancer J. Clinicians 27, 26-41 (1977). 2. Parker, R. T., Parker, C. H., and Wilbanks, G. D. Cancer of the ovary, Amer. J. Obstet. Gynecol. 108, 878-888 (1970). 3. Tobias, .I. S. and Griffiths, C. T. Management of ovarian carcinoma, New Eng/. J. Med. 294, 877-882 (1976). 4. Reimer, R. R., Hoover, R., Fraumein, J. F., Jr., and Young, R. C. Acute leukemia following alkylating agent therapy of ovarian cancer, Amer. Sot. C/in. Oncol. (Abstracts) 18, 33 1 (1977). 5. Creasman, W. T., and Rutledge, F. The prognostic value of peritoneal cytology in gynecologic malignant disease, Amer. J. Obstet. Gynecol. 110, 733-781 (1971). 6. Knapp, R. C., and Friedman, E. A. Aortic lymph node metastases in early ovarian cancer, Amer. .I. Obstet. Gynecol. 119, 1013-1017 (1974). 7. Douglas, B., MacDonald, J. S., and Baker, J. W. Lymphography in carcinoma of the ovary, Proc. Roy.
Sot.
Med.
64, 400-403
(1971).
8. Smith, J. P., Delgado, G., and Rutledge, F. Second-look operation in ovarian carcinoma, Cancer 38, 1438-1442 (1976). 9. Bergman, F. Carcinoma of the ovary, Acta Obstet. Gynecol. Scandinav. 45, 21 I-231 (1966). IO. Morrow, C. P., DiSaia, P. J., and Townsend, D. E. Current management of endometrial carcinoma, Obstet. Gynecol. 42, 399-406 (1973). 1I. Rutledge, F. N., Fletcher, G. H., and MacDonald, E. J. Pelvic lymphadenectomy as an adjunct to radiation therapy in treatment for cancer of the cervix. Amer. J. Roentgenol. 93,607-614 (1965).
ONCOLOGY
6,
447-450
Retroperitoneal
(1978)
Metastatic
of Ovarian
Cancer
T. CREASMAN, M.D.,FACOG,l SAMIRABU-GHAZALEH, JFACOG, AND H. J. SCHMIDT, M.D., FACOG
WILLIAM
Division
of Gynecologic Duke University
patients
with
M.D.,
Oncology, Department of Obstetrics and Gynecology, Medical Center, Durham, North Carolina 27710 Received
Four
Spread
ovarian
December
cancer,
after
7, 1977
chemotherapy
or
combined
immunochemo-
therapy, were found to have retroperitoneal disease at the time laparotomy, even though there was no evidence of intra-abdominal cancer can metastasize to both the pelvic and para-aortic lymph
of second-look exploratory residual cancer. Ovarian nodes, and therefore these
areas with
extent
must ovarian
be evaluated cancer.
in order
to assess
appropriately
the true
of disease
in patients
Ovarian cancer is the third most common female genital malignancy, yet the number of women dying from this disease is equal to the combined deaths from carcinoma of the corpus and cervix, the number one and two most frequent pelvic cancers [I]. There are several reasons to account for this poor prognosis. No early detection mechanism is yet available in ovarian cancer; in fact, two thirds of all patients diagnosed with this malignancy have Stage III or IV disease at the time of exploratory laparotomy. As a result, surgery is of limited benefit except in early disease or when considerable debulking can be performed. Radiation of large abdominal-pelvic masses has not proved effective. Single agent chemotherapy, to date, appears to be as effective as multiple agents without the latter’s toxicity; unfortunately, only 50% of patients receiving a single agent chemotherapy will have an objective response and some patients respond only for a few months [2, 31. Therefore, the lack of early diagnosis and apparent capability of the tumor to resist current therapy account for the poor prognosis in ovarian cancer. There are some patients treated with chemotherapy who will have a dramatic clinical response with complete disappearance of ascites and masses and who may come to a second-look laparotomy to determine the true effect of the chemotherapy and the possibility of stopping the drug. It is important to discontinue the drug if disease is not demonstrated, as there are reports of secondary malignancies in patients who have been on long-term alkylating agents [41. A very thorough evaluation of the abdominal cavity must be made to determine lack of residual disease in this type of patient. If no ascites is present, peritoneal ’ Author
to whom
requests
for
reprints
should
be sent.
