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Prognostic significance of morphology of tumor and retroperitoneal lymph nodes in epithelial carcinoma of the ovary
GYNECOLOGIC
ONCOLOGY
18,
87-93 (1984)
Prognostic Significance of Morphology of Tumor and Retroperitoneal Lymph Nodes in Epithelial Carcinoma of the Ovary I. Correlation with Lymph Node Metastasis SIDNEY
S. CHEN, M.D., FACOG,* AND LOUISE LEE, M.D., FCAPt
Departments of *Obstetrics and Gynecology and tpathology, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York 11042 and School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794
Received January 25, 1983 The prognostic indices based on a morphologic study of tumor and retroperitoneal lymph nodes in 63 patients with epithelial carcinoma of the ovary are reported. The purpose of the study was to identify those variables most frequently related to nodal involvement. The cases in the series consisted of 11 Stage I, 10 Stage II, 34 Stage III, and 8 Stage IV. Histologic distribution was 60.4% serous type, 11.1% mutinous, 6.3% endometrioid, 6.3% clear cell, and 15.9% unclassified. All patients had maximal surgery and selective biopsy of para-aortic and pelvic lymph nodes. The results showed statistically significant variables associated with nodal metastasis in both primary tumor and regional lymph nodes. The indices in primary tumor were grade of tumor, vascular invasion, lymphocytic infiltration, and stromal fibrosis; those in lymph node were type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. The nodes with lymphocyte depletion were associated with nodal spread in 81.3% of cases. It is concluded that morphologic study of tumor and lymph node could identify prognostic factors predicting regional nodal metastasis in ovarian carcinoma.
INTRODUCTION Because of the dismal outlook for patients affected by ovarian cancer, investigators have attempted to elucidate important risk factors most frequently associated with prognosis [l-6]. These risk factors, such as stage of disease, regional nodal metastasis, stromal cellular reaction in tumor, titer of carcinoembryonic antigen (5), amount of residual tumor (6), response to chemotherapy, and status of second-look laparotomy, have been related closely to tumor recurrence. In carcinoma of the cervix [ 1,7], endometrium [8], vulva [9], and breast [ 10,111,studies have been conducted to establish regional lymph node metastasis as the critical determinant of their survival. Even though a staging laparotomy is required for treatment of all ovarian cancer, information regarding these risk factors associated with frequent retroperitoneal lymph node metastasis is still lacking [4]. In the present study, risk factors associated with nodal metastasis were identified by pathologic examinations of morphology of tumor and retroperitoneal lymph nodes in a group of patients with newly diagnosed ovarian carcinoma. We found positive correlation between selected factors and nodal spread. 87
0090-8258/84 $1.50 Copyright 0 1984 by Academic Press, Inc. All rights of reproduction in any form reserved.
88
CHEN
AND
LEE
MATERIALS AND METHODS
From January 1975 through December 1981, 140 patients with newly diagnosed epithelial carcinoma of the ovary had their initial surgery performed at the Long Island Jewish-Hillside Medical Center, New Hyde Park, New York. Among these patients, 65 underwent maximal surgery, consisting of bilateral salpingo-oophorectomy, omentectomy, total abdominal hysterectomy, appendectomy, and a selective biopsy of para-aortic and pelvic lymph nodes. Additional cytoreductive procedures were also carried out in all advanced stagesas indicated. The technique of the selective nodal biopsy was described previously [4]. Morphology of both tumor and retroperitoneal nodes was examined to identify any risk factor correlated with lymphatic spread to regional nodes, primarily para-aortic and pelvic. The risk factors assessed from the tumor were grade of tumor, histologic type, lymphocytic infiltration in the stroma, vascular invasion, and stromal fibrosis. The variables analyzed in retroperitoneal lymph nodes were presence of cancer involvement, type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. The criteria of morphologic assessments are the following. For tumor.
1. Grades I, II, and III according to FIG0 classification. 2. Vascular invasion, presence of cancer cells in either lymphatic or venous space. 3. Lymphocytic infiltration, 2-t or 3 + , was considered positive. 4. Stromal fibrosis, marked fibroblastic proliferation in the stroma of the tumor (3+) was positive. For retroperitoneal
lymph nodes.
