The prognostic significance of the size of the largest nodes in metastatic carcinoma from the uterine cervix

GYNECOLOGIC

ONCOLOGY

19, 187- 193 ( 1984)

The Prognostic Significance of the Size of the Largest Nodes in Metastatic Carcinoma from the Uterine Cervix TAKEO

INOUE, M.D.,’

Department

TSUTOMU

CHIHARA,

of Gynecology and Department Kanokoden, Chikusa-ku,

M.D.,

AND Kozo MORITA,

of Radiation Therapy, Nagoya 464, Japan

Aichi

Cancer

M.D. Center,

Received December 15, 1983 Sizes of the largest metastatic nodes were evaluated as a prognostic factor in 152 patients with Stage IB to IIB cervical carcinomas treated by radical hysterectomy and postoperative irradiation. Of the 152 cases, the largest positive nodes were 4 positive nodes increased along with an increase in the size of the largest nodes (P < 0.05). Disease-free periods for 58 patients with recurrent cancer were
INTRODUCTION

Node size has been an important factor in radiologic diagnosis of metastasized carcinoma of the uterine cervix [6-8,101, and most authors consider that a metastasis must have a diameter of at least 5 to 10 mm to be detected lymphographically [6]. Ginaldi et a1.[2] stated in their computed tomography study that discrete nodes greater than 1.5 cm were to be considered enlarged and abnormal. Accuracy depended on the size of the metastasis, and had little to do with the number of nodes involved [7]. Despite the diagnostic value, the size of nodes in metastatic carcinoma has rarely been evaluated as a prognostic factor in patients after radical hysterectomy [ 1,9]. The purpose of this study is to statistically analyze 152 patients with cervical ’ To whom reprints should be addressed at the Department of Gynecology.

187 0090-8258/84

$1.50

Copyright 0 1984 by Academic Press. Inc. All rights of reproduction in any form reserved.

188

INOUE,

CHIHARA,

AND

MORITA

nodal metastases, and attempt to elucidate the relationships between the size of the largest metastatic nodes and other prognostic factors such as clinical stage, number of positive nodes, depth of tumor invasion, tumor cell type, and parametrial extension. MATERIALS AND METHODS Subjects for this study included 152 patients with cervical nodal metastases who underwent radical hysterectomy and bilateral pelvic lymphadenectomy at the Aichi Cancer Center in Nagoya, Japan, from 1968 to 1980. All 152 patients were followed for more than 3 years after surgery. All patients were staged according to the FIG0 staging system at the time of clinical examination without anesthesia, and their stages were not changed after surgery. The removed uteri and lymph nodes were fixed in 10% formalin for more than 24 hr and processed for histologic examination. The fixed uteri were sectioned vertically throught the cervical canal. A sagittal section of the posterior wall and two or more sections from the most thickened sites of the tumor were stained with hematoxylin and eosin. All slides of the lesion were reviewed, and the maximum depth of tumor invasion was measured [4]. When tumor cells were found in the parametrial tissues and not in parametrial lymph nodes, the patients were classified as having parametrial extension [3]. Each tumor was classified as nonkeratinizing large cell carcinoma, keratinizing squamous cell carcinoma, small cell carcinoma, and adenocarcinoma according to the criteria proposed by Reagan et al. [4,12]. Nine to sixty-five (mean 25) resected lymph nodes were examined to see if they contained metastatic cells. The maximum diameter of the positive nodes was measured, and the node with the greatest diameter was selected as the largest positive node. Radical hysterectomy and pelvic lymphadenectomy were performed according to Kobayashi’s technique [5], and included wide excision of the cardinal ligament, the paravaginal tissues, and the upper one-third of the vagina. Positive nodes were unresectable in 17 patients, because they adhered to the external or internal iliac veins. These cases underwent total hysterectomy with or without lymphadenectomy. Almost all patients with nodal metastases were given external irradiation to the entire pelvis at the level of the L4 vertebra. The given doses were 4000-6300 rad at a daily rate of 180-200 rad to those patients treated from 1968 to 1973, and 4000 rad at a daily rate of 180 rad to those patients treated from 1974 to 1980. Statistical analysis was carried out by x2 when the number of cases was more than 5, and by Fisher’s exact probability when the number of cases was 5 or less.