447 0090-8258/78/0065-0447$01.00/O Copyright Q 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
448
CREASMAN,
ABU-GHAZALEH,
AND
SCHMIDT
cytology on first entering the peritoneal cavity should be obtained from the pelvis as well as the lateral abdomina1 gutters. Prognostically, peritoneal cytology appears to be extremely important [5]. Evaluation of the diaphragms is critical, as this is the lymphatic exit of the peritoneal cavity. Any nodules in these areas should be biopsied. The omentum, if not previously removed, should be evaluated and partial omentectomy should be performed. The omentum is rich in macrophages and can phagocytize foreign (malignant) particles within the abdominal cavity. A nidus of malignant cells may be present microscopically which could enlarge if the omentum were left in situ. The bowel and its mesentery must be thoroughly evaluated and any suspicious area must be biopsied. Multiple peritoneal biopsies should be obtained, particularly in the pelvis, of any irregular areas or at adhesion sites. Recently, retroperitoneal spaces and lymph node evaluation have been carried out as part of the second-look procedure. The findings of four patients within 3 months with no gross disease intraperitoneally, with negative peritoneal cytology, and with metastasis to the retroperitoneal spaces, particularly in the lymph nodes, prompted this report. MATERIALS
AND METHODS
At the time of the second-look laparotomy, the retroperitoneal nodal area is sampled after thorough evaluation of the peritoneal cavity as noted above. This is done on all patients without demonstrable disease within the abdominal cavity but also in those patients with resectable residual disease. The small intestines are displaced to the upper abdomen and the peritoneum over the bifurcation of the aorta is incised. The lymph node fatpad over the upper common iliacs, vena cava, and aorta is removed in toto up to the vicinity of the renal vessels. The pelvic nodes are also sampled. The retroperitoneal pelvic areas are opened and the pararectal and paravesical spaces are entered. The main vessels are outlined. The lymphatic tissue from the lower common iliacs is removed along with the nodal tissue from the external iliacs down to the inguinal ligament. The lymphatic tissue from the obturator fossa superior to the obturator nerve is removed. There is no attempt to do a thorough lymphadenectomy as it is done in the surgical management of early invasive carcinoma fof the cervix. Any enlarged nodes are removed separately and submitted for pathological evaluation. Any extranodal enlarged tissue in the retroperitoneal space is also removed if feasible. Biopsy of only enlarged clinically positive nodes is inadequate as microscopic disease may be in other nodes and not appreciated with the palpating finger. Hemovacs are placed in the retroperitoneal spaces for proper drainage. Three patients, after initial surgery, received a year of combined chemotherapy-immunotherapy (Alkeranlcornybacterium parvum). No clinical evidence of disease was present at the end of 1 year in two patients; however, some small nodules were present just above the cuff in the third patient, but these had been stable for a period of time. A second-look exploratory laparotomy was performed. No intraperitoneal disease was present and all peritoneal cytology was negative for malignant cells in these three patients. One patient had metastatic disease in the pelvic lymph nodes involving only the right obturator fossa with
METASTATIC
SPREAD OF OVARIAN
CANCER
449
multiple other nodes in both the pelvic and para-aortic regions negative. One patient had disease in the para-aortic area with the pelvic regions free of metastasis. In the third patient the pelvic and para-aortic lymph nodes were negative for metastasis but tumor was present above the vaginal cuff in the retroperitoneal area. One additional patient was found to have Stage IC ovarian carcinoma treated with a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy in 1975. She was placed on chlorambucil. Eighteen months later a right inguinal node was appreciated. Biopsies showed metastatic disease. On referral, no clinical abdominal or pelvic disease was noted and a second-look procedure was performed. No intraperitoneal disease was present and peritoneal cytology was negative for tumor cells. Metastatic disease was present in the right external iliac nodal area with all other lymph nodes being negative (Table 1). All four of these patients have received external irradiation to the appropriate area. COMMENT
