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Histologic grade and lymph node metastasis in squamous cell carcinoma of the cervix
GYNECOLOGIC
ONCOLOGY
12, 348-354 (1981)
Histologic Grade and Lymph Node Metastasis in Squamous Cell Carcinoma of the Cervix C. K. CHUNG, M.D. ,* WILLIAM A. NAHHAS, M.D. ,t RICHARD ZAINO, M.D.* JOHN A. STRYKER, M.D.,* AND RODRIGUE MORTEL, M.D.t *Division of Radiation Oncology, Department of Radiology, tDivision of Gynecologic Oncology, Department of Obstetrics & Gynecology, and *Department of Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033
Accepted June 6, 1981
One hundred fifty-nine patients with squamous cell carcinoma of the cervix who underwent laparotomy were evaluated with regard to histologic grade, clinical stage, and surgical stage. Pelvic and/or paraaortic node metastases were also studied. Patients with poorly differentiated tumors, regardless of clinical stage, demonstrated pelvic and/or paraaortic nodal metastases more frequently than patients with better differentiated tumors. In patients with poorly differentiated tumors, staging discrepancies were more common. These findings suggest that histologic grading should be taken into consideration in the treatment planning of patients with cervical carcinoma.
INTRODUCTION Squamous cell carcinomas have historically been subclassified according to their degree of histopathologic differentiation in an effort to estimate their capacity for malignant behavior. The relationship between histologic grading of cervical cancer and survival has been the subject of numerous publications [l-7]. However, the correlation between histologic grade and lymph node metastases has not been extensively reviewed. The purpose of this dicussion is to present our experience with surgical staging in patients with cervical cancer in an attempt to determine the difference between clinical and surgical staging, the incidence of pelvic and extrapelvic nodal metastases, and the significance of the histologic grade of the primary tumor. MATERIALS AND METHODS From September 1972 to June 1980 a total of 159 patients with invasive squamous cell carcinoma of the cervix, Stages IB through IV*, underwent pretreatment laparotomy at the Milton S. Hershey Medical Center of the Pennsylvania State University. Prior to surgery the clinical stage (FIGO) was determined utilizing examination under anesthesia, chest X ray, IVP, barium enema, cystoscopy, and 348 0090-8258/8l/060348-07$01.00/O Copyright All rights
8 1981 by Academic Press, Inc. of reproduction in any form reserved.
SQUAMOUS CELL CARCINOMA OF THE CERVIX
349
proctosigmoidoscopy. Surgical exploration was subsequently performed either in conjunction with radical hysterectomy and bilateral pelvic lymphadenectomy in patients with Stages IB and II* or as a separate procedure in patients with Stages II, through IV,. In all patients, the abdominal and pelvic organs were examined. In addition, paraaortic nodes were sampled and grossly enlarged nodes were biopsied. For the purpose of this study patients who had microscopic nodal disease found on the radical hysterectomy and lymphadenectomy specimen were included in surgical Stage IIB, whereas patients who had gross pelvic nodal involvement were grouped under surgical Stage III,. Primary tumors were graded and divided into three groups: well, moderately, or poorly differentiated. Well-differentiated tumors (Grade 1) were composed of cells having abundant keratin manifested by epithelial pearls, sparse mitotic activity, relatively little nuclear pleomorphism, and abundant cytoplasm (Fig. 1). In moderately differentiated tumors (Grade 2), keratinization was less conspicuous and mitotic activity and cellular pleomorphism were more evident (Fig. 2). Poorly differentiated tumors (Grade 3) were composed of cells lacking epithelial pearls and showing numerous mitoses with relatively little cytoplasm; keratinization was inconspicuous (Fig. 3). Grading of the tumors was done by a surgical pathologist. Biopsies were examined in their entirety while at least three sections of grossly visible tumor from the surgical specimen were examined. The entire cervix was sectioned if
FIG. 1. Well-differentiated squamous carcinoma-Nests plasm. There are multiple keratin pearls ( x 575).
of malignant cells have abundant cyto-
350
CHUNG
ET AL.
