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Keywords:

  • parametrium;
  • cervical cancer;
  • parametrectomy;
  • radical hysterectomy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Removal of the parametrial soft tissue is recommended for patients with cervical cancer undergoing radical hysterectomy. Parametrectomy results in significant morbidity. The objective of the study was to determine factors predictive of parametrial tumor spread and to define a subset of patients at low risk for parametrial disease.

METHODS.

Patients with invasive cervical cancer who underwent radical hysterectomy from 1989–2005 were examined. Analysis was performed to determine factors associated with parametrial tumor spread. Survival estimates were determined using the Kaplan-Meier method.

RESULTS.

A total of 594 patients were identified. Parametrial metastases were documented in 64 (10.8%). Factors associated with parametrial disease were: histology, advanced grade, deep cervical invasion, lymphovascular space invasion (LVSI), large tumor size, advanced stage, uterine or vaginal involvement, and pelvic or para-aortic lymph node metastases (P < .0001 for each). Parametrial metastases were associated with increased risk of recurrence and decreased disease-free and overall survivals (P < .0001). A subgroup analysis was performed to identify patients at low risk for parametrial spread. In pelvic node-negative women parametrial disease was noted in 6.0% (30/498) compared with 47.9% (34 of 71) of those with positive pelvic nodes (P < .0001). If further stratified to women with negative nodes, no LVSI, and tumors < 2 cm, the incidence of parametrial disease was only 0.4%.

CONCLUSIONS.

Parametrial spread is a strong predictor of recurrence and decreased survival. Parametrial invasion is rare in patients with small tumors, no LVSI, and negative pelvic nodes (no poor prognostic factors). Further study is warranted to determine the feasibility of omitting parametrectomy in these low-risk patients. Cancer 2007. © 2007 American Cancer Society.

Despite advances in the diagnosis and management of cervical cancer as well as the introduction of prophylactic human papillomavirus vaccines, the disease remains a major cause of cancer-related mortality.1, 2 Annually, it is estimated that 493,000 women worldwide will be diagnosed with cervical cancer and that 273,000 will die from the disease.2 Treatment options for women with disease confined to the cervix and upper vagina (stages IA-IIA) include either radical surgery or radiotherapy. A prospective study of 343 patients randomized to either radical hysterectomy or radiation showed that survival was similar between the 2 groups.3 As there is no clearly superior treatment for early-stage cervical cancer, the therapeutic modality used depends on patient related factors, side effect profiles, and physician preference.

The traditional type III Wertheim radical hysterectomy involves removal of the uterus, upper vagina, and uterosacral ligaments with ligation of the uterine artery at its origin and resection of the parametrium.4 Whereas radical hysterectomy is associated with excellent local tumor control, the operation is also associated with significant morbidity.5–9 Late morbidity was encountered in 38% of patients who underwent radical hysterectomy as part of a prospective trial. This included long-term urologic complications in a third of patients.5 Much of the morbidity associated with the procedure can be attributed to removal of the parametrial tissue adjacent to the cervix.10 The parametrial tissue contains autonomic fibers that play a critical role in bladder, bowel, and sexual function. These autonomic fibers are susceptible to damage during radical pelvic resections. The rationale for parametrectomy is to remove occult disease at the time of extirpation of the primary cervical lesion. However, for patients with early cervical tumors the utility of radical parametrial resection has been the subject of debate.11, 12 The objective of this study was to determine factors predictive of parametrial tumor spread and to define a subset of patients at low risk for parametrial disease who may be candidates for omission of parametrectomy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study approval was obtained from the Washington University School of Medicine Human Studies Committee. A search of institutional databases was performed to identify all women with invasive cervical cancer treated between 1989 and 2005. Patients who underwent a type II modified radical or type III radical hysterectomy as described by Piver et al.4 were eligible for inclusion. All procedures were performed at a single institution under the guidance of an attending gynecologic oncologist. Data on each patient's clinical course were abstracted from medical records. A prospectively maintained hospital tumor registry was queried to document the disease status and vital status of each patient.

Pathologic data were collected through review of pathology reports. All hysterectomy specimens were collected and processed in a routine manner. At the time of uterine removal the specimen margins were inked for processing. The parametrial tissue of all specimens was processed and examined for microscopic tumor spread. For patients with parametrial metastases the tumor spread was characterized as direct extension, nodal disease, or spread through vascular channels. Pathologic data abstracted included: histologic subtype, depth of tumor invasion, lymphovascular space invasion (LVSI), parametrial tumor spread, vaginal or uterine involvement, pelvic and para-aortic lymph node status, and status of the margins of excision. Depth of tumor invasion was categorized into thirds as outer third, inner third, or deep third invasion. The associations between these pathologic factors and parametrial tumor spread were evaluated using chi-square test or Fisher exact test as appropriate. The effect of parametrial metastases on prognosis was also examined. Overall survival (OS) was defined as the interval from surgery to death from any cause. Patients who were alive were censored at the date of last contact. Disease-free survival (DFS) was defined as the time interval from surgical resection to the first evidence of recurrence or death from any cause, whichever occurred first. Those patients alive without recurrence were censored at the date of last medical contact. OS and DFS rates were estimated by the Kaplan-Meier method and the differences between subjects with and those without parametrial metastases were compared by log-rank test. A P-value under 0.05 was taken to indicate statistical significance and all tests were 2-sided. The statistical analysis was performed using Statistical Analysis System (SAS) v. 9.1 (SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 594 subjects were identified. The mean age of the cohort was 43 years (range, 19–83). The median duration of follow-up was 59 months (range, 1–201 months). Squamous cell carcinomas were most frequent (67.5%), whereas 22.7% of patients had adenocarcinomas. The stage distribution for the cohort included: IA1 (2.2%), IA2 (5.6%), IB1 (79.0%), IB2 (5.2%), and IIA (1.9%). Whereas 19 (3.2%) patients underwent type II modified radical hysterectomies, the majority (96.8%) underwent type III radical hysterectomies. Seventy-one (12%) patients had pelvic nodal metastases, whereas 1.7%10 had para-aortic nodal disease.