Nodal metastases were found (40%), IIA in 11 (7%), and IIB largest positive nodes were
RESULTS in 152 of 604 cases whose stages were IB in 60 in 81 (53%). Of the 152 cases, the sizes of the mm in 24 (16%), IO-20 mm in 74 (49%), 220 in 17 (11%) (Table 1). Patient distribution was with IB and IIA. The frequency of cases with

LARGEST

NODES

IN

CERVICAL

TABLE SIZE

OF LARGEST

METASTATIC

NODES

189

CANCER

1 RELATING

TO CLINICAL

STAGE

No. (%) Size of nodes

Stage IB

Cl0 mm lo-20 mm 220 mm Unresectable

9 37 9 5

Total

60( 100)

Stage IIA

Stage IIB

2 W-3) 6 (55) 2 (18)

(15) (62) (15)

(8)

13 (16) 31 (38)b 26 (32)d 11 (14)

1 (9) ll(100)

81(100)

a-d Significant differences between a & b and c & d (P < 0.05).

20-mm sized nodes was the highest in cases with small cell cancer, and was lowest in adenocarcinoma. This frequency was significantly lower in cases with a depth of invasion of IO-20 mm than in the remaining cases (P < 0.05). Patients with parametrial extension were associated with more ?=20-mm nodes than those without parametrial extension. Recurrent carcinomas were found in 58 of the 152 cases. The interval from surgery to recurrence was within 1 year in 26 (45%), 1-3 years in 27 (46%), and 3 or more years in 5 (9%) (Table 4). Patients with
OF LARGEST

METASTATIC

NODES

2

RELATING

TO NUMBER

OF POSITIVE

NODES

Size of largest metastatic nodes

Number of positive nodes

Cl0 mm

1 2 or 3 4 or more Total

lo-20 mm

220 mm

13 (54) 9 (38) 2 w

35 (47)b 26 (35) 13 (18)

9 (24) 15 (41) 13 (35)’

24(100)

74(100)

37(100)

No. (%)

o-f Significant differences between a & c, b & c, d & f, and e & f (P < 0.05).

190

INOUE,

CHIHARA,

AND

MORITA

TABLE 3 PATIENTS WITH METASTATIC NODES 5 20 MM RELATING TO OTHER PROGNOSTIC FACTORS

Prognostic factors Tumor cell type Nonkeratinizing large cell Keratinizing squamous cell Small cell Adenocarcinoma Depth of tumor invasion
No.

cw

36/108 lo/23 s/9 3112

(33%) (43%) (56%) (25%)

7116 22179 15138 10/19

W%) (28%)b (39%) (53%)

26184 28168

(31%) (41%)

’ This included cases with unresectable positive nodes. b A significant difference between this case and the remaining cases (P < 0.05).

of 23 years (P < 0.001). Patients with positive nodes of lo-20 mm showed a significantly high percentage of cases whose disease-free interval was l-3 years (P < 0.005). Patients with 220 mm and/or unresectable positive nodes included a significantly greater number of cases with a disease-free interval of less than 1 year than those cases with <20-mm nodes (P < 0.001). All of the five patients in whom cancer recurred 33 years after surgery survived more than 5 years after surgery, and eventually expired. Two patients in whom recurrent cancers

DISEASE-FREE

PERIODS IN

TABLE 4 58 PATIENTS RELATING TO SIZE OF LARGEST METASTATIC NODES No. (%)

Years

after surgery

Size of largest metastatic nodes
lo-20 mm

220 mm

Unresectable

--cl

1

1 (20) 3 (60)h

6 (21)b 20t (72)’ 2 (7)

8*

1-3 23-t

(89) 1 (ll)P 0 COY

11 (69)d 5 (31) 0 (OY

Total

5 (100)

28 (100)

9 (100)

16 (100)

(20)

o-t Significant differences between (a +b) & (c +d) (P < O.OOl), e & f (P < 0.05), f & g (P < 0.05), h & i (P < O.Ol), and h & Cj+k) (P < 0.005). * One patient is disease free 8 years after recurrence in her neck nodes. t One patient survived 6 years after vaginal recurrence. $ All five patients survived more than 5 years after surgery.