1. Type of lymph node reaction, lymphocyte predominance, germinal center predominance, lymphocyte depletion, and unstimulated, as described by Tsakraklides et al. [7]. 2. Sinus histiocytosis, marked histiocytosis (3+) was positive. 3. Nodal fibrosis, 2 + or 3 + , was grouped as positive. Special emphasis was given to correlation of these risk factors from tumor as well as node and nodal metastasis. Two cases were excluded from the series since the removed lymph nodes were completely replaced by tumor, precluding adequate morphologic assessment. The clinical stages of this series of 63 were as follows: 11 (17.5%) Stage I, 10 (15.9%) Stage II, 34 (53.9%) Stage III, and 8 (12.7%) Stage IV. Histologic distributions were 38 (60.4%) serous type, 7 (11.1%) mutinous, 4 (6.3%) endometrioid, 4 (6.3%) clear cell, and 10 (15.9%) unclassified. Grades of tumor of this group were 12 (19.0%) Grade I, 10 (15.9%) Grade II, and 41 (65.1%) Grade III. All specimens were processed in routine pathology laboratory tests, reviewed by a gynecologic pathologist (C.Y.L.), and surgery was executed by the same gynecologic oncologist (S.S.C.).
INDICES FOR LYMPH
89
NODE METASTASIS
RESULTS Significant prognostic variables, which were linked to regional lymph node dissemination, have been identified in both tumor and retroperitoneal lymph nodes based upon morphologic study. The risk factors in the primary tumor which correlated with nodal metastasis were grade of tumor, vascular invasion (either lymphatic or venous), lymphocytic infiltration in the stroma, and stromal fibrosis. As seen in Table 1, a progressive increment of involvement of abdominal lymph nodes with increasing tumor dedifferentiation was demostrated, from 16.7% in Grade I to 61.0% in Grade III. The statistical difference of nodal spread between differentiated ovarian tumors (Grades I and II) and undifferentiated Grade III was significant (P < 0.005). Identification of malignant cells in either lymphatic or venous spaces was most frequently associated with positive nodes (Table 2, P < 0.025). A strong lymphocytic penetration around cancer cells, which is a defense immunologic response by the host, was less frequently connected with metastatic node (Table 3, P < 0.005). TABLE 1 THE GRADE OF TUMOR AND RETROPERITONEAL
Grade
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
16.7% (2) 30.0% (3) 61.0% (25) 30
83.3% (10) 70.0% (7) 39.0% (16) 33
12 10 41 63
I
II III Total
Note. P < 0.005 between Grade l-3 tumors. TABLE 2 VASCULAR
INVASION
Vascular invasion
IN TUMOR AND RETROPERITONEAL
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
70.0% (14) 37.2% (16) 30
30.0% (6) 62.8% (27) 33
20 43 63
Positive Negative Total Note.
LYMPH
P < 0.025.
TABLE 3 LYMPH~CYTK
Lymphocytic
reaction
Positive Negative Total Note.
P < 0.005.
REACTION
IN TUMOR AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
7.7% (1) 58.0% (29) 30
92.3% (12) 42.0% (21) 33
13 50 63
90
CHEN
AND
LEE
Another risk variable indicating a favorable host response was a marked fibroblastic proliferation in the stroma, as seen in Table 4 (P < 0.005). In a comparison of two groups of patients, as seen in Table 5, one group with Grade I and II tumors, negative vascular invasion, strong lymphocytic reaction and appreciable stromal fibrosis, and another group with Grade III tumor, positive vascular invasion, absence of lymphocytic reaction, and fibroblastic proliferation, the former group, possessing excellent host factors, showed infrequent nodal involvement. The incidences of this involvement in the two groups were 0.0 and 84.6%, respectively (P < 0.005). On the other hand, risk variables in the regional lymph nodes which associated closely with nodal metastasis were type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. Both involved and uninvolved retroperitoneal nodes were systematically examined as proposed by the WHO [12]. Their morphologic changes were quite consistent in both metastatic and nonmetastatic ones. A type of nodal reaction with lymphocyte depletion was linked to metastasis in 81.3% of cases (Table 6), while nodes with lymphocyte predominance and germinal center predominance had only metastatic rates of 37.5 and 27.3%, respectively. The unstimulated node had an intermediate incidence of 41.7%. The statistical difference between lymphocyte depletion and nodes with abundant lymphocytes, as in lymphocyte predominance and germinal center predominance, was significant (P < 0.005). Another manifestation of poor immunocompetence was a weak sinus histiocytosis, which had a nodal involvement rate of 74.3% (Table 7, P < 0.005). TABLE 4 STROMAL
Stromal fibrosis
FIBROSIS IN TUMOR AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
17.9% (5) 71.4% (25) 30
82.1% (23) 28.6% (IO) 33
28 35 63
Positive Negative Total Note. P < 0.005.