Parametrial metastases were documented in 64 (10.8%) patients. Table 1 displays an analysis of factors associated with parametrial involvement. Parametrial disease was strongly associated with histology, advanced grade, deep cervical invasion, LVSI, large tumor size, uterine and vaginal involvement, pelvic and para-aortic lymph node metastases, and advanced stage (P < .0001 for all). Table 2 shows the patterns of parametrial spread. Of those with parametrial disease, bilateral parametrial involvement was seen in 25%, whereas 44% had right-sided spread and 31% had metastasis to the left parametrium. Direct tumor extension was noted in 52%, parametrial nodal metastases were seen in 41%, and 27% of patients had tumor spread through vascular channels.

Table 1. Factors Associated With Parametrial Metastases
 Parametrium negative no. (%)Parametrium positive no. (%)P
  1. LVSI indicates lymphovascular space invasion.

Subjects530 (89.2)64 (10.8) 
Residual tumor  < .0001
 No171 (32.3) 
 Yes359 (67.7)64 (100) 
Histology  < .0001
 Squamous352 (66.4)49 (76.6) 
 Adenocarcinoma131 (24.7)4 (6.3) 
 Other42 (7.9)11 (17.2) 
 Unknown5 (0.9) 
Grade  < .0001
 176 (14.3)1 (1.6) 
 2223 (42.1)36 (56.3) 
 3112 (21.1)25 (39.1) 
 Unknown119 (22.5)2 (3.1) 
Depth of invasion (thirds)  < .0001
 None175 (33.0)0 (—) 
 Outer90 (17.0)2 (3.1) 
 Middle98 (18.5)8 (12.5) 
 Deep117 (22.1)43 (67.2) 
 Unknown50 (9.4)11 (17.2) 
LVSI  <.0001
 Negative363 (68.5)6 (9.4) 
 Positive156 (29.4)54 (84.4) 
 Unknown11 (2.1)4 (6.3) 
Tumor size  <.0001
 < 2 cm330 (62.3)7 (10.9) 
 > 2 cm174 (32.8)54 (84.4) 
 Unknown26 (4.9)3 (4.7) 
Uterine involvement  <.0001
 Negative507 (95.7)43 (67.2) 
 Positive23 (4.3)21 (32.8) 
Vaginal involvement  < .0001
 Negative513 (96.8)49 (76.6) 
 Positive17 (3.2)15 (23.4) 
Vaginal margins  .168
 Negative525 (99.1)62 (96.9) 
 Positive5 (0.9)2 (3.1) 
Pelvic lymph nodes  <.0001
 Negative468 (88.3)30 (46.9) 
 Positive37 (7.0)34 (53.1) 
 Unknown25 (4.7) 
Para-aortic lymph nodes  <.0001
 Negative425 (80.2)51 (79.7) 
 Positive4 (0.8)6 (9.4) 
 Unknown101 (19.1)7 (10.9) 
Stage  <.0001
 IA113 (2.5) 
 IA233 (6.2) 
 IB1419 (79.1)50 (78.1) 
 IB221 (4.0)10 (15.6) 
 IIA7 (1.3)4 (6.3) 
 Unknown37 (7.0)  
Table 2. Patterns of Parametrial Metastatic Involvement
 Patients no. (%)
  • *

    Patients may have had multiple patterns of parametrial involvement.

Side of involvement
 Right28 (43.8)
 Left20 (31.3)
 Bilateral16 (25.0)
Pattern of involvement*
 Direct tumor extension33 (51.6)
 Lymph node metastasis26 (40.6)
 Lymphovascular spread17 (26.6)

Parametrial involvement was a strong predictor of survival. The risk of recurrence was 22% in women with a positive parametrium compared with 5% for those without parametrial disease (P < .0001). At last follow-up 27.8% of the subjects with parametrial metastases had died from cervical cancer compared with 6.6% without parametrial spread. Figure 1 displays a Kaplan-Meier plot of progression-free survival (P < .0001). Similar trends were noted for OS (P < .0001) (Fig. 2).

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Figure 1. Kaplan-Meier graph of disease-free survival based on parametrial spread.