Ovarian cancer can and does spread to the retroperitoneal lymphatics. Knapp and Friedman [6] found metastasis in the para-aortic lymph nodes in 5 of 26 patients with clinical Stage I carcinomas of the ovary. Nine patients had pelvic node biopsies, all of which were negative for metastatic disease, even though three of these patients had tumor in the para-aortic nodes. Lymphangiograms have identified metastatic disease in both the pelvic and para-aortic nodes although metastases in these patients were not confirmed histologically [7]. Smith and associates [8] reported four patients, with negative intraperitoneal “secondlook” operation, who succumbed after chemotherapy was stopped. One of the four patients had a positive para-aortic node found at surgery. Autopsy studies, although biased because of end stage disease evaluation, nevertheless note a high incidence of nodal disease both in the pelvic and para-aortic regions [93. The knowledge that ovarian cancer can metastasize to the lymph nodes is well known although evaluation of para-aortic and pelvic lymph nodes is not routine in the primary therapy of this disease. In part, this is due to the extensive abdominal carcinomatosis present in many patients at the time of the primary surgery. In early stage disease or when considerable debulking can be carried out, it may be worthwhile to sample the pelvic and para-aortic nodes at the time of initial surgery. In patients who come to second-look laparotomy after chemotherapy, these areas must be evaluated to determine the true extent of residual disease. These four patients add evidence that metastatic disease to the retroperitoneal areas may be much higher than previously thought. Retroperitoneal node metasTABLE
I
Stage
Drug therapy
Positive second-look findings
IC IIC IIC III
Chlorambucil AlkeraniC. parvum AlkeraniC. parvum Alkeran/C. parvum
Right external iliac lymph node Perivaginal retroperitoneal nodule Para-aortic lymph node Right obturator lymph node
CREASMAN,
450
ABU-GHAZALEH,
AND SCHMIDT
tasis helps to explain why patients with negative second-look operations later develop recurrences and die. The use of radiotherapy in patients with only retroperitoneal disease seems logical since this type of therapy has proven beneficial in patients with nodal disease in both cervical and endometrial malignancies [ 10, 111. We have used radiation therapy in the treatment of an additional patient with ovarian cancer that had residual disease only in the retroperitoneal area and she is without evidence of disease now approaching 5 years. On the other hand, the use of radiation therapy in patients with significant intra-abdominal disease has not been beneficial. It would appear from the previous reports as well as the present report that patients with ovarian cancer should have both the pelvic and para-aortic nodes sampled at the time of primary operative therapy or at second-look. Metastasis in the lymph nodes in early ovarian cancer may be another reason why survival is poor. Nore odded in proof. Since the submission of this report an additional patient has been seen with only nodal metastasis present at time of second look operation. Initially she had Stage III disease treated with surgery followed by one year of Alkeran-C. ptrr\wm combined chemoimmunotherapy and then the second look.
REFERENCES 1. Silberberg, E. Cancer statistics, 1977, Ca-A Cancer J. Clinicians 27, 26-41 (1977). 2. Parker, R. T., Parker, C. H., and Wilbanks, G. D. Cancer of the ovary, Amer. J. Obstet. Gynecol. 108, 878-888 (1970). 3. Tobias, .I. S. and Griffiths, C. T. Management of ovarian carcinoma, New Eng/. J. Med. 294, 877-882 (1976). 4. Reimer, R. R., Hoover, R., Fraumein, J. F., Jr., and Young, R. C. Acute leukemia following alkylating agent therapy of ovarian cancer, Amer. Sot. C/in. Oncol. (Abstracts) 18, 33 1 (1977). 5. Creasman, W. T., and Rutledge, F. The prognostic value of peritoneal cytology in gynecologic malignant disease, Amer. J. Obstet. Gynecol. 110, 733-781 (1971). 6. Knapp, R. C., and Friedman, E. A. Aortic lymph node metastases in early ovarian cancer, Amer. .I. Obstet. Gynecol. 119, 1013-1017 (1974). 7. Douglas, B., MacDonald, J. S., and Baker, J. W. Lymphography in carcinoma of the ovary, Proc. Roy.
Sot.
Med.
64, 400-403
(1971).
8. Smith, J. P., Delgado, G., and Rutledge, F. Second-look operation in ovarian carcinoma, Cancer 38, 1438-1442 (1976). 9. Bergman, F. Carcinoma of the ovary, Acta Obstet. Gynecol. Scandinav. 45, 21 I-231 (1966). IO. Morrow, C. P., DiSaia, P. J., and Townsend, D. E. Current management of endometrial carcinoma, Obstet. Gynecol. 42, 399-406 (1973). 1I. Rutledge, F. N., Fletcher, G. H., and MacDonald, E. J. Pelvic lymphadenectomy as an adjunct to radiation therapy in treatment for cancer of the cervix. Amer. J. Roentgenol. 93,607-614 (1965).