TABLE 5 LOCAL
VARIABLES
IN TUMOR AND RETROPERITONEAL
Local variable Grade 1 and 2 tumors, stromal fibrosis, no vascular invasion, lymphocytic reaction Grade 3 tumor, vascular invasion, no stromal fibrosis, and no lymphocytic reaction Total Note. P < 0.005.
LYMPH NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
0.0% (0)
100.0% (7)
7
84.6% (11) 11
15.4% (2) 9
13 20
Total
INDICES FOR LYMPH
91
NODE METASTASIS
TABLE 6 THE TYPE OF LYMPH
NODE REACTION
Type Lymphocyte predominance Germinal center predominance Lymphocyte depletion Unstimulated Total
AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
37.5% 27.3% 81.3% 41.7%
62.5% 72.7% 18.7% 58.2%
(9) (3) (13) (5) 30
(15) (8) (3) (7) 33
Total 24 11 16 12 63
Note. P < 0.005 between lymphocyte and germinal center predominances and lymphocyte depletion group. TABLE 7 SINUS HISTVXYTOSIS
Sinus histiocytosis
IN LYMPH
NODE AND RETROPERITONEAL
NODAL
METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
14.3% (4) 74.3% (26) 30
85.7% (24) 25.7% (9) 33
28 35 63
Marked Weak Total Note. P < 0.005.
TABLE 8 FIBROSIS IN LYMPH
NODE AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Fibrosis
Positive lymph node metastasis
Negative lymph node metastasis
Total
Positive Negative Total
92.3% (12) 36.0% (18) 30
7.7% (1) 64.0% (32) 33
13 50 63
Note.
P < 0.005.
As expected, a replacement of normal lymphoid tissues by fibrous elements in the regional nodes gave frequent nodal metastasis of 92.3% (Table 8, P < 0.005). COMMENTS
Frustrations in the management of ovarian cancer are our failure in early detection by any screening method and the grim outlook for patients receiving aggressive postoperative chemotherapy [131. Since a screening technique for this malignancy is far from a reality, identification of risk variables associated with regional intra-abdominal node metastasis might shed some light on the virulence of tumor and more objectively predict individual outcome. Barber and his colleagues
92
CHEN AND LEE
[2], in defining local tumor risk factors, including histologic type and grade and nuclear grade, have reported a positive correlation with 2-year survival. They also added stromal reactions of lymphocytes, plasma cells, and polymorphonuclear leukocytes as the risk factors and found less distinct relationships. In ovarian dysgerminomas, Asadourian and Taylor [3] have documented that marked lymphocytic infiltration in the stroma is associated with a more favorable prognosis. Gusberg and his associates [I] have outlined a profile of virulence indices for cervical carcinoma. The indices which most often correlated with positive pelvic nodes are lymphocytic infiltration, stromal response, and histologic grade. Chen et al. [14] from the same institution have also reported tumor virulence of squamous cell carcinoma of the cervix as a function of ultrastructural morphology and lymphatic invasion. In breast cancer, Black et al. [lo] and Chabon and his group [15] have reported marked stromal reactions as an excellent immunologic host response in achieving cure. Studies of prognostic factors from regional lymph nodes are few except in breast [lO,ll] and cervical cancer [7]. The latter has shown a coupling of nodes with lymphocyte depletion and metastasis. Weigand et al. [l l] in studying 175 patients with breast carcinoma have concluded that local blood vessel invasion and axillary lymph node involvement are two discriminatory fctors related to early recurrence. Cottier et al. [12] have proposed a standardized system of reporting human lymph node morphology in relation to immunological function in the Bulletin of World Health Organization. We had utilized the system in our study and found it