GYNECOLOGIC
ONCOLOGY
47, 76-79 (1992)
Peritoneal Cytology in Patients with Uterine Cervical Carcinoma Kozo ITO, M.D. ,l AND KIICHIRONODA, M.D. Department
of Obstetrics
and Gynecology,
Kinki
University
School
of Medicine,
377-2,
Ohno-Higashi,
Osaka-Sayama,
Osaka
589, Japan
Received April 2, 1991
We studied the relationship betweencytological diagnosisof peritoneal washingand pathohistologicalfindings in 97 casesof stageIb and 103 casesof stageIIa or b cervical carcinoma. No positivecytology wasfound in 24 casesclassifiedaspT1 by pTNM classification.Positive cytology was found in 8 out of 40 cases with retroperitoneallymph node metastasis,2 out of 5 caseswith uterine corpus infiltration, and 3 out of 4 caseswith ovarian metastasis.Negative cytology wasoften found even in caseswith metastasisto severalretroperitoneallymph nodes,while positive cytology wasalso found in caseswithout metastasis.The mechanism of cervical carcinoma metastasizingto retroperitoneal lymph nodesmay not be the sameas that of spreadinginto the abdominalcavity. Many caseswith positive peritoneal cytology tendedto recur with peritonealcarcinomaas comparedto those with negative cytology. The above findings indicate that chemotherapy, including intraperitonealadministration, is necessaryin addition to radiation therapy for patientswith cervical carcinoma with positive peritoneal washings. 0 1992 Academic press, tnc. INTRODUCTION
Peritoneal washing is used to stage disease and is helpful in predicting prognosis and deciding on therapeutic modalities in cases of ovarian and endometrial carcinomas. Because of its efficacy, it is included in the FIG0 staging scheme for these cancers. In cervical carcinoma, peritoneal washing is not included in staging, and its clinical significance is completely unclear even though experience with the technique has been reported since the early 1960s [l]. Since early 1982, peritoneal cytology has been performed on all patients with the diagnosis of invasive cancer of the cervix undergoing laparotomy at the Department of Obstetrics and Gynecology, Kinki University School of Medicine Hospital. In the present study, the relationship between peritoneal washing and patho’ To whom correspondence and reprint requests should be addressed at Department of Obstetrics and Gynecology, Kinki University School of Medicine. 76 0090-8258/92
$4.00
Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
histological findings and prognosis was studied. The usefulness of peritoneal washing in predicting prognosis and deciding the method of therapy was evaluated. MATERIALS
AND METHODS
From September 1982 to December 1989, a total of 200 patients (age 34-77 years) with cervical carcinoma were operated on at the Department of Obstetrics and Gynecology, Kinki University School of Medicine Hospital (Osaka, Japan). The diagnoses were confirmed postoperatively by pathologic examinations. All peritoneal cytology specimens were obtained at the time of surgery by aspiration of peritoneal fluid when present or by peritoneal washings. The latter was accomplished by the instillation of 20 ml of sterile saline into the pelvis and washing the uterus, fallopian tubes, and ovaries. The fluid was allowed to collect in the cul-de-sac, aspirated, and sent to the cytology laboratory. The peritoneal fluids were centrifuged at 1500 rpm for 15 min. The smear and filter preparations were fixed in 95% alcohol and stained with a modified Papanicolaou stain, and the cell block sections were stained with hematoxylin and eosin. In the cytological examination of peritoneal fluids, the following items were studied: identification of squamous cell, nuclear size, nucleus: cytoplasm ratio, and nucleus with abundant granular hyperchromasia. The criteria for diagnosis of positive cytology included the size, shape, color, and number of nuclei and nucleoli as well as their chromatin structure. The cytoplasm was evaluated for the amount, pattern, color, and phagocytosis. Emphasis was also placed on the arrangement of cellular aggregates as well as on observations regarding the noncellular background. The specimens were then classified as follows: Class I, no atypical cells; Class II, atypical cells present but probably benign; Class III, atypical cells present that were suspicious for malignancy but inconclusive; Class IV, atypical cells highly suggestive of malignancy; and Class V, conclusive
77
CYTOLOGY AND UTERINE CERVICAL CARCINOMA TABLE 1
TABLE 2
Relationship between Peritoneal Cytology and Stage Ib and IIa or b (II) Cervical Carcinoma
Relationship between Peritoneal Cytology and pTNM Stages Ha or b Cervical Carcinoma Cytology
Cytology Stage
Positive
Negative
Total
Ib II
0 10 (9.7%)
97 (100%) 93
97 103
Total
10 (5.0%)
190 (95.0%)
200
pTNM
Positive Tl T2 T3 T4
Note. P > 0.05.