FIG. 2. Moderately differentiated squamous carcinoma-The cells are arranged in nests separated by fibrovascular stroma. There are moderate quantities of cytoplasm; no keratin pearls are present ( x 575).
FIG. 3. Poorly differentiated squamous carcinoma-Cells cytoplasm; mitoses are numerous ( x 575).
with hyperchromatic nuclei and scant
SQUAMOUS
CELL
CARCINOMA
OF THE
351
CERVIX
no tumor was grossly identified. Grading was done without reference to or knowledge of clinical and surgical stage or of lymph node metastases. RESULTS
Surgical staging showed that no patients had disease less extensive than was detected clinically (Table 1). In 34 patients (21%), either the local tumor was more advanced than predicted clinically or there were metastases involving the pelvic or paraaortic lymph nodes. The influence of histologic grade on staging accuracy is shown in Tables 2 and 3. Of the 159 patients in this series, 27 (22%) had Grade 3 tumors. These patients had more staging discrepancies than those with Grade 1 or 2 tumors (63% vs 14%). Twelve of the seventeen patients (71%) with surgical Stage IV, had Grade 3 tumors. Of 159 patients, 32 had lymph node metastases: 15 pelvic only, 14 pelvic and paraaortic, and 3 paraaortic only (Table 4). The incidence of lymph node me-
TABLE 1 CLINICAL
STAGE BY SURGICAL STAGE
Surgical stage Clinical stage
1,
III,
III,
IV,
IV,
Total
11, IL III, III, IV*
91 0 0 0 0 0
0 11 0 0 0 0
3 0 14 0 0 0
0 0 0 0 0 0
11 3 0 0 8 0
0 0 0 0 0 1
5 1 3 1 5 2
110 15 17 1 13 3
Total
91
11
17
0
22
1
17
159
TABLE 2 RESULTS OF SURGICAL
STAGE BY CLINICAL
STAGE AND HISTOLOGIC GRADE
Results of surgical stage Clinical stage
No. patients with more advanced stage No. patients with less advanced stage
~
1, 11, B III,
B
IV, Total
0
” Percentage is given in parentheses.
Grades 1 and 2
Grade 3
14/% (15)” 2/12 (17) l/l4 (7) 010 (0) 219 (22) O/l (0)
7114 (50) 213 (67) 213 (67) l/l (100) 314 (75) 212 (100)
191132(14)
17127 (63)
352
CHUNG
ET AL.
TABLE CLINICAL
VERSUS SURGICAL
3
STAGE: FUNCTION
OF HISTOLOGIC
GRADE
Histologic grade Patient distribution Clinical stage 1, 11, 11, III, III, IV.4
Total Surgical stage 1, 11, II, III, III, IV* IV,
Total
No.
G-l
G-2
G-3
110 15 17 1 13 3 159
25 3 3 0 2 0 33
71 9 11 0 7 1 99
14 3 3 1 4 2 27
91 11 17 0 22 1 17 159
19 3 5 0 4 0 2 33
65 7 11 0 12 1 3 99
7 1 1 0 6 0 12 27
tastasis was higher in patients with Grade 3 tumors compared to those with Grade 1 or 2. Three out of twelve patients (25%) with Grade 1 or 2 tumors and pelvic node metastases also had additional paraaortic nodal involvement, whereas 11 out of 17 (65%) patients with Grade 3 tumors and positive pelvic nodes also had paraaortic nodal involvement (Table 4). The incidence of pelvic and paraaortic node metastasis by histologic grade and clinical stage is listed in Table TABLE DISTRIBUTION
4
OF NODAL
METASTASIS
Nodal metastases Clinical stage
Histologic grade G-l G-3 G-l G-3 G-l G-3 G-l G-3
and 2 and 2 and 2 and 2
G-l and 2 G-3 Total
No. patients
Pelvic only
Pelvic and paraaortic
Paraaortic only
96 14 26 6 9 5 1 2
Total 9 (9) 7 (50)
2
(8)
4 3 5 0 2
(67) (33) (100) (0) (100)
132 27
9 6
3 11
2 1
14 (11) 18 (67)
159
15
14
3
32 (20)
’ Percentage is given in parentheses.