extremely useful. Ree and Fanger [ 161have observed paracortical alteration in tumor-draining lymph nodes, but we could not confirm this alteration in ovarian carcinoma. In present study, Grade III tumor, vascular invasion, lack of lymphocytic infiltration, and fibroblastic proliferation, as identified locally in the tumor and node with lymphocyte depletion, no sinus histiocytosis, and marked fibrosis, as in regional retroperitoneal lymph nodes, were the risk variables predicting nodal involvement and ultimate demise of patients. All patients with these unfavorable host factors might call for immunotherapy besides vigorous chemotherapy. Because of the small sample size of our study and the many risk variables analyzed, a larger study is needed to confirm our findings. We would make a strong plea that when reporting the survival for ovarian cancer, risk variables of this kind should be included in order to understand the nature and history of this deadly disease. REFERENCES 1. Gusberg, S. B., Yannopoulos, K., and Cohen, C. J. Virulence indices and lymph nodes in cancer of the cervix, Amer. J. Roent. Rad. Ther. Nucl. Med. 111, 273-277 (1971). 2. Barber, H. R. K., Sommers, S. C., Snyder, R., and Kwon, T. H. Histologic and nuclear grading and stromal reactions as indices for Amer. J. Obstet. Gynecol. 121, 795-807 (1975). 3. Asadourian, L. A., and Taylor, H. B. Dysgerminoma, Obstet. Gynecol. 33, 370-379 (1969). 4. Chen, S. S., and Lee, L. Incidence of para-aortic and pelvic lymph node metastases in epithelial carcinoma of the ovary, Gynecol. Oncol., 16, 95-100 (1983). 5. DiSaia, P. J., Haverbach, B. J., Dyce, B. J., and Morrow, C. P. Carcinoembryonic antigen in patients with gynecologic malignancies Amer. J. Obstet. Gynecol. 121, 159-163 (1975). 6. Wharton, J. T., and Herson, J. Surgery for common epithelial tumors of the ovary Cancer 48, 582-589 (1981).
INDICES FOR LYMPH NODE METASTASIS
93
7. Tsakraklides, V., Anastassiades, 0. T., and Kersey, J. H. Prognostic significance of regional lymph node histology in uterine cervical cancer, Cancer 31, 860-868 (1973). 8. Berman, M. L., Ballon, S. C., Lagasse, L. D., and Watring, W. G. Prognosis and treatment of endometrial cancer, Amer. J. Obstet. Gynecol. 136, 679-688 (1980). 9. Way, S. The anatomy of the lymphatic drainage of the vulva and its influence on the radical operation for carcinoma, Ann. R. Co/l Surg. Engl. 3, 187-209 (1948). 10. Black, M. M., Speer, F. D., and Opler, S. R. Structural representations of tumor-host relationships in mammary carcinoma. Biologic and prognostic significance, Amer. J. Clin. Pathol. 26, 250265 (1956). 11. Weigand, R. A., Isenberg, W. M., Russo, J., Brennen, M. J., Rich M. A., and the Breast Cancer Prognostic Study Associates. Blood vessel invasion and axillary lymph node involvement as prognostic indicators for human breast cancer, Cancer 50, 962-969 (1982). 12. Cottier, H., Turk, J., and Sobin, L. A proposal for a standardized system of reporting human lymph node morphology in relation to immunological function, Bull. W.H.O. 47, 375-408 (1972). 13. American Cancer Society. Cancer statistics, Cu. 32, 15-41 (1982). 14. Chen, S. S., Spiegelman, I., and Cohen, C. J. Tumor virulence as a function of ultrastructural morphology and lymphatic invasion in patients with squamous cell carcinoma of the cervix uteri, Gynecol. Oncol. 4, 194-203 (1976). 15. Chabon, A. B., Takeuchi, S., and Sommers, S. C. Histologic difference in breast carcinoma of Japanese and American women, Cancer 33, 1577-1579 (1974). 16. Ree, H., and Fanger, H. Paracortical alteration in lymphadenopathic and tumor-draining lymph nodes: Histologic study, Hum. Pathol. 6, 363-372 (1975).