0 9 (11.7%) 0 1
Total
10 (9.7%)
Negative
Total
24 (100%) 68 0 1
24 77 0 2
93 (90.3%)
103
Note. P > 0.05.
for malignancy. The relationship between cytological diagnosis and pathohistological findings and prognosis in 200 patients with uterine cervical carcinoma was studied. Significance in difference among the groups was tested using analysis of variance, the Newan-Kuels method, or x2 test. We used the method of Kaplan and Meier to evaluate the analysis of survival curve. RESULTS The number of patients is shown in Table 1. None of the 97 cases of Stage Ib cervical carcinoma had positive cytology, but 10 (9.7%) of the 103 cases of stage IIa or b cervical carcinoma had a positive diagnosis (Table 1). Peritoneal fluid present at the time of laparotomy was more likely to be positive than that from peritoneal washing. We studied the relationship between positive cytology and the extent of primary focus and metastasis to retroperitoneal lymph nodes and ovary in 103 patients of stage IIa or b treated with radical hysterectomy. Using the pTNM classification, positive cytology was not found in any of the 24 pT1 cases. However, positive results were found in 9 (11.7%) out of the 77 pT2 cases showing cancer infiltration into the parametrium. Positivity was seen in 1 pT4 case with infiltration (Table 2). As shown in Table 2, peritoneal cytology tended to be positive with spread
into the parametrium and bladder. The relationship between peritoneal cytology and the histological type of cervical carcinoma was investigated. Peritoneal cytology did not show any relationship to the histological type of cervical carcinoma (Table 3). Positive cytology was more frequently found in cases with retroperitoneal lymph node metastasis than in cases without metastasis (Table 4). Also studied was the relationship between peritoneal cytology and uterine corpus infiltration (Table 5) and with ovarian metastasis (Table 6). Prognosis evaluated by KaplanMeier’s method tended to be poorer in cases with positive cytology of the peritoneal washing than in those with negative results (Figs. 1 and 2). Four out of 10 cases with positive cytology showed recurrence. The recurrences were in the peritoneum in 4 of 4 cases with positive cytology, while 6 of the 93 cases with negative cytology showed recurrence, none involving the peritoneum. Among 6 cases with negative cytology, 2 had local recurrences and 4 had distant metastases (Table 7). From Table 6, positive peritoneal cytology is defined as an independent risk factor for recurrence of uterine cervical carcinoma. Cases with positive cytology showed a tendency to develop peritoneal metastases and treatment with intraperitoneal chemotherapy is advisable for patients with positive peritoneal cytology.
TABLE 3 HistologicalType and Peritoneal Cytology (Stage IIa or b Cervical Carcinoma) Cytology Positive
Type Keratinizing Nonkeratinizing large cell Nonkeratinizing small cell Adenocarcinoma Adenosquamous carcinoma Total
4 5 0 0 1
(18.2%) (8.3%) (0.0%) (0.0%) (11.1%)
Negative 9 (10.2%) 9 (10.2%) 9 (10.2%)
10
18 55 6 6 8
(81.8%) (91.7%) (100.0%) (100.0%) (88.9%)
Total 79 (89.8%) 79 (89.8%) 79 (89.8%)
88 6 9
93
103
78
IT0 AND NODA
TABLE 4 RelationshipbetweenPeritoneal Cytology and Lymphnode Metastasisin Stage IIa or b Cervical Carcinoma Cytology Node metastasis
Positive
Negative
Negative
7 (25%)* 1 (8.3%)* 2 (3.2%)*
21 11 61
28 12 63
Total
10
93
103
Positive
several one
Total positive
I
I
,
I
12
24
I
36
48
60
TABLE 5 RelationshipbetweenPeritoneal Cytology and Uterine Corpus Infiltration in StageIIa or b Cervical Carcinoma
FIG. 2. Survival in all patients by cytological findings. Relationship between cytology and prognosis was examined by the Kaplan-Meier method. (pT2Nl Cases) (P > 0.05)
Cytology
DISCUSSION
corpus infiltration
Positive
Negative
Positive Negative
2 (40.0%) 8 (8.1%)
3 90
5 98
Total
10
93
103
Total
Note. P < 0.05.
