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Retrograde Lymphatic Spread: A Likely Route for Metastatic Ovarian Cancers of Gastrointestinal Origin
GYNECOLOGIC ONCOLOGY ARTICLE NO.
66, 372–377 (1997)
GO974793
Retrograde Lymphatic Spread: A Likely Route for Metastatic Ovarian Cancers of Gastrointestinal Origin Ting-Chang Chang,* Chan-Chao Changchien,* Chih-Wen Tseng,* Chyong-Huey Lai,* Chih-Jen Tseng,* Shung-Eing Lin,† Chia-Shu Wang,‡ Kuan-Jen Huang,* Hung-Hsueh Chou,* Yen-Ying Ma,* Suei Hsueh,§ Hock-Liew Eng,§ and Hong-Arh Fan† *Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; †Department of Proctology; ‡Department of General Surgery; and §Department of Pathology, Chang Gung Memorial Hospital and Chang Gung Medical College, Taoyuan, Taiwan Received August 5, 1996
In order to outline the pathways of gastrointestinal malignancies metastasizing to the ovaries, we reviewed 103 cases of metastatic ovarian tumors, and also performed para-aortic lymph node sampling on 11 patients at operation for metastatic ovarian tumors. Of the 103 patients, 74% (26/35) with gastric cancer and 67% (45/ 67) with colorectal cancer had lymph node metastasis at or before the diagnosis of ovarian tumor. Intraperitoneal metastases presented in 49 and 42% of patients with gastric and with colorectal cancers, respectively. Twenty-three percent of gastric cancer patients and 25% of colorectal cancer patients presented with both lymph node and intraperitoneal metastases. The ovary was the first or among the early metastatic organs diagnosed in 51 of the 53 patients with metachronous ovarian metastases. Only 4 patients with colorectal cancer and none with gastric cancer showed parenchymal organ metastases. These 4 patients also showed intraperitoneal lesions, and 3 of these 4 patients had node metastasis. Among the 11 patients who underwent prospective para-aortic lymph node sampling during operation for the ovarian tumors, only 1 had enlarged para-aortic nodes depicted by computed tomography, 2 had grossly enlarged (§1.5 cm) para-aortic lymph nodes noted at surgery, and 6 of the 7 patients with gastric cancer and all 3 with colorectal cancer had metastatic nodes histologically. Among the 58 nodes taken from these patients, 67% showed metastatic foci. We concluded that lymph node metastasis is frequently seen in patients with metastatic ovarian tumors of gastrointestinal origin, and hypothesized that retrograde lymphatic spread is a likely route for the metastases. q 1997 Academic Press
INTRODUCTION
Since the establishment of the metastatic nature in most Krukenberg tumors by Schlagenhaufer in 1902 [1], it has been demonstrated that many carcinomas, including that of thyroid, breast, stomach, gallbladder, pancreas, colon, rectum, and malignancies arising from the female genital tract may metastasize to the ovaries [2–5]. Most of the nongenital cancers metastasizing to the ovaries are those arising from the gastrointestinal tract. However, the metastatic pathways
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MATERIALS AND METHODS
Patients with histology-proven metastatic ovarian cancers originating from gastrointestinal malignancies between January 1984 and March 1996 were obtained from the pathology registry of Chang Gung Memorial Hospital Linkou Medical Center and Kaoshiung Chang Gung Memorial Hospital. Medical information including the patient’s age, menopausal status, diagnosis dates, sites, stage, and treatments for both primary and ovarian tumors were retrieved from medical records. The histology of both primary and metastatic tumors, serial image studies of chest X ray and computed tomography of the abdomen and pelvis were reviewed. Other studies including magnetic resonance image (MRI), bone scan, and abdominal and pelvic ultrasonography were also reviewed if present. Special attention was focused on the metastatic sites that were diagnosed concurrently with the primary tumor. This information was classified into three
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of these ovarian tumors have not yet been established [6]. Three possible pathways have been postulated: (1) transcoelomic dissemination with surface implantation, including metastasis through direct continuity of the primary tumor, (2) lymphatic flow metastasis, and (3) blood-borne metastasis. Unfortunately, the state of intraperitoneal, lymph nodes, and parenchymal organ metastases, as the markers of different metastatic pathways, were rarely mentioned in the English literature. Recently, the retroperitoneal lymph node status was described in a report of nongenital cancers metastatic to the ovary [2], and only 8 of the 82 patients had information on the lymph node status. To further outline the metastatic pathways in ovarian tumors that originate from the gastrointestinal tract, we retrospectively reviewed the medical records and histologic slides of 103 patients with histologyproven metastatic ovarian cancer, and prospectively performed para-aortic lymph node sampling on 11 patients at the surgery for metastatic ovarian tumors.