ONCOLOGY
18,
87-93 (1984)
Prognostic Significance of Morphology of Tumor and Retroperitoneal Lymph Nodes in Epithelial Carcinoma of the Ovary I. Correlation with Lymph Node Metastasis SIDNEY
S. CHEN, M.D., FACOG,* AND LOUISE LEE, M.D., FCAPt
Departments of *Obstetrics and Gynecology and tpathology, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York 11042 and School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794
Received January 25, 1983 The prognostic indices based on a morphologic study of tumor and retroperitoneal lymph nodes in 63 patients with epithelial carcinoma of the ovary are reported. The purpose of the study was to identify those variables most frequently related to nodal involvement. The cases in the series consisted of 11 Stage I, 10 Stage II, 34 Stage III, and 8 Stage IV. Histologic distribution was 60.4% serous type, 11.1% mutinous, 6.3% endometrioid, 6.3% clear cell, and 15.9% unclassified. All patients had maximal surgery and selective biopsy of para-aortic and pelvic lymph nodes. The results showed statistically significant variables associated with nodal metastasis in both primary tumor and regional lymph nodes. The indices in primary tumor were grade of tumor, vascular invasion, lymphocytic infiltration, and stromal fibrosis; those in lymph node were type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. The nodes with lymphocyte depletion were associated with nodal spread in 81.3% of cases. It is concluded that morphologic study of tumor and lymph node could identify prognostic factors predicting regional nodal metastasis in ovarian carcinoma.
INTRODUCTION Because of the dismal outlook for patients affected by ovarian cancer, investigators have attempted to elucidate important risk factors most frequently associated with prognosis [l-6]. These risk factors, such as stage of disease, regional nodal metastasis, stromal cellular reaction in tumor, titer of carcinoembryonic antigen (5), amount of residual tumor (6), response to chemotherapy, and status of second-look laparotomy, have been related closely to tumor recurrence. In carcinoma of the cervix [ 1,7], endometrium [8], vulva [9], and breast [ 10,111,studies have been conducted to establish regional lymph node metastasis as the critical determinant of their survival. Even though a staging laparotomy is required for treatment of all ovarian cancer, information regarding these risk factors associated with frequent retroperitoneal lymph node metastasis is still lacking [4]. In the present study, risk factors associated with nodal metastasis were identified by pathologic examinations of morphology of tumor and retroperitoneal lymph nodes in a group of patients with newly diagnosed ovarian carcinoma. We found positive correlation between selected factors and nodal spread. 87
0090-8258/84 $1.50 Copyright 0 1984 by Academic Press, Inc. All rights of reproduction in any form reserved.
88
CHEN
AND
LEE
MATERIALS AND METHODS
From January 1975 through December 1981, 140 patients with newly diagnosed epithelial carcinoma of the ovary had their initial surgery performed at the Long Island Jewish-Hillside Medical Center, New Hyde Park, New York. Among these patients, 65 underwent maximal surgery, consisting of bilateral salpingo-oophorectomy, omentectomy, total abdominal hysterectomy, appendectomy, and a selective biopsy of para-aortic and pelvic lymph nodes. Additional cytoreductive procedures were also carried out in all advanced stagesas indicated. The technique of the selective nodal biopsy was described previously [4]. Morphology of both tumor and retroperitoneal nodes was examined to identify any risk factor correlated with lymphatic spread to regional nodes, primarily para-aortic and pelvic. The risk factors assessed from the tumor were grade of tumor, histologic type, lymphocytic infiltration in the stroma, vascular invasion, and stromal fibrosis. The variables analyzed in retroperitoneal lymph nodes were presence of cancer involvement, type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. The criteria of morphologic assessments are the following. For tumor.
1. Grades I, II, and III according to FIG0 classification. 2. Vascular invasion, presence of cancer cells in either lymphatic or venous space. 3. Lymphocytic infiltration, 2-t or 3 + , was considered positive. 4. Stromal fibrosis, marked fibroblastic proliferation in the stroma of the tumor (3+) was positive. For retroperitoneal
lymph nodes.