TABLE 6 RelationshipbetweenPeritoneal Cytology and Ovarian Metastasisin Stage IIa or b Cervical Carcinoma Cytology Ovarian metastasis
Positive
Negative
Positive Negative
3 (75%) 7 (7.1%)
1 92
4 99
Total
10
93
103
Total
Note. P < 0.01.
14L.-L--LJ,L-------I-l~,------~~,,---. negative
l-7
5 50 ! 1
I
70 (M)
Months
* P < 0.01.
(%I 100
cytology
I
positive
cytology
cytology
(n=37)
(n=Z)
1
In ovarian and endometrial carcinoma, peritoneal washing is an established factor for evaluation of prognosis and is a component in clinical staging by the International Federation of Obstetricians and Gynecologists (FIGO) [2]. However, it is rarely applied to cervical carcinoma. In the present paper, we describe the significance of cytology of peritoneal washing in cervical carcinoma. A few workers have reported on the cytology of peritoneal washing in cervical carcinoma. Creasman et al. found positive results in 7% of cases with cervical carcinoma [3]. Keetle et al. [4] reported a high positive rate of 20.3% in cases as stage Ib or more progressive stages. In the present study, the rate was zero in pT1 cases and 11.7% in pT2 cases. Negative cytology was frequently found even in cases with metastasis to several retroperitoneal lymph nodes. On the other hand, positive cytology was frequently found even in cases without metastasis to lymph nodes; the mechanism of metastasis to retroperitoneal lymph nodes may differ from that of spread into abdominal cavity in cervical carcinoma. Positive cytology of peritoneal fluids or washing is thought to result from spread to the abdominal cavity from the parametrium of TABLE 7 RelationshipbetweenPeritonealCytology and Recurrent 10 Casesin Stage IIa or b Cervical Carcinoma Cytology
01
12
24
36
48
60
70 (M)
Months
FIG. between method. than in
1. Survival in all patients by cytological findings. Relationship cytology and prognosis was examined by the Kaplan-Meier Prognosis tended to be poorer in cases with positive cytology those with negative cytology. (pT2NO Cases) (P > 0.05)
Recurrence site Peritonitis carcinomatosa Local recurrence Distant metastasis Total
Positive
Negative
4 0 0
0 2 4
4
6
CYTOLOGY
AND UTERINE
the uterine cervix. In this study, we could not find any evidence to support this speculation of spread to the abdominal cavity. We performed radiation therapy on cases of parametrium infiltration and retroperitoneal lymph node metastasis. On the other hand, we performed chemotherapy on cases with positive peritoneal washing. The prognosis of cervical carcinoma tended to be poorer in cases with positive cytology than in cases with negative cytology. Positive cytological cases showed frequent recurrence (peritonitis carcinomatosa). The above findings indicate that chemotherapy including intraperitoneal administration should be performed in addition to radiation therapy for cervical carcinoma with positive cytology of peritoneal washing.
CERVICAL
CARCINOMA
79
REFERENCES ‘. Creasman, W. T., and Rutledge, F. The prognostic value of peri-
toneal cytology in gynecologic malignant disease, Am. J. Obsrer. Gynecol. 110, 773-178 (1971).
2.
Proposals by Oncology Committee approved by Executive Board of FIG0 (1988).
3. Creasman, W. T., Disaia, P. J., Blessing, J., Wilkinson, R. H., Johnston, W., and Weed, J. C. Prognostic significance of peritoneal
ccytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals, Gynecol. 141, 921-927 (1981).
Am.
J. Obstet.
4. Keettle, W. C., Pixley, E. E., and Buchsbaum, H. J. Experience with peritoneal cytology in the management of gynecologic malignancies, Am. .I. Obstet. Gynecol. 120, 174-182 (1974).