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categories: intraperitoneal metastases, lymph node metastases, and parenchymal organ metastases, as described below. Intraperitoneal metastases include the following: (1) Malignant cells in the peritoneal fluid or washing cytology; (2) presence of histology-proven metastatic lesions over the peritoneum, serosa, or omentum diagnosed at the time of surgery for the primary tumor, or before the diagnosis of ovarian metastasis; and (3) ovarian metastatic tumor directly contacting the primary tumor (e.g., sigmoid cancer). Lymph node metastases are: (1) Histologic evidence of lymph node metastasis, which was taken either at the surgery for primary tumor or before the diagnosis of ovarian metastasis; (2) presence of enlarged para-aortic or pelvic lymph nodes measuring no less than 1.5 cm in dimension, disclosed by computed tomography in patients with gastrointestinal malignancies and without other medical history that might relate to such an enlargement. Parenchymal organ metastasis includes any metastasis over the parenchyma of lung, bone, liver, kidney, adrenal gland, pancreas, thyroid, liver, or other parenchymal organs at or before the diagnosis of ovarian metastasis. The verification of metastasis that was diagnosed based on image studies without histologic or cytological evidence was through the follow-up image studies. Serial serum carcinoembryonic antigen (CEA) titers before and after treatment were also used as a reference of disease status. From February 1992 to June 1996, prospective lower paraaortic lymph node sampling was performed at the time of surgery for ovarian tumors in patients with ovarian metastases originating from gastrointestinal malignancies. Student’s t test and x2 test with Yate’s correction were applied for the comparison of frequency distributions in different groups. A two-tailed P less than 0.05 was declared as statistically significant. RESULTS
One hundred three patients with metastatic ovarian tumors arising from the gastrointestinal tract were retrospectively reviewed. There were 67 patients with colorectal carcinomas, 35 patients with gastric carcinomas, and 1 patient with gallbladder carcinoma. The median ages at the diagnosis of colorectal and of gastric malignancies were 46.7 and 36.9 years, respectively. The patient with gallbladder carcinoma was diagnosed at 44 years. Among the patients with colorectal cancer, the ovarian metastasis was diagnosed concurrently (within 1 month) with the primary tumor in 34 (51%) patients, while 2 patients had ovarian metastases diagnosed within the range of 1 to 6 months after the diagnosis of primary tumors, 8 patients within 7–12 months, 17 patients within 13–24 months, and 6 patients over 2 years after the diagnosis of primary tumor (Table 1). Of the patients with gastric tumor as the primary, 23 (66%) patients presented with gastric and ovarian tumor concurrently. Fifteen of these
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23 had the chief complaint of low abdominal symptoms (distention, fullness, dull pain, or discomfort) and the ovarian tumors were discovered a few days before the diagnosis of gastric malignancies. All of the histology of these 103 cases were adenocarcinomas, and all the ovarian metastatic tumors were consistent with their primary cancers, but tumor necrosis was more obvious in some of their ovarian counterparts. Signet ring cells were seen in 23 (66%) patients with gastric primary and in 12 (19%) patients with colorectal primary. Bilateral ovarian involvement was noted in 79% (26/33) of gastric primary and 40% (27/67) of colorectal primary. Two gastric cancer patients had undergone unilateral oophorectomy for benign tumors before the diagnosis of gastric malignancy. Preservation of the contralateral, grossly normal ovary was undertaken in 25 of the 40 patients with unilateral ovarian tumor originating from colorectal malignancies. Frozen section for the wedge resection on the preserved ovary to rule out the possibility of metastasis had been performed in 8 patients. Two patients developed metastatic tumor over the preserved ovary: One 59-year-old patient having received hemicolectomy for descending colon cancer and left salpingo-oophorectomy for serous cystadenoma at primary operation developed a 25-cm right ovarian metastatic tumor 30 months after the surgery; One 50-year-old woman underwent a right hemicolectomy and right salpingo-oophorectomy for transverse colon cancer and a 6-cm metastatic ovarian tumor had a grossly normal left ovary at the operation, which was preserved according to her request. Six months after the surgery, the left ovary became a 20-cm metastatic tumor along with 2500 ml ascites. Forty-two patients with colorectal cancer and 23 patients with gastric cancer received chemotherapy after surgery. 5Fluorouracil (5-FU) with or without leucovorum was used as the adjuvant therapy for patients with colorectal cancer. The combinations of 5-FU with cisplatin, or doxorubicin, or both, were applied for the treatment of gastric cancer. One patient with sigmoid cancer and one with rectal cancer received adjuvant pelvic irradiation. Of the patients with metachronous ovarian tumors, 14 received chemotherapy after surgery with similar regimens. Lymph node metastasis, as a marker of lymphatic flow metastasis that resulted in an ovarian metastasis, presented in 74% (26/35) of the gastric cancer patients at the diagnosis of primary tumor and in 67% (45/67) of the colorectal patients at the diagnosis of primary malignancy. Intraperitoneal lesions, as an evidence of transcoelomic dissemination into the ovary, were present in 17 (49%) and 28 (42%) of the patients with gastric and colorectal cancer at the diagnosis of primary tumor, respectively. Eight gastric cancer patients and 17 colorectal cancer patients presented with both lymph node metastasis and intraperitoneal lesions. All gastric cancer patients presented with either lymph node metastasis or intraperitoneal lesions, or both, while no one presented with
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TABLE 1 Primary Sites, Age, and Interval between Diagnosis of Primary Tumors and Ovarian Metastasis in 103 Patients Interval from diagnosis to ovarian metastasisb
a b
Site
Agea
õ1
1–6
7–12
13–24
ú24
Total n
Colon/rectum Stomach Gallbladder Total
19–79 (46.7) 21–65 (36.9) 44
34 23 1 58
2 0 0 2
8 2 0 11
17 7 0 25
6 3 0 9
67 35 1 103
Range and median age in years at the diagnosis of primary tumor. Interval from the diagnosis of primary tumor to the diagnosis of ovarian metastasis in months.
parenchymal organ involvement before or at the diagnosis of ovarian involvement. Three patients with colorectal cancer showed metastatic lesions over liver parenchyma and one showed pulmonary metastasis. Two of the three patients with liver metastasis and the one with pulmonary lesion had histologic evidence of metastasis. The diagnosis of another one was based on abdominal CT findings and was verified by the follow-up CT studies which showed progressive enlarged intrahepatic lesions and the appearance of daughter tumors 5 months after treatment. Nonelevated serum a-fetoprotein and progressive elevated CEA marker were noted along with the hepatic tumor growth. These four patients also had intraperitoneal lesions. Three of these four patients had lymph node metastasis (Table 2). Double gastrointestinal cancers were noted in a 58-year-old woman who had undergone a subtotal gastrectomy for gastric cancer, and no (0/24) lymph node metastasis was noted. She developed a cecal cancer and a synchronous metastatic right ovarian tumor 31 months after the gastric surgery. Positive (3/17) regional lymph nodes and no intraperitoneal metastasis were discovered during operation, and liver and pancreatic metastases developed 1 year later. Histology of these metastatic sites was consistent with that of cecal cancer and was different from that of gastric malignancy.