LARGEST

~-YEAR

RESULTS

NODES

RELATING

IN

CERVICAL

TABLE

5

191

CANCER

TO SIZE OF LARGEST

METASTATIC

NODES No. (%)

Size of nodes

No. of cases

Cl0 mm lo-20 mm 320 mm Unresectable

Disease

22 72 33 17

Total differences

between

Living

20 (91) 46 (64)b 24 (73)’ 1 (6)d

144

a-d Significant

free

91 a L b (P < 0.05)

63

21 52 25 3

(95) (72)b (76)’ (18)d

101

70

and c & d (P < 0.001).

were found within 3 years after surgery, one in the neck nodes and the other in the vagina, survived more than 6 years after the recurrence. The former patient is still living, and enjoys a favorable prognosis. These facts indicate the 3-year disease-free rates are of prognostic value much the same as are 5-year survival rates in patients with nodal metastases. Table 5 shows the 3-year results of 144 patients excluding 8 patients who died of intercurrent disease within 3 years with no evidence of recurrence. Threeyear disease-free rates showed significant reductions between cases with positive nodes 20mm and unresectable positive nodes (P < 0.001). The same reductions were found in the 3-year survival rates. Table 6 shows 3-year disease-free rate relating to sizes and number of positive nodes. The rates were 84, 73, and 38% for cases with one, two or three, and four or more positive nodes, respectively. The difference between cases with two or three and four or more was highly significant (P < 0.005). In cases with three or fewer positive nodes, disease-free rate for cases with nodes 20-mm nodes showed a twofold better disease-free rate than those with nodes of lo-20 mm. This discrepancy resulted from an improvement of the treatment for these cases. Disease-free rate of cases with four or more positive

~-YEAR

DISEASE-FREE

RATES

RELATING

TABLE 6 TO SIZE OF LARGEST METASTATIC POSITIVE

Size of largest Number positive

of nodes


1

2 or 3 4 or more y--c Significant

819 O/l differences

between

AND

NUMBER

OF

nodes

mm

lo-20

mm

(89)” (0)

No. 25134 18/26 3/12

(%) (74)’ (69)“ (25)

12/12(100)

NODES

NODES

(a + 6) & (c + d), and d & e (P <: 0.09.

320

mm

919 (100) 9/13 (69) 6/11 (55)

INOUE, CHIHARA, AND MORITA

192

TABLE AN

IMPROVEMENT

IN TREATMENT

OF PATIENTS

I WITH

FOUR OR MORE POSITIVE

NODES

3-Year disease-free rate Size of the largest nodes Treated years 1968-1974 1975-1980


lo-20 mm

220 mm

Total

o/o O/l (0)

118 (13) 214 (50)

O/l (0) 600 (60)

119 (11) S/l5 (53)b

‘,* Significant difference between a and b (P < 0.05.