SQUAMOUS
CELL
CARCINOMA
OF THE
CERVIX
353
TABLE 5 INCIDENCE
OF PELVK
AND PARAAORTIC
NODE METAWASES
Paraaortic node metastases
Pelvic node metastases Clinical stage
1,
Total
Grades 1
and 2
Grade 3
Grades 1 and 2
Grade 3
2196 (2)
3/14 (21)
O/l
(0)
212 (100)
5/132 (4)
12/27 (44)
8/96
(8)
604
O/l
(0)
212 (loo)
12/132 (9)
(43)
17/27 (63)
’ Percentage is given in parentheses.
5. Regardless of clinical stage, patients with Grade 3 tumors had a higher incidence of pelvic and paraaortic nodal spread. DISCUSSION This study demonstrates that clinical staging is often inaccurate in determining the true extent of disease in patients with cervical cancer. The finding of positive paraaortic nodes in 25% of patients supports this conclusion. This high incidence of paraaortic spread is of major concern because the site of metastasis is out of the conventional field of radiation therapy. In addition, patients with Grade 3 tumors had a significantly higher incidence of paraaortic node metastases as compared to those with well- or moderately differentiated tumors. Our study confirms Gusberg’s [8] and Abdulhayoglu’s [l] findings that an increased incidence of pelvic node metastasis is associated with poorly differentiated tumors. We are also in agreement with Sedlacek’s [9] report that in patients with Grade 3 tumors staging discrepancies were more common, and that regardless of clinical stage, paraaortic node metastases were more frequent in Grade 3 lesions than in Grade 1 or 2. Moreover, of patients with positive pelvic nodes, the chance of coexisting paraaortic nodal disease is significantly higher with Grade 3 tumors as compared to Grade 1 or 2. Based on these observations, histologic grade is an important adjunct to the clinical evaluation and treatment planning of patients with squamous cell carcinoma of the cervix. Consideration should be given to pretreatment laparotomy in patients with poorly differentiated tumors. REFERENCES 1. Abdulhayoglu, G., Rich, W. M., Reynolds, J., and DiSaia, P. J. Selective radiation therapy in Stage Is uterine cervical carcinoma following radical pelvic surgery, Gynecol. Oncol. 10, 84-92 (1980). 2. Beecham, J. B., Halvorsen, T., and Kolbenstuedt, A. Histologic classification, lymph node metastases and patient survival in Stage I, cervical carcinoma, Gynecol. Oncol. 6, 95-105 (1978). 3. Goeller, J. R. Carcinoma of the cervix: Clinicopathologic correlation of 196 cases, Amer. J. Clin. Parho/. 66, 775-785 (1976).
354
CHUNG ET AL.
4. Gunderson, L. L., Weems, W. S., Hebertson, R. M., ef al. Correlation of histopathology with clinical results following radiotherapy for carcinoma of the cervix, Amer. J. Roentgenol. Radium Ther. Nucl. Med. 120, 14-87 (1974). 5. Ng, A. B. P., and Atkin, N. B. Histologic cell types and DNA value in the prognosis of squamous cell carcinoma of uterine cervix, Erir. J. Cancer 28, 322-331 (1973). 6. Reagan, J. W., and Fu, Y. S. Histologic types and prognosis of cancer of the uterine cervix, ZnZ. .Z. Radial. Oncol. Biol. Phys. 5, 1015-1020 (1979). 7. Wentz, W. B., and Lewis, G. C., Jr. Correlation of histologic morphology and survival in cervical cancer following radiation therapy, Obster. Gynecol. 26, 228-232 (1965). 8. Gusberg, S. B., Yannopoulos, K., and Cohen, C. J. Virulence indices and lymph nodes in cancer of the cervix, Amer. .J. Roentgenol. Ther. Nucl. Med. 3, 213-277 (1971). 9. Sedlacek, T. V., Mangan, C. E., Giuntoli, R. L., et 01. Exploratory celiotomy for cervical carcinoma: The role of histologic grading, Gynecol. Oncol. 6, 138-144 (1978).