Altogether, 46 (45%) of these 103 patients showed intraperitoneal lesions, and 71 (69%) had lymph node metastasis at the diagnosis of primary malignancy. Parenchymal organ metastasis was only observed in 4 patients with colorectal cancer and none with gastric cancer (Table 2). When comparing the frequencies of intraperitoneal metastasis and lymph node metastasis between patient groups of pre- and postmenopausal status among 89 patients with known status at presentation, intraperitoneal metastasis was present in 43% of premenopausal patients and 46% of postmenopausal patients, while lymph node metastasis was present in 70 and 72% of pre- and postmenopausal patients, respectively (P ú 0.05). Eleven patients with metastatic ovarian tumors, including 7 of gastric origin, 3 of colorectal origin, and one of gallbladder origin, underwent prospective lower para-aortic (L1-L3 level) lymph node sampling at the surgery for the ovarian tumor(s). The primary tumor and its ovarian metastasis were operated concurrently on 3 patients with gastric cancer and one with sigmoid colon cancer. The other 7 patients were with metachronous ovarian tumors. Five gastric cancer patients and 1 colon cancer patient showed no intraperitoneal lesions (Table 3). The other 2 gastric cancer patients showed multiple small (£0.5 cm) serosal lesions over the bladder
TABLE 2 Presence of Intraperitoneal Lesions, Lymph Node Metastasis, and Parenchymal Organ Involvement in 103 Patients at or before the Diagnosis of Metastatic Ovarian Tumor Intraperitoneal lesionsa
Lymph nodeb
Parenchymal organa,b
Primary tumor
Present
Absent
Unknown
Present
Absent
Present
Absent
Gastricc Colond Gallbladder
17 28 1
15 30 0
3 9 0
26 45 0
9 22 1
0 4e 0
35 63 1
Total
46
45
12
71
32
4
99
a
Frequency of intraperitoneal lesions versus frequency of parenchymal organ involvement, P õ 0.001. Frequency of lymph node metastasis versus that of parenchymal organ involvement, P õ 0.001. c 8 patients presented with both lymph node metastasis and intraperitoneal lesions. d 17 patients presented with both lymph node metastasis and intraperitoneal lesions. e 3 patients with hepatic metastasis and one with pulmonary lesion. All 4 patients had intraperitoneal lesions, and 3 also had lymph node metastases. b
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TABLE 3 Lymph Node Metastasis Diagnosed by CT Scan, Gross Lymph Node Size, and Histology in 11 Patients Who Underwent Prospective Para-aortic Lymph Node Sampling at Operation for Metastatic Ovarian Tumors Para-aortic lymph nodeb Primary tumor
Intraperitoneala
CT
Gross
Histology
Parenchymal organc
Gastric (n Å 7) Colon (n Å 3) Gallbladder (n Å 1) Total (n Å 11)
2 2 1 5
1 0 0 1
1 1 0 2
6 3 0 9
0 0 0 0
a
Presence of histology-proved intraperitoneal lesions. Presence of para-aortic lymph node metastasis by different criteria: CT, lymph node size §1.5 cm; gross, lymph node size §1.5 cm; histology, presence of metastatic foci. c Parenchymal organ metastasis diagnosed by image study with or without histologic evidence. b
dome and lower pelvic peritoneum. Two colorectal cancer patients had tumor seedings over the pelvic cavity, and the patient with the gallbladder tumor showed omental cake and multiple confluent metastatic pelvic lesions. None of these patients presented with parenchymal metastasis at the diagnosis of ovarian tumor based on chest X ray, CT of abdomen and pelvis, and abdominal sonography. Only 1 of these 11 patients showed enlarged lymph nodes by CT. At least 4 lymph nodes were sampled from each patient. Most lymph nodes taken were smooth in surface and soft in consistency, measured up to 1.0 cm in the largest dimension, and were free from the adjacent tissue. Only 2 patients had enlarged (§1.5 cm in the largest dimension) lymph nodes over the lower para-aortic region. Six of the 7 patients with gastric cancer and all 3 patients with colon cancer had metastatic nodes histologically. The patient with gallbladder malignancy showed no metastatic nodes. Among all the 58 nodes taken from these 11 patients, 39 (67%) showed metastatic foci. DISCUSSION
Although the nature of metastatic ovarian tumors has been established for nearly a century and thoroughly reviewed recently [7], the metastatic pathway of tumors originating from the gastrointestinal tract is still in the hypothetical stage. Description related to this issue is rare in the literature. Frequently, patients with metastatic ovarian tumors are handled by different doctors at different periods of the disease process, and the continuity of observation is interrupted. The rare incidence of this disease entity also provides little chance for the clinician to make a comprehensive observation. Furthermore, ovarian metastasis is often viewed as a late presentation of cancer [8], and the patient is often treated with palliative measures which frequently do not include a comprehensive assessment of disease extension. As a result, no one has convincingly described the pathway of metastasis to the ovaries from cancers of the gastrointestinal tract [9].
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It is less disputable that ovarian metastases of breast cancer are through either a retrograde lymphatic route or a systemic hematogenous dissemination but not through an intraperitoneal course. In a study of 59 ovarian metastases from breast cancer, 80% of metastases were from patients with stage II and III diseases, and none presented with stage I disease [10]. The high incidence of positive lymph nodes and the presence of ovarian metastasis among patients with advanced breast cancer indicate that lymphatic pathway is important for ovarian metastasis, while the hematogenous route is less conspicuous [10]. The rare but substantial incidence of testicular metastasis from various primary malignancies also indicates that pathways other than the intraperitoneal route are present for metastasis to the gonad [11–14]. However, the incidence of lymph node metastasis and parenchymal organ involvement was not mentioned in these reports. Our investigation suggests that both transcoelomic dissemination and retrograde lymphatic flow are likely to be common metastatic routes for ovarian tumor of gastric and colorectal origin. They often presented before the diagnosis of ovarian metastasis or at the surgery for both primary and ovarian tumors, while parenchymal metastasis is rarely detected before or at the diagnosis of ovarian tumors. The incidence of lymph node metastasis in our group is higher than that (47%) of 538 patients with stage III colorectal cancer treated at our hospital during the same period [15]. In an investigation of ovarian metastasis on 30 autopsied patients with gastric cancer by Hirono et al., they noticed that the capsules of the ovarian tumors were usually intact, although many cases concurrently showed marked peritoneal dissemination [16]. The authors noticed that metastatic cells first reach the stroma of ovarian hilus, then spread into the medulla or cortex, and later grow diffusely. While cancer cells reach the capsule of the ovary in many instances, they seldom break and invade it. These findings favor the hypothesis that lymphatic spread is a major route of ovarian metastasis, even in the presence of intraperitoneal lesions.
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In a histomorphological study on 10 ‘‘early’’ Krukenberg tumors with only slight swelling of the ovary [17], it was also noticed that lymph vessel permeation in the ovarian hilum was observed in all cases. After the signet-ring cells spread diffusely in the lymph vessels, they leak and infiltrate the ovarian stroma, and eventually produce stroma edema and proliferation. CEA staining revealed many CEA-positive tumor cells in the proliferated stroma in which tumor cells failed to be detected. The result of our study is consistent with these histologic studies. Inguinal lymph node metastasis is occasionally observed in cervical cancer patients with primary lymph node group involvement. This retrograde lymph node metastasis can be explained by lymphatic flow regurgitation due to the occlusion of upper lymphatic drainage resulting from advanced lymphatic metastasis. This model could also be applied to the mechanism of ovarian metastasis from gastrointestinal malignancies since both lymphatic channels that drain the gastrointestinal tract and ovaries ultimately link with the lumbar lymphatic chain [9]. More than 20% of patients in our series showed both peritoneal and lymph node metastasis. It might indicate that lymph node metastasis was also correlated to the peritoneal metastasis. In a retrospective study on 1108 patients with gastric cancer [18], multivariate analysis showed that lymph node metastasis is an independent factor for peritoneal dissemination. We also suspected that the proportion of lymph node metastasis might be underestimated by routine histologic examination, since early micrometastasis with sparse and small foci might not be present in the section examined. Our data are inconsistent with that of 51 patients treated at Royal Marsden Hospital as reported by Taylor et al. [19]: Of those patients, the ovary was the sole site of metastasis in 5 cases. In the remaining cases, there were 23 with liver, 16 with lung, 16 with peritoneal, 20 with lymph node, and 2 with abdominal wall metastases. We suspected this difference is due to: (1) The patients in our series were retrieved from pathology registration, and all had undergone oophorectomy with histologic evidence of metastasis, while those of Royal Marsden were from hospital-based cancer registry and only 17 (33%) patients had received operation for the ovarian tumor(s). Since surgery is not indicated for patients with extensive disease, our group tends to represent those with limited metastasis which includes the ovary. (2) As in our experience, image study including CT scan underestimated the lymph node metastasis; hence, there might show a higher percentage of patients with metastatic lymph node had the 51 patients in Taylor’s series undergone lymph node sampling for histologic study. (3) The time point of observation along the disease process was also different. In our series, the metastasis status was registered at the diagnosis of primary cancer or before the diagnosis of ovarian metastasis, while that of Taylor’s
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was observed at the diagnosis of ovarian metastasis or after. Indeed, most patients in our group developed parenchymal organ metastases, at widely differing times after ovarian metastasis. However, the parenchymal lesions were not detectable by image studies at operation for the primary tumor. We suppose that hematogenous metastasis, which is often detected after the establishment of lymphatic metastasis, originates from circulating tumor cells of systemic lymphatic flow. The median ages at diagnosis of primary tumor of both gastric and colorectal malignancy patients in our study were approximately 15 years younger than that of those with gastric and colorectal cancers in general. This indicates that the younger female patients with gastrointestinal tumors tend to develop ovarian metastasis more than the older patients. However, our study does not support the hypothesis that the postovulatory rearrangement of the ovarian surface attributes to the metastasis since the incidences of intraperitoneal lesions were similar in the premenopausal and postmenopausal patients. We surmise that either the tumors in the younger patients are more aggressive to develop metastasis or the younger victims of gastrointestinal cancers hold a weaker immunity to overcome tumor metastasis. Our prospective intervention on 11 patients with metastatic ovarian tumors indicated that the incidence of lymph node metastasis was underestimated if only image study such as computed tomography was applied for the estimation of lymph node metastasis. Since not all of our retrospective cases underwent a thorough lymphadenectomy, and only those with obvious enlarged lymph node were judged as lymph node metastasis by computed tomography, the incidence of lymph node metastasis might have been underestimated. In a study of 521 patients undergoing surgery for gastric carcinoma, it showed that 12% of patients were macroscopically node-negative but histologically node-positive [20]. When the criterion is §1.5-cm nodes in CT scan as metastatic nodes, most of the histologically proven paraaortic lymph nodes in our prospective series do no meet this criterion. Based on the improvement of CT resolution, it has been suggested that nodes §0.8 cm are metastatic in the absence of other indications for enlarged lymph nodes. This new guideline should be tested in the future. In conclusion, the presence of lymph node metastasis at the diagnosis of primary gastrointestinal malignancies is frequently seen in patients with ovarian metastasis. This suggests that retrograde lymphatic flow metastasis is a common route for ovarian metastasis. The low incidence of parenchymal organ involvement before or at the diagnosis of metastatic ovarian tumor and the frequent coincidence of lymph node metastasis in patients with parenchymal organ involvement do not support the hematogenous route of ovarian metastasis as a common metastatic pathway. However, it must be emphasized that our observation on the correlation between lymph node metastasis and the development of ovar-
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ian tumor only provides indirect evidence for the possibility of retrograde lymphatic flow metastasis. Further study on the presence of lymphatic flow regurgitating into the ovarian circulation and the intraperitoneal implantation into the ovarian stroma are necessary for the establishment of a direct confirmation. REFERENCES
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1. Schlagenhaufer E: Uber ds metastatic Ovarian Karcinoma nach Krebs des Magens, Darmes und anderer Bauchorgane. Monatachr Geburtshilfe 15:485, 1902
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2. Petru E, Pickel H, Heydarfadai M, Lahousen M, Haas J, Schaider H, Tamussino K: Nongenital cancers metastatic to the ovary. Gynecol Oncol 44:83–86, 1992 3. Yakushiji M, Tazaki T, Nishimura H, Kato T: Krukenberg tumors of the ovary: a clinicopathologic analysis of 112 cases. Acta Obstet Gynaecol Jpn 39:479–485, 1987
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4. Ulbright TM, Roth LM, Stehman FB: Secondary ovarian neoplasia. A clinicopathologic study of 35 cases. Cancer 53:1164–1174, 1984