ONCOLOGY
47, 76-79 (1992)
Peritoneal Cytology in Patients with Uterine Cervical Carcinoma Kozo ITO, M.D. ,l AND KIICHIRONODA, M.D. Department
of Obstetrics
and Gynecology,
Kinki
University
School
of Medicine,
377-2,
Ohno-Higashi,
Osaka-Sayama,
Osaka
589, Japan
Received April 2, 1991
We studied the relationship betweencytological diagnosisof peritoneal washingand pathohistologicalfindings in 97 casesof stageIb and 103 casesof stageIIa or b cervical carcinoma. No positivecytology wasfound in 24 casesclassifiedaspT1 by pTNM classification.Positive cytology was found in 8 out of 40 cases with retroperitoneallymph node metastasis,2 out of 5 caseswith uterine corpus infiltration, and 3 out of 4 caseswith ovarian metastasis.Negative cytology wasoften found even in caseswith metastasisto severalretroperitoneallymph nodes,while positive cytology wasalso found in caseswithout metastasis.The mechanism of cervical carcinoma metastasizingto retroperitoneal lymph nodesmay not be the sameas that of spreadinginto the abdominalcavity. Many caseswith positive peritoneal cytology tendedto recur with peritonealcarcinomaas comparedto those with negative cytology. The above findings indicate that chemotherapy, including intraperitonealadministration, is necessaryin addition to radiation therapy for patientswith cervical carcinoma with positive peritoneal washings. 0 1992 Academic press, tnc. INTRODUCTION
Peritoneal washing is used to stage disease and is helpful in predicting prognosis and deciding on therapeutic modalities in cases of ovarian and endometrial carcinomas. Because of its efficacy, it is included in the FIG0 staging scheme for these cancers. In cervical carcinoma, peritoneal washing is not included in staging, and its clinical significance is completely unclear even though experience with the technique has been reported since the early 1960s [l]. Since early 1982, peritoneal cytology has been performed on all patients with the diagnosis of invasive cancer of the cervix undergoing laparotomy at the Department of Obstetrics and Gynecology, Kinki University School of Medicine Hospital. In the present study, the relationship between peritoneal washing and patho’ To whom correspondence and reprint requests should be addressed at Department of Obstetrics and Gynecology, Kinki University School of Medicine. 76 0090-8258/92
$4.00
Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
histological findings and prognosis was studied. The usefulness of peritoneal washing in predicting prognosis and deciding the method of therapy was evaluated. MATERIALS
AND METHODS
From September 1982 to December 1989, a total of 200 patients (age 34-77 years) with cervical carcinoma were operated on at the Department of Obstetrics and Gynecology, Kinki University School of Medicine Hospital (Osaka, Japan). The diagnoses were confirmed postoperatively by pathologic examinations. All peritoneal cytology specimens were obtained at the time of surgery by aspiration of peritoneal fluid when present or by peritoneal washings. The latter was accomplished by the instillation of 20 ml of sterile saline into the pelvis and washing the uterus, fallopian tubes, and ovaries. The fluid was allowed to collect in the cul-de-sac, aspirated, and sent to the cytology laboratory. The peritoneal fluids were centrifuged at 1500 rpm for 15 min. The smear and filter preparations were fixed in 95% alcohol and stained with a modified Papanicolaou stain, and the cell block sections were stained with hematoxylin and eosin. In the cytological examination of peritoneal fluids, the following items were studied: identification of squamous cell, nuclear size, nucleus: cytoplasm ratio, and nucleus with abundant granular hyperchromasia. The criteria for diagnosis of positive cytology included the size, shape, color, and number of nuclei and nucleoli as well as their chromatin structure. The cytoplasm was evaluated for the amount, pattern, color, and phagocytosis. Emphasis was also placed on the arrangement of cellular aggregates as well as on observations regarding the noncellular background. The specimens were then classified as follows: Class I, no atypical cells; Class II, atypical cells present but probably benign; Class III, atypical cells present that were suspicious for malignancy but inconclusive; Class IV, atypical cells highly suggestive of malignancy; and Class V, conclusive
77
CYTOLOGY AND UTERINE CERVICAL CARCINOMA TABLE 1
TABLE 2
Relationship between Peritoneal Cytology and Stage Ib and IIa or b (II) Cervical Carcinoma
Relationship between Peritoneal Cytology and pTNM Stages Ha or b Cervical Carcinoma Cytology
Cytology Stage
Positive
Negative
Total
Ib II
0 10 (9.7%)
97 (100%) 93
97 103
Total
10 (5.0%)
190 (95.0%)
200
pTNM
Positive Tl T2 T3 T4
Note. P > 0.05.