ONCOLOGY
12, 348-354 (1981)
Histologic Grade and Lymph Node Metastasis in Squamous Cell Carcinoma of the Cervix C. K. CHUNG, M.D. ,* WILLIAM A. NAHHAS, M.D. ,t RICHARD ZAINO, M.D.* JOHN A. STRYKER, M.D.,* AND RODRIGUE MORTEL, M.D.t *Division of Radiation Oncology, Department of Radiology, tDivision of Gynecologic Oncology, Department of Obstetrics & Gynecology, and *Department of Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033
Accepted June 6, 1981
One hundred fifty-nine patients with squamous cell carcinoma of the cervix who underwent laparotomy were evaluated with regard to histologic grade, clinical stage, and surgical stage. Pelvic and/or paraaortic node metastases were also studied. Patients with poorly differentiated tumors, regardless of clinical stage, demonstrated pelvic and/or paraaortic nodal metastases more frequently than patients with better differentiated tumors. In patients with poorly differentiated tumors, staging discrepancies were more common. These findings suggest that histologic grading should be taken into consideration in the treatment planning of patients with cervical carcinoma.
INTRODUCTION Squamous cell carcinomas have historically been subclassified according to their degree of histopathologic differentiation in an effort to estimate their capacity for malignant behavior. The relationship between histologic grading of cervical cancer and survival has been the subject of numerous publications [l-7]. However, the correlation between histologic grade and lymph node metastases has not been extensively reviewed. The purpose of this dicussion is to present our experience with surgical staging in patients with cervical cancer in an attempt to determine the difference between clinical and surgical staging, the incidence of pelvic and extrapelvic nodal metastases, and the significance of the histologic grade of the primary tumor. MATERIALS AND METHODS From September 1972 to June 1980 a total of 159 patients with invasive squamous cell carcinoma of the cervix, Stages IB through IV*, underwent pretreatment laparotomy at the Milton S. Hershey Medical Center of the Pennsylvania State University. Prior to surgery the clinical stage (FIGO) was determined utilizing examination under anesthesia, chest X ray, IVP, barium enema, cystoscopy, and 348 0090-8258/8l/060348-07$01.00/O Copyright All rights
8 1981 by Academic Press, Inc. of reproduction in any form reserved.
SQUAMOUS CELL CARCINOMA OF THE CERVIX
349
proctosigmoidoscopy. Surgical exploration was subsequently performed either in conjunction with radical hysterectomy and bilateral pelvic lymphadenectomy in patients with Stages IB and II* or as a separate procedure in patients with Stages II, through IV,. In all patients, the abdominal and pelvic organs were examined. In addition, paraaortic nodes were sampled and grossly enlarged nodes were biopsied. For the purpose of this study patients who had microscopic nodal disease found on the radical hysterectomy and lymphadenectomy specimen were included in surgical Stage IIB, whereas patients who had gross pelvic nodal involvement were grouped under surgical Stage III,. Primary tumors were graded and divided into three groups: well, moderately, or poorly differentiated. Well-differentiated tumors (Grade 1) were composed of cells having abundant keratin manifested by epithelial pearls, sparse mitotic activity, relatively little nuclear pleomorphism, and abundant cytoplasm (Fig. 1). In moderately differentiated tumors (Grade 2), keratinization was less conspicuous and mitotic activity and cellular pleomorphism were more evident (Fig. 2). Poorly differentiated tumors (Grade 3) were composed of cells lacking epithelial pearls and showing numerous mitoses with relatively little cytoplasm; keratinization was inconspicuous (Fig. 3). Grading of the tumors was done by a surgical pathologist. Biopsies were examined in their entirety while at least three sections of grossly visible tumor from the surgical specimen were examined. The entire cervix was sectioned if
FIG. 1. Well-differentiated squamous carcinoma-Nests plasm. There are multiple keratin pearls ( x 575).
of malignant cells have abundant cyto-
350
CHUNG
ET AL.