1. Type of lymph node reaction, lymphocyte predominance, germinal center predominance, lymphocyte depletion, and unstimulated, as described by Tsakraklides et al. [7]. 2. Sinus histiocytosis, marked histiocytosis (3+) was positive. 3. Nodal fibrosis, 2 + or 3 + , was grouped as positive. Special emphasis was given to correlation of these risk factors from tumor as well as node and nodal metastasis. Two cases were excluded from the series since the removed lymph nodes were completely replaced by tumor, precluding adequate morphologic assessment. The clinical stages of this series of 63 were as follows: 11 (17.5%) Stage I, 10 (15.9%) Stage II, 34 (53.9%) Stage III, and 8 (12.7%) Stage IV. Histologic distributions were 38 (60.4%) serous type, 7 (11.1%) mutinous, 4 (6.3%) endometrioid, 4 (6.3%) clear cell, and 10 (15.9%) unclassified. Grades of tumor of this group were 12 (19.0%) Grade I, 10 (15.9%) Grade II, and 41 (65.1%) Grade III. All specimens were processed in routine pathology laboratory tests, reviewed by a gynecologic pathologist (C.Y.L.), and surgery was executed by the same gynecologic oncologist (S.S.C.).
INDICES FOR LYMPH
89
NODE METASTASIS
RESULTS Significant prognostic variables, which were linked to regional lymph node dissemination, have been identified in both tumor and retroperitoneal lymph nodes based upon morphologic study. The risk factors in the primary tumor which correlated with nodal metastasis were grade of tumor, vascular invasion (either lymphatic or venous), lymphocytic infiltration in the stroma, and stromal fibrosis. As seen in Table 1, a progressive increment of involvement of abdominal lymph nodes with increasing tumor dedifferentiation was demostrated, from 16.7% in Grade I to 61.0% in Grade III. The statistical difference of nodal spread between differentiated ovarian tumors (Grades I and II) and undifferentiated Grade III was significant (P < 0.005). Identification of malignant cells in either lymphatic or venous spaces was most frequently associated with positive nodes (Table 2, P < 0.025). A strong lymphocytic penetration around cancer cells, which is a defense immunologic response by the host, was less frequently connected with metastatic node (Table 3, P < 0.005). TABLE 1 THE GRADE OF TUMOR AND RETROPERITONEAL
Grade
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
16.7% (2) 30.0% (3) 61.0% (25) 30
83.3% (10) 70.0% (7) 39.0% (16) 33
12 10 41 63
I
II III Total
Note. P < 0.005 between Grade l-3 tumors. TABLE 2 VASCULAR
INVASION
Vascular invasion
IN TUMOR AND RETROPERITONEAL
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
70.0% (14) 37.2% (16) 30
30.0% (6) 62.8% (27) 33
20 43 63
Positive Negative Total Note.
LYMPH
P < 0.025.
TABLE 3 LYMPH~CYTK
Lymphocytic
reaction
Positive Negative Total Note.
P < 0.005.
REACTION
IN TUMOR AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
7.7% (1) 58.0% (29) 30
92.3% (12) 42.0% (21) 33
13 50 63
90
CHEN
AND
LEE
Another risk variable indicating a favorable host response was a marked fibroblastic proliferation in the stroma, as seen in Table 4 (P < 0.005). In a comparison of two groups of patients, as seen in Table 5, one group with Grade I and II tumors, negative vascular invasion, strong lymphocytic reaction and appreciable stromal fibrosis, and another group with Grade III tumor, positive vascular invasion, absence of lymphocytic reaction, and fibroblastic proliferation, the former group, possessing excellent host factors, showed infrequent nodal involvement. The incidences of this involvement in the two groups were 0.0 and 84.6%, respectively (P < 0.005). On the other hand, risk variables in the regional lymph nodes which associated closely with nodal metastasis were type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. Both involved and uninvolved retroperitoneal nodes were systematically examined as proposed by the WHO [12]. Their morphologic changes were quite consistent in both metastatic and nonmetastatic ones. A type of nodal reaction with lymphocyte depletion was linked to metastasis in 81.3% of cases (Table 6), while nodes with lymphocyte predominance and germinal center predominance had only metastatic rates of 37.5 and 27.3%, respectively. The unstimulated node had an intermediate incidence of 41.7%. The statistical difference between lymphocyte depletion and nodes with abundant lymphocytes, as in lymphocyte predominance and germinal center predominance, was significant (P < 0.005). Another manifestation of poor immunocompetence was a weak sinus histiocytosis, which had a nodal involvement rate of 74.3% (Table 7, P < 0.005). TABLE 4 STROMAL
Stromal fibrosis
FIBROSIS IN TUMOR AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
17.9% (5) 71.4% (25) 30
82.1% (23) 28.6% (IO) 33
28 35 63
Positive Negative Total Note. P < 0.005.
TABLE 5 LOCAL
VARIABLES
IN TUMOR AND RETROPERITONEAL
Local variable Grade 1 and 2 tumors, stromal fibrosis, no vascular invasion, lymphocytic reaction Grade 3 tumor, vascular invasion, no stromal fibrosis, and no lymphocytic reaction Total Note. P < 0.005.
LYMPH NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
0.0% (0)
100.0% (7)
7
84.6% (11) 11
15.4% (2) 9
13 20
Total
INDICES FOR LYMPH
91
NODE METASTASIS
TABLE 6 THE TYPE OF LYMPH
NODE REACTION
Type Lymphocyte predominance Germinal center predominance Lymphocyte depletion Unstimulated Total
AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
37.5% 27.3% 81.3% 41.7%
62.5% 72.7% 18.7% 58.2%
(9) (3) (13) (5) 30
(15) (8) (3) (7) 33
Total 24 11 16 12 63
Note. P < 0.005 between lymphocyte and germinal center predominances and lymphocyte depletion group. TABLE 7 SINUS HISTVXYTOSIS
Sinus histiocytosis
IN LYMPH
NODE AND RETROPERITONEAL
NODAL
METASTASIS
Positive lymph node metastasis
Negative lymph node metastasis
Total
14.3% (4) 74.3% (26) 30
85.7% (24) 25.7% (9) 33
28 35 63
Marked Weak Total Note. P < 0.005.
TABLE 8 FIBROSIS IN LYMPH
NODE AND RETROPERITONEAL
LYMPH
NODE METASTASIS
Fibrosis
Positive lymph node metastasis
Negative lymph node metastasis
Total
Positive Negative Total
92.3% (12) 36.0% (18) 30
7.7% (1) 64.0% (32) 33
13 50 63
Note.
P < 0.005.
As expected, a replacement of normal lymphoid tissues by fibrous elements in the regional nodes gave frequent nodal metastasis of 92.3% (Table 8, P < 0.005). COMMENTS
Frustrations in the management of ovarian cancer are our failure in early detection by any screening method and the grim outlook for patients receiving aggressive postoperative chemotherapy [131. Since a screening technique for this malignancy is far from a reality, identification of risk variables associated with regional intra-abdominal node metastasis might shed some light on the virulence of tumor and more objectively predict individual outcome. Barber and his colleagues
92
CHEN AND LEE
[2], in defining local tumor risk factors, including histologic type and grade and nuclear grade, have reported a positive correlation with 2-year survival. They also added stromal reactions of lymphocytes, plasma cells, and polymorphonuclear leukocytes as the risk factors and found less distinct relationships. In ovarian dysgerminomas, Asadourian and Taylor [3] have documented that marked lymphocytic infiltration in the stroma is associated with a more favorable prognosis. Gusberg and his associates [I] have outlined a profile of virulence indices for cervical carcinoma. The indices which most often correlated with positive pelvic nodes are lymphocytic infiltration, stromal response, and histologic grade. Chen et al. [14] from the same institution have also reported tumor virulence of squamous cell carcinoma of the cervix as a function of ultrastructural morphology and lymphatic invasion. In breast cancer, Black et al. [lo] and Chabon and his group [15] have reported marked stromal reactions as an excellent immunologic host response in achieving cure. Studies of prognostic factors from regional lymph nodes are few except in breast [lO,ll] and cervical cancer [7]. The latter has shown a coupling of nodes with lymphocyte depletion and metastasis. Weigand et al. [l l] in studying 175 patients with breast carcinoma have concluded that local blood vessel invasion and axillary lymph node involvement are two discriminatory fctors related to early recurrence. Cottier et al. [12] have proposed a standardized system of reporting human lymph node morphology in relation to immunological function in the Bulletin of World Health Organization. We had utilized the system in our study and found it extremely useful. Ree and Fanger [ 161have observed paracortical alteration in tumor-draining lymph nodes, but we could not confirm this alteration in ovarian carcinoma. In present study, Grade III tumor, vascular invasion, lack of lymphocytic infiltration, and fibroblastic proliferation, as identified locally in the tumor and node with lymphocyte depletion, no sinus histiocytosis, and marked fibrosis, as in regional retroperitoneal lymph nodes, were the risk variables predicting nodal involvement and ultimate demise of patients. All patients with these unfavorable host factors might call for immunotherapy besides vigorous chemotherapy. Because of the small sample size of our study and the many risk variables analyzed, a larger study is needed to confirm our findings. We would make a strong plea that when reporting the survival for ovarian cancer, risk variables of this kind should be included in order to understand the nature and history of this deadly disease. REFERENCES 1. Gusberg, S. B., Yannopoulos, K., and Cohen, C. J. Virulence indices and lymph nodes in cancer of the cervix, Amer. J. Roent. Rad. Ther. Nucl. Med. 111, 273-277 (1971). 2. Barber, H. R. K., Sommers, S. C., Snyder, R., and Kwon, T. H. Histologic and nuclear grading and stromal reactions as indices for Amer. J. Obstet. Gynecol. 121, 795-807 (1975). 3. Asadourian, L. A., and Taylor, H. B. Dysgerminoma, Obstet. Gynecol. 33, 370-379 (1969). 4. Chen, S. S., and Lee, L. Incidence of para-aortic and pelvic lymph node metastases in epithelial carcinoma of the ovary, Gynecol. Oncol., 16, 95-100 (1983). 5. DiSaia, P. J., Haverbach, B. J., Dyce, B. J., and Morrow, C. P. Carcinoembryonic antigen in patients with gynecologic malignancies Amer. J. Obstet. Gynecol. 121, 159-163 (1975). 6. Wharton, J. T., and Herson, J. Surgery for common epithelial tumors of the ovary Cancer 48, 582-589 (1981).
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7. Tsakraklides, V., Anastassiades, 0. T., and Kersey, J. H. Prognostic significance of regional lymph node histology in uterine cervical cancer, Cancer 31, 860-868 (1973). 8. Berman, M. L., Ballon, S. C., Lagasse, L. D., and Watring, W. G. Prognosis and treatment of endometrial cancer, Amer. J. Obstet. Gynecol. 136, 679-688 (1980). 9. Way, S. The anatomy of the lymphatic drainage of the vulva and its influence on the radical operation for carcinoma, Ann. R. Co/l Surg. Engl. 3, 187-209 (1948). 10. Black, M. M., Speer, F. D., and Opler, S. R. Structural representations of tumor-host relationships in mammary carcinoma. Biologic and prognostic significance, Amer. J. Clin. Pathol. 26, 250265 (1956). 11. Weigand, R. A., Isenberg, W. M., Russo, J., Brennen, M. J., Rich M. A., and the Breast Cancer Prognostic Study Associates. Blood vessel invasion and axillary lymph node involvement as prognostic indicators for human breast cancer, Cancer 50, 962-969 (1982). 12. Cottier, H., Turk, J., and Sobin, L. A proposal for a standardized system of reporting human lymph node morphology in relation to immunological function, Bull. W.H.O. 47, 375-408 (1972). 13. American Cancer Society. Cancer statistics, Cu. 32, 15-41 (1982). 14. Chen, S. S., Spiegelman, I., and Cohen, C. J. Tumor virulence as a function of ultrastructural morphology and lymphatic invasion in patients with squamous cell carcinoma of the cervix uteri, Gynecol. Oncol. 4, 194-203 (1976). 15. Chabon, A. B., Takeuchi, S., and Sommers, S. C. Histologic difference in breast carcinoma of Japanese and American women, Cancer 33, 1577-1579 (1974). 16. Ree, H., and Fanger, H. Paracortical alteration in lymphadenopathic and tumor-draining lymph nodes: Histologic study, Hum. Pathol. 6, 363-372 (1975).