0 9 (11.7%) 0 1
Total
10 (9.7%)
Negative
Total
24 (100%) 68 0 1
24 77 0 2
93 (90.3%)
103
Note. P > 0.05.
for malignancy. The relationship between cytological diagnosis and pathohistological findings and prognosis in 200 patients with uterine cervical carcinoma was studied. Significance in difference among the groups was tested using analysis of variance, the Newan-Kuels method, or x2 test. We used the method of Kaplan and Meier to evaluate the analysis of survival curve. RESULTS The number of patients is shown in Table 1. None of the 97 cases of Stage Ib cervical carcinoma had positive cytology, but 10 (9.7%) of the 103 cases of stage IIa or b cervical carcinoma had a positive diagnosis (Table 1). Peritoneal fluid present at the time of laparotomy was more likely to be positive than that from peritoneal washing. We studied the relationship between positive cytology and the extent of primary focus and metastasis to retroperitoneal lymph nodes and ovary in 103 patients of stage IIa or b treated with radical hysterectomy. Using the pTNM classification, positive cytology was not found in any of the 24 pT1 cases. However, positive results were found in 9 (11.7%) out of the 77 pT2 cases showing cancer infiltration into the parametrium. Positivity was seen in 1 pT4 case with infiltration (Table 2). As shown in Table 2, peritoneal cytology tended to be positive with spread
into the parametrium and bladder. The relationship between peritoneal cytology and the histological type of cervical carcinoma was investigated. Peritoneal cytology did not show any relationship to the histological type of cervical carcinoma (Table 3). Positive cytology was more frequently found in cases with retroperitoneal lymph node metastasis than in cases without metastasis (Table 4). Also studied was the relationship between peritoneal cytology and uterine corpus infiltration (Table 5) and with ovarian metastasis (Table 6). Prognosis evaluated by KaplanMeier’s method tended to be poorer in cases with positive cytology of the peritoneal washing than in those with negative results (Figs. 1 and 2). Four out of 10 cases with positive cytology showed recurrence. The recurrences were in the peritoneum in 4 of 4 cases with positive cytology, while 6 of the 93 cases with negative cytology showed recurrence, none involving the peritoneum. Among 6 cases with negative cytology, 2 had local recurrences and 4 had distant metastases (Table 7). From Table 6, positive peritoneal cytology is defined as an independent risk factor for recurrence of uterine cervical carcinoma. Cases with positive cytology showed a tendency to develop peritoneal metastases and treatment with intraperitoneal chemotherapy is advisable for patients with positive peritoneal cytology.
TABLE 3 HistologicalType and Peritoneal Cytology (Stage IIa or b Cervical Carcinoma) Cytology Positive
Type Keratinizing Nonkeratinizing large cell Nonkeratinizing small cell Adenocarcinoma Adenosquamous carcinoma Total
4 5 0 0 1
(18.2%) (8.3%) (0.0%) (0.0%) (11.1%)
Negative 9 (10.2%) 9 (10.2%) 9 (10.2%)
10
18 55 6 6 8
(81.8%) (91.7%) (100.0%) (100.0%) (88.9%)
Total 79 (89.8%) 79 (89.8%) 79 (89.8%)
88 6 9
93
103
78
IT0 AND NODA
TABLE 4 RelationshipbetweenPeritoneal Cytology and Lymphnode Metastasisin Stage IIa or b Cervical Carcinoma Cytology Node metastasis
Positive
Negative
Negative
7 (25%)* 1 (8.3%)* 2 (3.2%)*
21 11 61
28 12 63
Total
10
93
103
Positive
several one
Total positive
I
I
,
I
12
24
I
36
48
60
TABLE 5 RelationshipbetweenPeritoneal Cytology and Uterine Corpus Infiltration in StageIIa or b Cervical Carcinoma
FIG. 2. Survival in all patients by cytological findings. Relationship between cytology and prognosis was examined by the Kaplan-Meier method. (pT2Nl Cases) (P > 0.05)
Cytology
DISCUSSION
corpus infiltration
Positive
Negative
Positive Negative
2 (40.0%) 8 (8.1%)
3 90
5 98
Total
10
93
103
Total
Note. P < 0.05.
TABLE 6 RelationshipbetweenPeritoneal Cytology and Ovarian Metastasisin Stage IIa or b Cervical Carcinoma Cytology Ovarian metastasis
Positive
Negative
Positive Negative
3 (75%) 7 (7.1%)
1 92
4 99
Total
10
93
103
Total
Note. P < 0.01.
14L.-L--LJ,L-------I-l~,------~~,,---. negative
l-7
5 50 ! 1
I
70 (M)
Months
* P < 0.01.
(%I 100
cytology
I
positive
cytology
cytology
(n=37)
(n=Z)
1
In ovarian and endometrial carcinoma, peritoneal washing is an established factor for evaluation of prognosis and is a component in clinical staging by the International Federation of Obstetricians and Gynecologists (FIGO) [2]. However, it is rarely applied to cervical carcinoma. In the present paper, we describe the significance of cytology of peritoneal washing in cervical carcinoma. A few workers have reported on the cytology of peritoneal washing in cervical carcinoma. Creasman et al. found positive results in 7% of cases with cervical carcinoma [3]. Keetle et al. [4] reported a high positive rate of 20.3% in cases as stage Ib or more progressive stages. In the present study, the rate was zero in pT1 cases and 11.7% in pT2 cases. Negative cytology was frequently found even in cases with metastasis to several retroperitoneal lymph nodes. On the other hand, positive cytology was frequently found even in cases without metastasis to lymph nodes; the mechanism of metastasis to retroperitoneal lymph nodes may differ from that of spread into abdominal cavity in cervical carcinoma. Positive cytology of peritoneal fluids or washing is thought to result from spread to the abdominal cavity from the parametrium of TABLE 7 RelationshipbetweenPeritonealCytology and Recurrent 10 Casesin Stage IIa or b Cervical Carcinoma Cytology
01
12
24
36
48
60
70 (M)
Months
FIG. between method. than in
1. Survival in all patients by cytological findings. Relationship cytology and prognosis was examined by the Kaplan-Meier Prognosis tended to be poorer in cases with positive cytology those with negative cytology. (pT2NO Cases) (P > 0.05)
Recurrence site Peritonitis carcinomatosa Local recurrence Distant metastasis Total
Positive
Negative
4 0 0
0 2 4
4
6
CYTOLOGY
AND UTERINE
the uterine cervix. In this study, we could not find any evidence to support this speculation of spread to the abdominal cavity. We performed radiation therapy on cases of parametrium infiltration and retroperitoneal lymph node metastasis. On the other hand, we performed chemotherapy on cases with positive peritoneal washing. The prognosis of cervical carcinoma tended to be poorer in cases with positive cytology than in cases with negative cytology. Positive cytological cases showed frequent recurrence (peritonitis carcinomatosa). The above findings indicate that chemotherapy including intraperitoneal administration should be performed in addition to radiation therapy for cervical carcinoma with positive cytology of peritoneal washing.
CERVICAL
CARCINOMA
79
REFERENCES ‘. Creasman, W. T., and Rutledge, F. The prognostic value of peri-
toneal cytology in gynecologic malignant disease, Am. J. Obsrer. Gynecol. 110, 773-178 (1971).
2.
Proposals by Oncology Committee approved by Executive Board of FIG0 (1988).
3. Creasman, W. T., Disaia, P. J., Blessing, J., Wilkinson, R. H., Johnston, W., and Weed, J. C. Prognostic significance of peritoneal
ccytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals, Gynecol. 141, 921-927 (1981).
Am.
J. Obstet.
4. Keettle, W. C., Pixley, E. E., and Buchsbaum, H. J. Experience with peritoneal cytology in the management of gynecologic malignancies, Am. .I. Obstet. Gynecol. 120, 174-182 (1974).