FIG. 2. Moderately differentiated squamous carcinoma-The cells are arranged in nests separated by fibrovascular stroma. There are moderate quantities of cytoplasm; no keratin pearls are present ( x 575).
FIG. 3. Poorly differentiated squamous carcinoma-Cells cytoplasm; mitoses are numerous ( x 575).
with hyperchromatic nuclei and scant
SQUAMOUS
CELL
CARCINOMA
OF THE
351
CERVIX
no tumor was grossly identified. Grading was done without reference to or knowledge of clinical and surgical stage or of lymph node metastases. RESULTS
Surgical staging showed that no patients had disease less extensive than was detected clinically (Table 1). In 34 patients (21%), either the local tumor was more advanced than predicted clinically or there were metastases involving the pelvic or paraaortic lymph nodes. The influence of histologic grade on staging accuracy is shown in Tables 2 and 3. Of the 159 patients in this series, 27 (22%) had Grade 3 tumors. These patients had more staging discrepancies than those with Grade 1 or 2 tumors (63% vs 14%). Twelve of the seventeen patients (71%) with surgical Stage IV, had Grade 3 tumors. Of 159 patients, 32 had lymph node metastases: 15 pelvic only, 14 pelvic and paraaortic, and 3 paraaortic only (Table 4). The incidence of lymph node me-
TABLE 1 CLINICAL
STAGE BY SURGICAL STAGE
Surgical stage Clinical stage
1,
III,
III,
IV,
IV,
Total
11, IL III, III, IV*
91 0 0 0 0 0
0 11 0 0 0 0
3 0 14 0 0 0
0 0 0 0 0 0
11 3 0 0 8 0
0 0 0 0 0 1
5 1 3 1 5 2
110 15 17 1 13 3
Total
91
11
17
0
22
1
17
159
TABLE 2 RESULTS OF SURGICAL
STAGE BY CLINICAL
STAGE AND HISTOLOGIC GRADE
Results of surgical stage Clinical stage
No. patients with more advanced stage No. patients with less advanced stage
~
1, 11, B III,
B
IV, Total
0
” Percentage is given in parentheses.
Grades 1 and 2
Grade 3
14/% (15)” 2/12 (17) l/l4 (7) 010 (0) 219 (22) O/l (0)
7114 (50) 213 (67) 213 (67) l/l (100) 314 (75) 212 (100)
191132(14)
17127 (63)
352
CHUNG
ET AL.
TABLE CLINICAL
VERSUS SURGICAL
3
STAGE: FUNCTION
OF HISTOLOGIC
GRADE
Histologic grade Patient distribution Clinical stage 1, 11, 11, III, III, IV.4
Total Surgical stage 1, 11, II, III, III, IV* IV,
Total
No.
G-l
G-2
G-3
110 15 17 1 13 3 159
25 3 3 0 2 0 33
71 9 11 0 7 1 99
14 3 3 1 4 2 27
91 11 17 0 22 1 17 159
19 3 5 0 4 0 2 33
65 7 11 0 12 1 3 99
7 1 1 0 6 0 12 27
tastasis was higher in patients with Grade 3 tumors compared to those with Grade 1 or 2. Three out of twelve patients (25%) with Grade 1 or 2 tumors and pelvic node metastases also had additional paraaortic nodal involvement, whereas 11 out of 17 (65%) patients with Grade 3 tumors and positive pelvic nodes also had paraaortic nodal involvement (Table 4). The incidence of pelvic and paraaortic node metastasis by histologic grade and clinical stage is listed in Table TABLE DISTRIBUTION
4
OF NODAL
METASTASIS
Nodal metastases Clinical stage
Histologic grade G-l G-3 G-l G-3 G-l G-3 G-l G-3
and 2 and 2 and 2 and 2
G-l and 2 G-3 Total
No. patients
Pelvic only
Pelvic and paraaortic
Paraaortic only
96 14 26 6 9 5 1 2
Total 9 (9) 7 (50)
2
(8)
4 3 5 0 2
(67) (33) (100) (0) (100)
132 27
9 6
3 11
2 1
14 (11) 18 (67)
159
15
14
3
32 (20)
’ Percentage is given in parentheses.
SQUAMOUS
CELL
CARCINOMA
OF THE
CERVIX
353
TABLE 5 INCIDENCE
OF PELVK
AND PARAAORTIC
NODE METAWASES
Paraaortic node metastases
Pelvic node metastases Clinical stage
1,
Total
Grades 1
and 2
Grade 3
Grades 1 and 2
Grade 3
2196 (2)
3/14 (21)
O/l
(0)
212 (100)
5/132 (4)
12/27 (44)
8/96
(8)
604
O/l
(0)
212 (loo)
12/132 (9)
(43)
17/27 (63)
’ Percentage is given in parentheses.
5. Regardless of clinical stage, patients with Grade 3 tumors had a higher incidence of pelvic and paraaortic nodal spread. DISCUSSION This study demonstrates that clinical staging is often inaccurate in determining the true extent of disease in patients with cervical cancer. The finding of positive paraaortic nodes in 25% of patients supports this conclusion. This high incidence of paraaortic spread is of major concern because the site of metastasis is out of the conventional field of radiation therapy. In addition, patients with Grade 3 tumors had a significantly higher incidence of paraaortic node metastases as compared to those with well- or moderately differentiated tumors. Our study confirms Gusberg’s [8] and Abdulhayoglu’s [l] findings that an increased incidence of pelvic node metastasis is associated with poorly differentiated tumors. We are also in agreement with Sedlacek’s [9] report that in patients with Grade 3 tumors staging discrepancies were more common, and that regardless of clinical stage, paraaortic node metastases were more frequent in Grade 3 lesions than in Grade 1 or 2. Moreover, of patients with positive pelvic nodes, the chance of coexisting paraaortic nodal disease is significantly higher with Grade 3 tumors as compared to Grade 1 or 2. Based on these observations, histologic grade is an important adjunct to the clinical evaluation and treatment planning of patients with squamous cell carcinoma of the cervix. Consideration should be given to pretreatment laparotomy in patients with poorly differentiated tumors. REFERENCES 1. Abdulhayoglu, G., Rich, W. M., Reynolds, J., and DiSaia, P. J. Selective radiation therapy in Stage Is uterine cervical carcinoma following radical pelvic surgery, Gynecol. Oncol. 10, 84-92 (1980). 2. Beecham, J. B., Halvorsen, T., and Kolbenstuedt, A. Histologic classification, lymph node metastases and patient survival in Stage I, cervical carcinoma, Gynecol. Oncol. 6, 95-105 (1978). 3. Goeller, J. R. Carcinoma of the cervix: Clinicopathologic correlation of 196 cases, Amer. J. Clin. Parho/. 66, 775-785 (1976).
354
CHUNG ET AL.
4. Gunderson, L. L., Weems, W. S., Hebertson, R. M., ef al. Correlation of histopathology with clinical results following radiotherapy for carcinoma of the cervix, Amer. J. Roentgenol. Radium Ther. Nucl. Med. 120, 14-87 (1974). 5. Ng, A. B. P., and Atkin, N. B. Histologic cell types and DNA value in the prognosis of squamous cell carcinoma of uterine cervix, Erir. J. Cancer 28, 322-331 (1973). 6. Reagan, J. W., and Fu, Y. S. Histologic types and prognosis of cancer of the uterine cervix, ZnZ. .Z. Radial. Oncol. Biol. Phys. 5, 1015-1020 (1979). 7. Wentz, W. B., and Lewis, G. C., Jr. Correlation of histologic morphology and survival in cervical cancer following radiation therapy, Obster. Gynecol. 26, 228-232 (1965). 8. Gusberg, S. B., Yannopoulos, K., and Cohen, C. J. Virulence indices and lymph nodes in cancer of the cervix, Amer. .J. Roentgenol. Ther. Nucl. Med. 3, 213-277 (1971). 9. Sedlacek, T. V., Mangan, C. E., Giuntoli, R. L., et 01. Exploratory celiotomy for cervical carcinoma: The role of histologic grading, Gynecol. Oncol. 6, 138-144 (1978).