nodes was significantly improved from 11% for patients treated from 1968 to 1974 to 53% for those treated from 1975 to 1980 (P < 0.05) (Table 7). DISCUSSION It is evident from this retrospective analysis that the sizes of the largest positive nodes are closely linked with clinical stages and number of positive nodes. The frequency of cases with nodes lo-20 mm decreased, and those with nodes 220 mm increased when carcinomas advanced from Stage IB to IIB (P < 0.05) (Table 1). Distribution of cases with one positive node decreased, and those with four or more positive nodes increased when size of the largest nodes developed greater than 20 mm (P < 0.01) (Table II). Kolbenstvedt [7] reported that size of the largest metastasis was 10 mm or less in 46 out of 77 cases. Ginaldi et al. [2] stated from a computed tomography study that 12 out of 24 cases had abnormal lymph nodes with a size of greater than 15 mm. However, these authors mentioned no relationships between the size of positive nodes and other prognostic factors. This study presents further evidence that the size of the largest positive nodes is a valuable prognostic factor in patients with nodal metastases from the cervix. The disease-free interval after surgery was shortened significantly as the size of the largest nodes increased (Table 4). In addition, cancers recurred in significantly fewer cases with nodes ~10 mm than in those cases with nodes lo-20 mm (Table 5). A problem to be settled is how to detect metastases in nodes ~10 mm before initiating therapy. Most authors consider that a metastasis must have a diameter of at least 5 to 10 mm to be detected lymphographically [6]. At our hospital, those patients who have parametrial or nodal tumors from the uterine cervix are given postoperative irradiation. This study clearly indicates progress in treating this disease. The 3-year disease-free rate was significantly improved from 11 to 53% in patients with four or more positive nodes. Piver et al. [ 1 I] reported that the 5-year survival rate of patients with four or more positive nodes was 38% for IB cases and 17% for IIA cases. Although 3-year diseasefree rate and 5-year survival rate are not equal, our improved data, including IIB cases, are significant. From this improvement, a-20-mm nodes are not a factor of poor prognosis but a factor of having four or more positive nodes. It is our opinion that patients with lymphographically determined 320-mm nodes should be operated on when the stage is IIB or less.

LARGEST

NODES

IN

CERVICAL

CANCER

193

ACKNOWLEDGMENT The authors thank Miss Miwako

Okumura for her helpful work in the analysis of this data. DCCCDCMPCC!

1. Baltzer, J., Lohe, K. J., Kopcke, W., and Zander, J. Histological criteria for the prognosis in patient with operated squamous cell carcinoma of the cervix, Gynecol. Oncol. 13, 184-194 (1982). 2. Ginaldi, S., Wallace, S., Jing, B., and Bernardino, M. Carcinoma of the cervix: Lymphangiography and computed tomography, Amer. J. Roenfgenol. 136, 1087-1091 (1981). 3. Inoue, T., and Okumura, M. Prognostic significance of parametrial extension in patients with cervical carcinoma Stages IB, HA, and IIB. A study of 628 cases treated by radical hysterectomy and lymphadenectomy with or without postoperative irradiation, Cancer in press. 4. Inoue, T. Prognostic significance of the depth of invasion relating to nodal metastases, parametrial extension, and cell types, Cancer in press. 5. Kobayashi, T. Abdominal radical hysterectomy with pelvic lymphadenectomy for cancer of the cervix, Nanzando, Tokyo (1961). 6. Koehler, P. R., Wohl, G. T., and Schaffer, B. Lymphangiography-A survey of its current status, Amer. J. Roentgenol. 91, 1216-1221 (1964). 7. Kolbenstvedt, A. Lymphography in the diagnosis of metastases from carcinoma of the uterine cervix Stages I and II, Acta Ragiol. [Diagn.] 16, 81-97 (1975). 8. Lee, J. K. T., Stanley, R. J., Sage], S. S., and MacClennan, B. L. Accuracy of CT in detecting intraabdominal and pelvic lymph node metastases from pelvic cancers, Amer. J. Roentgenol. 131, 675-679

(1978).

9. Mitani, Y., Fijii, J., Ishizu, S., and Matsukado, M. Lymph node metastases of carcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 84, 515-522 (1962). 10. Piver, M. S., Wallace, S., and Castro, J. R. The accuracy of lymphangiography in carcinoma of the uterine cervix. Amer. J. Roentgenol. 111, 278-283 (1971). 11. Piver, M. S., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma, Obstet. Gynecol. 46, 507-510 (1975). 12. Reagan, J. W., Hamonic, M. J., and Wentz, W. B. Analytical study of the cells in cervical squamous-cell cancer, Lab. Invest. 6, 241-250 (19571.