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5. Birnkrant A, Sampson J, Sugarbaker PH: Ovarian metastasis from colorectal cancer. Dis Colon Rectum 29:767–771, 1986 6. el Mansouri A, Moumen M, Louahlia A, el Fares F: Krukenberg’s tumor: still a somber prognosis—4 cases. J Gynecol Obstet Biol Reprod 22:497–500, 1993 7. Young RH, Scully RE: Metastatic tumors in the ovary: a problemoriented approach and review of the recent literature. Semin Diag Pathol 8:250–276, 1991 8. Mazur MT, Hsueh S, Gersell DJ: Metastases to the female genital tract. Analysis of 325 cases. Cancer 53:1978–1984, 1984 9. DiSaia PJ, Creasman WT: Germ Cell, Stromal, and Other Ovarian
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Tumors, in Clinical Gynecologic Oncology, St. Louis, Mosby Year Book, 1993, pp 451–453 Gagnon Y, Tetu B: Ovarian metastases of breast carcinoma. A clinicopathologic study of 59 cases. Cancer 64:892–898, 1989 London MZ, Grossman SN: Secondary testicular tumor resembling Krukenberg’s tumor: a case report. J Urol 62:713, 1949 Meacham RB, Matu SA, Espada R, Wheeler TM, Schum CW, Scardino PT: Testicular metastasis as the first manifestation of colon cancer. J Urol 140:621, 1988 Haupt HM, Mann RB, Trump DL, Abeloff MD: Metastatic carcinoma involving the testis. Cancer 54:709–714, 1984 Zuk RJ, Trotter SE, Baithun SL: ‘‘Krukenberg’’ tumor of the testis. Histopathology 14:214–216, 1989 Tang R, Wang JY, Chen JS, Chang-Chien CR, Tang S, Lin SE, You YT, Hsu KC, Ho YS, Fan HA: Survival impact of lymph node metastasis in TNM stage III carcinoma of the colon and rectum. J Am Coll Surg 180:705–712, 1995 Hirono M, Taniyama K, Matsuki K, Nakagami K, Niimoto M, Hattori T. Clinico-pathological studies on ovarian metastasis from gastric cancer. Jpn J Surg 13:25–31, 1983 Tazaki T, Nishimura H, Yakushiji M, Matsumura T, Higashijima H, Morisaki H: Histomorphological studies of Krukenberg tumor on early ovarian metastatic lesion. Acta Obstet Gynaecol Jpn 42:353–359, 1990 Maehara Y, Moriguchi S, Kakeji Y, Kohnoe S, Korenaga D, Haraguchi M, Sugimachi K: Pertinent risk factors and gastric carcinoma with synchronous peritoneal dissemination or liver metastasis. Surgery 110:820–823, 1991 Taylor AE, Nicolson VMC, Cunningham D: Ovarian metastases from primary gastrointestinal malignancies: the Royal Marsden Hospital experience and implications for adjuvant treatment. Br J Cancer 71:92– 96, 1995 Adachi Y, Mori M, Maehara Y, Sugimachi K: Macroscopically nodenegative but histologically node-positive gastric carcinoma. Br J Surg 82:1254–1256, 1995
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Retrograde Lymphatic Spread: A Likely Route for Metastatic Ovarian Cancers of Gastrointestinal Origin Ting-Chang Chang,* Chan-Chao Changchien,* Chih-Wen Tseng,* Chyong-Huey Lai,* Chih-Jen Tseng,* Shung-Eing Lin,† Chia-Shu Wang,‡ Kuan-Jen Huang,* Hung-Hsueh Chou,* Yen-Ying Ma,* Suei Hsueh,§ Hock-Liew Eng,§ and Hong-Arh Fan† *Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; †Department of Proctology; ‡Department of General Surgery; and §Department of Pathology, Chang Gung Memorial Hospital and Chang Gung Medical College, Taoyuan, Taiwan Received August 5, 1996
In order to outline the pathways of gastrointestinal malignancies metastasizing to the ovaries, we reviewed 103 cases of metastatic ovarian tumors, and also performed para-aortic lymph node sampling on 11 patients at operation for metastatic ovarian tumors. Of the 103 patients, 74% (26/35) with gastric cancer and 67% (45/ 67) with colorectal cancer had lymph node metastasis at or before the diagnosis of ovarian tumor. Intraperitoneal metastases presented in 49 and 42% of patients with gastric and with colorectal cancers, respectively. Twenty-three percent of gastric cancer patients and 25% of colorectal cancer patients presented with both lymph node and intraperitoneal metastases. The ovary was the first or among the early metastatic organs diagnosed in 51 of the 53 patients with metachronous ovarian metastases. Only 4 patients with colorectal cancer and none with gastric cancer showed parenchymal organ metastases. These 4 patients also showed intraperitoneal lesions, and 3 of these 4 patients had node metastasis. Among the 11 patients who underwent prospective para-aortic lymph node sampling during operation for the ovarian tumors, only 1 had enlarged para-aortic nodes depicted by computed tomography, 2 had grossly enlarged (§1.5 cm) para-aortic lymph nodes noted at surgery, and 6 of the 7 patients with gastric cancer and all 3 with colorectal cancer had metastatic nodes histologically. Among the 58 nodes taken from these patients, 67% showed metastatic foci. We concluded that lymph node metastasis is frequently seen in patients with metastatic ovarian tumors of gastrointestinal origin, and hypothesized that retrograde lymphatic spread is a likely route for the metastases. q 1997 Academic Press
INTRODUCTION
Since the establishment of the metastatic nature in most Krukenberg tumors by Schlagenhaufer in 1902 [1], it has been demonstrated that many carcinomas, including that of thyroid, breast, stomach, gallbladder, pancreas, colon, rectum, and malignancies arising from the female genital tract may metastasize to the ovaries [2–5]. Most of the nongenital cancers metastasizing to the ovaries are those arising from the gastrointestinal tract. However, the metastatic pathways
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MATERIALS AND METHODS
Patients with histology-proven metastatic ovarian cancers originating from gastrointestinal malignancies between January 1984 and March 1996 were obtained from the pathology registry of Chang Gung Memorial Hospital Linkou Medical Center and Kaoshiung Chang Gung Memorial Hospital. Medical information including the patient’s age, menopausal status, diagnosis dates, sites, stage, and treatments for both primary and ovarian tumors were retrieved from medical records. The histology of both primary and metastatic tumors, serial image studies of chest X ray and computed tomography of the abdomen and pelvis were reviewed. Other studies including magnetic resonance image (MRI), bone scan, and abdominal and pelvic ultrasonography were also reviewed if present. Special attention was focused on the metastatic sites that were diagnosed concurrently with the primary tumor. This information was classified into three
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of these ovarian tumors have not yet been established [6]. Three possible pathways have been postulated: (1) transcoelomic dissemination with surface implantation, including metastasis through direct continuity of the primary tumor, (2) lymphatic flow metastasis, and (3) blood-borne metastasis. Unfortunately, the state of intraperitoneal, lymph nodes, and parenchymal organ metastases, as the markers of different metastatic pathways, were rarely mentioned in the English literature. Recently, the retroperitoneal lymph node status was described in a report of nongenital cancers metastatic to the ovary [2], and only 8 of the 82 patients had information on the lymph node status. To further outline the metastatic pathways in ovarian tumors that originate from the gastrointestinal tract, we retrospectively reviewed the medical records and histologic slides of 103 patients with histologyproven metastatic ovarian cancer, and prospectively performed para-aortic lymph node sampling on 11 patients at the surgery for metastatic ovarian tumors.
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categories: intraperitoneal metastases, lymph node metastases, and parenchymal organ metastases, as described below. Intraperitoneal metastases include the following: (1) Malignant cells in the peritoneal fluid or washing cytology; (2) presence of histology-proven metastatic lesions over the peritoneum, serosa, or omentum diagnosed at the time of surgery for the primary tumor, or before the diagnosis of ovarian metastasis; and (3) ovarian metastatic tumor directly contacting the primary tumor (e.g., sigmoid cancer). Lymph node metastases are: (1) Histologic evidence of lymph node metastasis, which was taken either at the surgery for primary tumor or before the diagnosis of ovarian metastasis; (2) presence of enlarged para-aortic or pelvic lymph nodes measuring no less than 1.5 cm in dimension, disclosed by computed tomography in patients with gastrointestinal malignancies and without other medical history that might relate to such an enlargement. Parenchymal organ metastasis includes any metastasis over the parenchyma of lung, bone, liver, kidney, adrenal gland, pancreas, thyroid, liver, or other parenchymal organs at or before the diagnosis of ovarian metastasis. The verification of metastasis that was diagnosed based on image studies without histologic or cytological evidence was through the follow-up image studies. Serial serum carcinoembryonic antigen (CEA) titers before and after treatment were also used as a reference of disease status. From February 1992 to June 1996, prospective lower paraaortic lymph node sampling was performed at the time of surgery for ovarian tumors in patients with ovarian metastases originating from gastrointestinal malignancies. Student’s t test and x2 test with Yate’s correction were applied for the comparison of frequency distributions in different groups. A two-tailed P less than 0.05 was declared as statistically significant. RESULTS
One hundred three patients with metastatic ovarian tumors arising from the gastrointestinal tract were retrospectively reviewed. There were 67 patients with colorectal carcinomas, 35 patients with gastric carcinomas, and 1 patient with gallbladder carcinoma. The median ages at the diagnosis of colorectal and of gastric malignancies were 46.7 and 36.9 years, respectively. The patient with gallbladder carcinoma was diagnosed at 44 years. Among the patients with colorectal cancer, the ovarian metastasis was diagnosed concurrently (within 1 month) with the primary tumor in 34 (51%) patients, while 2 patients had ovarian metastases diagnosed within the range of 1 to 6 months after the diagnosis of primary tumors, 8 patients within 7–12 months, 17 patients within 13–24 months, and 6 patients over 2 years after the diagnosis of primary tumor (Table 1). Of the patients with gastric tumor as the primary, 23 (66%) patients presented with gastric and ovarian tumor concurrently. Fifteen of these
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23 had the chief complaint of low abdominal symptoms (distention, fullness, dull pain, or discomfort) and the ovarian tumors were discovered a few days before the diagnosis of gastric malignancies. All of the histology of these 103 cases were adenocarcinomas, and all the ovarian metastatic tumors were consistent with their primary cancers, but tumor necrosis was more obvious in some of their ovarian counterparts. Signet ring cells were seen in 23 (66%) patients with gastric primary and in 12 (19%) patients with colorectal primary. Bilateral ovarian involvement was noted in 79% (26/33) of gastric primary and 40% (27/67) of colorectal primary. Two gastric cancer patients had undergone unilateral oophorectomy for benign tumors before the diagnosis of gastric malignancy. Preservation of the contralateral, grossly normal ovary was undertaken in 25 of the 40 patients with unilateral ovarian tumor originating from colorectal malignancies. Frozen section for the wedge resection on the preserved ovary to rule out the possibility of metastasis had been performed in 8 patients. Two patients developed metastatic tumor over the preserved ovary: One 59-year-old patient having received hemicolectomy for descending colon cancer and left salpingo-oophorectomy for serous cystadenoma at primary operation developed a 25-cm right ovarian metastatic tumor 30 months after the surgery; One 50-year-old woman underwent a right hemicolectomy and right salpingo-oophorectomy for transverse colon cancer and a 6-cm metastatic ovarian tumor had a grossly normal left ovary at the operation, which was preserved according to her request. Six months after the surgery, the left ovary became a 20-cm metastatic tumor along with 2500 ml ascites. Forty-two patients with colorectal cancer and 23 patients with gastric cancer received chemotherapy after surgery. 5Fluorouracil (5-FU) with or without leucovorum was used as the adjuvant therapy for patients with colorectal cancer. The combinations of 5-FU with cisplatin, or doxorubicin, or both, were applied for the treatment of gastric cancer. One patient with sigmoid cancer and one with rectal cancer received adjuvant pelvic irradiation. Of the patients with metachronous ovarian tumors, 14 received chemotherapy after surgery with similar regimens. Lymph node metastasis, as a marker of lymphatic flow metastasis that resulted in an ovarian metastasis, presented in 74% (26/35) of the gastric cancer patients at the diagnosis of primary tumor and in 67% (45/67) of the colorectal patients at the diagnosis of primary malignancy. Intraperitoneal lesions, as an evidence of transcoelomic dissemination into the ovary, were present in 17 (49%) and 28 (42%) of the patients with gastric and colorectal cancer at the diagnosis of primary tumor, respectively. Eight gastric cancer patients and 17 colorectal cancer patients presented with both lymph node metastasis and intraperitoneal lesions. All gastric cancer patients presented with either lymph node metastasis or intraperitoneal lesions, or both, while no one presented with
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TABLE 1 Primary Sites, Age, and Interval between Diagnosis of Primary Tumors and Ovarian Metastasis in 103 Patients Interval from diagnosis to ovarian metastasisb
a b
Site
Agea
õ1
1–6
7–12
13–24
ú24
Total n
Colon/rectum Stomach Gallbladder Total
19–79 (46.7) 21–65 (36.9) 44
34 23 1 58
2 0 0 2
8 2 0 11
17 7 0 25
6 3 0 9
67 35 1 103
Range and median age in years at the diagnosis of primary tumor. Interval from the diagnosis of primary tumor to the diagnosis of ovarian metastasis in months.
parenchymal organ involvement before or at the diagnosis of ovarian involvement. Three patients with colorectal cancer showed metastatic lesions over liver parenchyma and one showed pulmonary metastasis. Two of the three patients with liver metastasis and the one with pulmonary lesion had histologic evidence of metastasis. The diagnosis of another one was based on abdominal CT findings and was verified by the follow-up CT studies which showed progressive enlarged intrahepatic lesions and the appearance of daughter tumors 5 months after treatment. Nonelevated serum a-fetoprotein and progressive elevated CEA marker were noted along with the hepatic tumor growth. These four patients also had intraperitoneal lesions. Three of these four patients had lymph node metastasis (Table 2). Double gastrointestinal cancers were noted in a 58-year-old woman who had undergone a subtotal gastrectomy for gastric cancer, and no (0/24) lymph node metastasis was noted. She developed a cecal cancer and a synchronous metastatic right ovarian tumor 31 months after the gastric surgery. Positive (3/17) regional lymph nodes and no intraperitoneal metastasis were discovered during operation, and liver and pancreatic metastases developed 1 year later. Histology of these metastatic sites was consistent with that of cecal cancer and was different from that of gastric malignancy.
Altogether, 46 (45%) of these 103 patients showed intraperitoneal lesions, and 71 (69%) had lymph node metastasis at the diagnosis of primary malignancy. Parenchymal organ metastasis was only observed in 4 patients with colorectal cancer and none with gastric cancer (Table 2). When comparing the frequencies of intraperitoneal metastasis and lymph node metastasis between patient groups of pre- and postmenopausal status among 89 patients with known status at presentation, intraperitoneal metastasis was present in 43% of premenopausal patients and 46% of postmenopausal patients, while lymph node metastasis was present in 70 and 72% of pre- and postmenopausal patients, respectively (P ú 0.05). Eleven patients with metastatic ovarian tumors, including 7 of gastric origin, 3 of colorectal origin, and one of gallbladder origin, underwent prospective lower para-aortic (L1-L3 level) lymph node sampling at the surgery for the ovarian tumor(s). The primary tumor and its ovarian metastasis were operated concurrently on 3 patients with gastric cancer and one with sigmoid colon cancer. The other 7 patients were with metachronous ovarian tumors. Five gastric cancer patients and 1 colon cancer patient showed no intraperitoneal lesions (Table 3). The other 2 gastric cancer patients showed multiple small (£0.5 cm) serosal lesions over the bladder
TABLE 2 Presence of Intraperitoneal Lesions, Lymph Node Metastasis, and Parenchymal Organ Involvement in 103 Patients at or before the Diagnosis of Metastatic Ovarian Tumor Intraperitoneal lesionsa
Lymph nodeb
Parenchymal organa,b
Primary tumor
Present
Absent
Unknown
Present
Absent
Present
Absent
Gastricc Colond Gallbladder
17 28 1
15 30 0
3 9 0
26 45 0
9 22 1
0 4e 0
35 63 1
Total
46
45
12
71
32
4
99
a
Frequency of intraperitoneal lesions versus frequency of parenchymal organ involvement, P õ 0.001. Frequency of lymph node metastasis versus that of parenchymal organ involvement, P õ 0.001. c 8 patients presented with both lymph node metastasis and intraperitoneal lesions. d 17 patients presented with both lymph node metastasis and intraperitoneal lesions. e 3 patients with hepatic metastasis and one with pulmonary lesion. All 4 patients had intraperitoneal lesions, and 3 also had lymph node metastases. b
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TABLE 3 Lymph Node Metastasis Diagnosed by CT Scan, Gross Lymph Node Size, and Histology in 11 Patients Who Underwent Prospective Para-aortic Lymph Node Sampling at Operation for Metastatic Ovarian Tumors Para-aortic lymph nodeb Primary tumor
Intraperitoneala
CT
Gross
Histology
Parenchymal organc
Gastric (n Å 7) Colon (n Å 3) Gallbladder (n Å 1) Total (n Å 11)
2 2 1 5
1 0 0 1
1 1 0 2
6 3 0 9
0 0 0 0
a
Presence of histology-proved intraperitoneal lesions. Presence of para-aortic lymph node metastasis by different criteria: CT, lymph node size §1.5 cm; gross, lymph node size §1.5 cm; histology, presence of metastatic foci. c Parenchymal organ metastasis diagnosed by image study with or without histologic evidence. b
dome and lower pelvic peritoneum. Two colorectal cancer patients had tumor seedings over the pelvic cavity, and the patient with the gallbladder tumor showed omental cake and multiple confluent metastatic pelvic lesions. None of these patients presented with parenchymal metastasis at the diagnosis of ovarian tumor based on chest X ray, CT of abdomen and pelvis, and abdominal sonography. Only 1 of these 11 patients showed enlarged lymph nodes by CT. At least 4 lymph nodes were sampled from each patient. Most lymph nodes taken were smooth in surface and soft in consistency, measured up to 1.0 cm in the largest dimension, and were free from the adjacent tissue. Only 2 patients had enlarged (§1.5 cm in the largest dimension) lymph nodes over the lower para-aortic region. Six of the 7 patients with gastric cancer and all 3 patients with colon cancer had metastatic nodes histologically. The patient with gallbladder malignancy showed no metastatic nodes. Among all the 58 nodes taken from these 11 patients, 39 (67%) showed metastatic foci. DISCUSSION
Although the nature of metastatic ovarian tumors has been established for nearly a century and thoroughly reviewed recently [7], the metastatic pathway of tumors originating from the gastrointestinal tract is still in the hypothetical stage. Description related to this issue is rare in the literature. Frequently, patients with metastatic ovarian tumors are handled by different doctors at different periods of the disease process, and the continuity of observation is interrupted. The rare incidence of this disease entity also provides little chance for the clinician to make a comprehensive observation. Furthermore, ovarian metastasis is often viewed as a late presentation of cancer [8], and the patient is often treated with palliative measures which frequently do not include a comprehensive assessment of disease extension. As a result, no one has convincingly described the pathway of metastasis to the ovaries from cancers of the gastrointestinal tract [9].
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It is less disputable that ovarian metastases of breast cancer are through either a retrograde lymphatic route or a systemic hematogenous dissemination but not through an intraperitoneal course. In a study of 59 ovarian metastases from breast cancer, 80% of metastases were from patients with stage II and III diseases, and none presented with stage I disease [10]. The high incidence of positive lymph nodes and the presence of ovarian metastasis among patients with advanced breast cancer indicate that lymphatic pathway is important for ovarian metastasis, while the hematogenous route is less conspicuous [10]. The rare but substantial incidence of testicular metastasis from various primary malignancies also indicates that pathways other than the intraperitoneal route are present for metastasis to the gonad [11–14]. However, the incidence of lymph node metastasis and parenchymal organ involvement was not mentioned in these reports. Our investigation suggests that both transcoelomic dissemination and retrograde lymphatic flow are likely to be common metastatic routes for ovarian tumor of gastric and colorectal origin. They often presented before the diagnosis of ovarian metastasis or at the surgery for both primary and ovarian tumors, while parenchymal metastasis is rarely detected before or at the diagnosis of ovarian tumors. The incidence of lymph node metastasis in our group is higher than that (47%) of 538 patients with stage III colorectal cancer treated at our hospital during the same period [15]. In an investigation of ovarian metastasis on 30 autopsied patients with gastric cancer by Hirono et al., they noticed that the capsules of the ovarian tumors were usually intact, although many cases concurrently showed marked peritoneal dissemination [16]. The authors noticed that metastatic cells first reach the stroma of ovarian hilus, then spread into the medulla or cortex, and later grow diffusely. While cancer cells reach the capsule of the ovary in many instances, they seldom break and invade it. These findings favor the hypothesis that lymphatic spread is a major route of ovarian metastasis, even in the presence of intraperitoneal lesions.
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In a histomorphological study on 10 ‘‘early’’ Krukenberg tumors with only slight swelling of the ovary [17], it was also noticed that lymph vessel permeation in the ovarian hilum was observed in all cases. After the signet-ring cells spread diffusely in the lymph vessels, they leak and infiltrate the ovarian stroma, and eventually produce stroma edema and proliferation. CEA staining revealed many CEA-positive tumor cells in the proliferated stroma in which tumor cells failed to be detected. The result of our study is consistent with these histologic studies. Inguinal lymph node metastasis is occasionally observed in cervical cancer patients with primary lymph node group involvement. This retrograde lymph node metastasis can be explained by lymphatic flow regurgitation due to the occlusion of upper lymphatic drainage resulting from advanced lymphatic metastasis. This model could also be applied to the mechanism of ovarian metastasis from gastrointestinal malignancies since both lymphatic channels that drain the gastrointestinal tract and ovaries ultimately link with the lumbar lymphatic chain [9]. More than 20% of patients in our series showed both peritoneal and lymph node metastasis. It might indicate that lymph node metastasis was also correlated to the peritoneal metastasis. In a retrospective study on 1108 patients with gastric cancer [18], multivariate analysis showed that lymph node metastasis is an independent factor for peritoneal dissemination. We also suspected that the proportion of lymph node metastasis might be underestimated by routine histologic examination, since early micrometastasis with sparse and small foci might not be present in the section examined. Our data are inconsistent with that of 51 patients treated at Royal Marsden Hospital as reported by Taylor et al. [19]: Of those patients, the ovary was the sole site of metastasis in 5 cases. In the remaining cases, there were 23 with liver, 16 with lung, 16 with peritoneal, 20 with lymph node, and 2 with abdominal wall metastases. We suspected this difference is due to: (1) The patients in our series were retrieved from pathology registration, and all had undergone oophorectomy with histologic evidence of metastasis, while those of Royal Marsden were from hospital-based cancer registry and only 17 (33%) patients had received operation for the ovarian tumor(s). Since surgery is not indicated for patients with extensive disease, our group tends to represent those with limited metastasis which includes the ovary. (2) As in our experience, image study including CT scan underestimated the lymph node metastasis; hence, there might show a higher percentage of patients with metastatic lymph node had the 51 patients in Taylor’s series undergone lymph node sampling for histologic study. (3) The time point of observation along the disease process was also different. In our series, the metastasis status was registered at the diagnosis of primary cancer or before the diagnosis of ovarian metastasis, while that of Taylor’s
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was observed at the diagnosis of ovarian metastasis or after. Indeed, most patients in our group developed parenchymal organ metastases, at widely differing times after ovarian metastasis. However, the parenchymal lesions were not detectable by image studies at operation for the primary tumor. We suppose that hematogenous metastasis, which is often detected after the establishment of lymphatic metastasis, originates from circulating tumor cells of systemic lymphatic flow. The median ages at diagnosis of primary tumor of both gastric and colorectal malignancy patients in our study were approximately 15 years younger than that of those with gastric and colorectal cancers in general. This indicates that the younger female patients with gastrointestinal tumors tend to develop ovarian metastasis more than the older patients. However, our study does not support the hypothesis that the postovulatory rearrangement of the ovarian surface attributes to the metastasis since the incidences of intraperitoneal lesions were similar in the premenopausal and postmenopausal patients. We surmise that either the tumors in the younger patients are more aggressive to develop metastasis or the younger victims of gastrointestinal cancers hold a weaker immunity to overcome tumor metastasis. Our prospective intervention on 11 patients with metastatic ovarian tumors indicated that the incidence of lymph node metastasis was underestimated if only image study such as computed tomography was applied for the estimation of lymph node metastasis. Since not all of our retrospective cases underwent a thorough lymphadenectomy, and only those with obvious enlarged lymph node were judged as lymph node metastasis by computed tomography, the incidence of lymph node metastasis might have been underestimated. In a study of 521 patients undergoing surgery for gastric carcinoma, it showed that 12% of patients were macroscopically node-negative but histologically node-positive [20]. When the criterion is §1.5-cm nodes in CT scan as metastatic nodes, most of the histologically proven paraaortic lymph nodes in our prospective series do no meet this criterion. Based on the improvement of CT resolution, it has been suggested that nodes §0.8 cm are metastatic in the absence of other indications for enlarged lymph nodes. This new guideline should be tested in the future. In conclusion, the presence of lymph node metastasis at the diagnosis of primary gastrointestinal malignancies is frequently seen in patients with ovarian metastasis. This suggests that retrograde lymphatic flow metastasis is a common route for ovarian metastasis. The low incidence of parenchymal organ involvement before or at the diagnosis of metastatic ovarian tumor and the frequent coincidence of lymph node metastasis in patients with parenchymal organ involvement do not support the hematogenous route of ovarian metastasis as a common metastatic pathway. However, it must be emphasized that our observation on the correlation between lymph node metastasis and the development of ovar-
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ian tumor only provides indirect evidence for the possibility of retrograde lymphatic flow metastasis. Further study on the presence of lymphatic flow regurgitating into the ovarian circulation and the intraperitoneal implantation into the ovarian stroma are necessary for the establishment of a direct confirmation. REFERENCES
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