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Figure 2. Kaplan-Meier graph of overall survival based on parametrial spread.

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Subgroup analysis was performed to define a group of patients at low risk for parametrial tumor spread (Fig. 3). Among the 498 patients with negative pelvic lymph nodes parametrial disease was seen in only 6.0% of patients compared with 47.9% of those with positive pelvic nodes. If the pelvic node-negative patients are further stratified into those with tumors < 2 cm in size and without LVSI the risk of parametrial metastases was 0.4% (1 of 270 patients). Among these 270 patients, 2 (0.7%) recurrences were noted.

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Figure 3. Flowchart of risk of parametrial metastases. PM indicates parametrium; LVSI, lymphvascular space invasion.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the present series we documented parametrial metastases in 11% of patients with stage IA-IIA cervical cancer. Parametrial tumor spread was strongly correlated with other high-risk cervical features and lymph node metastases. Patients with parametrial disease were over 7 times more likely to have pelvic nodal metastases and nearly 12 times more likely to high para-aortic tumor spread than women with no parametrial disease. Our findings are in accord with previously published reports that have documented parametrial involvement in 4% to 39% of patients.13–23 As in these reports, parametrial metastases portended a poor prognosis with an increased risk of recurrence.

To better understand the patterns of tumor spread to the paracervical soft tissue several investigators have meticulously examined the parametrium with giant sections.17, 21, 24, 25 Initial studies revealed that tumor spread to the parametria occurred to both the medial and lateral parametrium and that the pattern of spread was unpredictable.17, 24, 25 In a series of 69 patients undergoing radical hysterectomy Benedetti-Panici et al.21 were able to identify parametrial lymph nodes in 93% of patients; the median number of nodes found was 5. Further examination revealed that the pattern of parametrial spread was through direct extension in 37%, through nodal metastases in 59%, and through lymphovascular channels in 52%. Lastly, the authors observed that all patients with positive pelvic nodes had parametrial disease, whereas 2 patients with parametrial involvement had negative pelvic nodes. On the basis of these findings they suggested that the parametrium was the first site of extracervical tumor spread. Some studies have found pelvic nodal disease in patients without parametrial spread, but patients with parametrial involvement are much more likely to have pelvic nodal metastases.14, 15, 23 These studies have suggested that the patterns of parametrial tumor spread are unpredictable and that patients at risk for parametrial disease should undergo complete excision of the parametrium.17, 21, 24, 25

To limit the operative morbidity associated with radical hysterectomy the challenge is to identify a subset of women at low risk for parametrial disease in whom parametrectomy could safely be avoided. In a series by Kinney et al.13 of 387 patients with early stage cervical cancer no patient with a tumor volume of less than or equal to 4.19 cm3 and no LVSI had parametrial disease. Similarly, Covens et al.14 identified a group of low-risk patients based on tumor-related factors. Patients with tumor ≤2 cm, negative pelvic lymph nodes, and a depth of stromal invasion ≤10 mm had a 0.6% incidence of parametrial metastases. The 5-year recurrence-free survival in this group was 96%. Our findings are in accord with their data. We sought to develop an algorithm that incorporated clinically identifiable factors to select a subset of patients at low risk for parametrial disease. For women with tumors < 2 cm in diameter, negative pelvic nodes, and no LVSI the risk of parametrial involvement was only 0.4%. The recurrence rate in this low-risk cohort was 0.7%.

Our data in conjunction with the studies cited above clearly support the hypothesis that a low-risk subset of patients with early-stage cervical cancer exists and that these patients may be candidates for a less radical procedure. Type II modified radical hysterectomy with removal of the medial half of the parametrium has been proposed for patients with stage IA2 and small IB lesions.5, 12, 18 Although associated with lower morbidity, the incidence of long-term complications remains significant.5 In addition, giant section studies of the parametrium reveal that over 50% of the parametrial nodes lie in the lateral portion of the parametrium.21 Our findings suggest that cervical conization or simple hysterectomy in combination with pelvic lymphadenectomy may be adequate treatment for low-risk, early-stage cervical cancer patients. Performance of a conization as initial management of patients with tumors grossly < 2 cm in diameter would allow adequate assessment of tumor size and LVSI. Patients with a tumor diameter of < 2 cm and no LVSI could then consider simple hysterectomy with pelvic lymphadenectomy. Those women with positive nodes require adjuvant radiotherapy in combination with chemotherapy regardless of the type of hysterectomy performed. Surgical advances with laparoscopic lymphadenectomy and sentinel node mapping may ultimately further decrease the morbidity associated with the management of these low-risk patients.26, 27

In conclusion, we have demonstrated that parametrial metastasis is an important prognostic factor in patients with cervical cancer. For low-risk women with tumors < 2 cm in diameter with negative pelvic lymph nodes and no LVSI the risk of parametrial involvement is minimal. Whether parametrectomy can be omitted in these low-risk patients will require further prospective evaluation. As less radical surgical approaches have become common for other solid tumors, such as breast and vulvar cancer, it is time to reevaluate the necessity of radical en bloc resection of early cervical tumors.28–31

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES