Histologic study of patterns of cervical involvement in FIGO stage II endometrial carcinoma

Abstract. Scurry J, Craighead P, Duggan M. Histologic study of patterns of cervical involvement in FIGO stage II endometrial carcinoma.
The pathology of cervical involvement in endometrial carcinoma has not been fully defined previously. We reviewed the histopathology of 66 hysterectomies of women with stage II endometrial carcinoma. Cervical spread was categorized as macroscopic or microscopic; stage IIA or IIB; direct spread, surface or lymphvascular metastasis; and size, number, and location. The cervical tumor was macroscopically identified in 15 (23%) women and microscopically identified in 51 (77%). Twenty-one patients (32%) were stage IIA and 45 (68%) stage IIB. The method of spread was direct spread in 28 patients, surface metastases in 27, lymphovascular in 3, both direct spread and surface metastases in 7 and both direct spread and lymphovascular in 1. The cervical tumor had a mean horizontal dimension of 3 mm and a median of 2 mm. There were multiple sites of cervical tumor in 31 (47%) patients and single in 35 (53%). The sites of spread, including cases with multiple sites, were the endocervix in 60 women (90%), transformation zone in 24 (37%), and ectocervix in 3 (5%). Most patients had minimal microscopic cervical tumor. Small examples of direct spread may be an artifact of definition depending on the histology of the isthmian-endocervical junction and many surface metastases appear to follow dilatation and curettage. In 7 of 66, 11%, however, the cervical tumor was greater than 5 mm depth of invasion and/or the result of lymphvascular metastasis. Survival studies are required to compare minimal stage II endometrial carcinoma patients and those with larger and/or lymphvascular derived cervical tumor. Patients with minimal stage II and stage I patients should also be compared.     

Surgical pathologic staging in apparent stage I endometrial carcinoma

A multicenter trial on apparent stage I endometrial carcinoma was performed to establish an intensive surgical staging, to formulate a treatment on the basis of the pathological extent of the disease and to determine the effectiveness of adjuvant medroxyprogesterone acetate therapy. The results of the first objective on 1,055 patients are herein reported. All patients had total abdominal hysterectomy, bilateral salpingo-oophorectomy, colpectomy of the superior third, and biopsy of lymph nodes positive or doubtful at radiological imaging or on surgical inspection. On the basis of the pathologic extent of the disease, patients were classified into five categories: disease outside the uterine corpus (RE); disease limited to endometrium (RO); disease with inner myometrial invasion and high or moderate grade (R1); disease with deep myometrial invasion or poor differentiation (R2); disease with positive retroperitoneal nodes (R3). One hundred and forty-six patients were RE, 163 RO, 382 R1, 341 R2 and 23 R3. The results showed a clinical understaging in 16% of the cases. According to the new FIGO classification, the relapse-free survival at 84 months was 96% for patients at stage IA, 92% for patients with stage IB-C, 86% for stage IIA-B, 76% for stage IIIA-B and 74% for patients at stage IIIC. These data confirm the importance of an intensive surgical staging in apparent stage I endometrial carcinoma.     

Stage II adenocarcinoma of the endometrium treated by two standard regimens of combined preoperative irradiation and surgery

We retrospectively analyzed 77 patients with stage II endometrial carcinoma treated with standard regimens of preoperative radiotherapy (RT) and surgery (S). The age range was 31–74 years with a median of 56.3 years. Thirty-three patients received 40 Gy whole pelvis RT followed by either radical or modified radical hysterectomy. Forty-four patients received 50 Gy whole pelvis RT and sequential intrauterine and intravaginal cesium-137 brachytherapy followed by a simple hysterectomy. Median follow-up was 111 months. No patient was lost to follow-up. The overall 5-year actuarial survival was 78%. There was no significant difference between the two treatment groups. Several prognostic variables were analyzed. Those with histologic grade I and II had 5-year survival of 89% and 83%, respectively, compared to 62% for grade III ( P =0.045). The 5-year survival for microscopic cervical involvement was 87% compared to 59% for gross involvement ( P = 0.008). Patients with negative or microscopic residual tumor in the surgical specimen and those with negative lymph nodes had less risk of treatment failure. Local failure occurred in only 9%. Major complications (3%) were seen only in the radical surgery group. Combined preoperative RT and S provide high cure rates with minimal complications for patients with stage II endometrial carcinoma. Patients with adverse prognostic factors are candidates for trials of more aggressive local and systemic therapy.     

Omentectomy, peritoneal biopsy and appendectomy in patients with clinical stage I endometrial carcinoma

Abstract. Saygili U, Kavaz S, Altunyurt S, Uslu T, Koyuncuoglu M, Erten O. Omentectomy, peritoneal biopsy, and appendectomy in patients with clinical stage I endometrial carcinoma.
The aim of this study was to evaluate whether omentectomy, appendectomy, and peritoneal biopsy should be a routine part of staging surgery in endometrial carcinoma. Data of 97 patients who had been diagnosed with clinical stage I endometrial carcinoma were reviewed. Associations in the data obtained, pelvic and para-aortic lymph node status, depth of myometrial invasion, grade, and histology were investigated. The chi-square (χ²) test was used for statistical analysis.
Of 97 patients, six (6%) had omental metastases, which was microscopic in four. There was a statistically significant relationship between omental metastasis and tumor grade ( P < 0.01). Deep myometrial invasion was significantly more common in patients with omental metastases. Tumor was found in one of 55 appendectomy specimens (2%). Omentectomy may be included in surgical staging in patients with deeply invasive or grade 3 endometrial cancer because of the possibility of omental metastasis in spite of what appears to be stage I disease in laparotomy. In other cases, omentectomy and appendectomy and biopsies from peritoneal sites should be performed in the presence of grossly suspicious disease.     

The clinical significance of malignant peritoneal cytology in stage I endometrial carcinoma

The prevalence of malignant peritoneal cytology in patients with International Federation of Obstetrics and Gynecology (1971) stage I endometrial carcinoma and its predictive value for recurrence of disease following hysterectomy were analyzed by numerically pooling the crude results of independent studies. Malignant cytology occurred in 8.3, 12.1 and 15.9% of patients with grade 1, 2 and 3 histology, respectively, and in 7.6% and 17.2% of patients with superficial and deep myometrial invasion, respectively. Prevalence was heterogeneous in the groups with grade 1 histology, grade 2 histology and superficial invasion, and homogeneous in the groups with grade 3 histology and deep invasion. This, together with a technical false positive rate of approximately 5% in the diagnosis of malignant cytology, suggests that the pooled values of prevalence for the low grade and superficially invasive groups may be overestimated. Malignant cytology was strongly associated with disease recurrence (pooled odds ratio of 4.7 with a 95% confidence interval of 3.5–6.3). Qualitative review of the literature suggests that this is largely due to the association of malignant cytology with other adverse prognostic factors which dominate the clinical course of the disease. In the absence of other adverse prognostic factors, the true prevalence of malignant cytology is low. This limits the clinical utility of cytology as an independent predictor of either overall recurrence or site of recurrence. Routine adjuvant treatment of patients with malignant cytology is therefore not justified.     

Clinical and pathologic significance of microsatellite instability in endometrial cancer

Abstract. Wong YF, Ip TY, Chung TKH, Cheung TH, Hampton GM, Wang VW, Chang AMZ. Clincal and pathologic significance of microsatellite instability in endometrial cancer.
Microsatellite instability (MSI) is identified as electrophoretic shifts in allele sizes of microsatellite DNA sequences. It is characteristic of a subset of sporadic colorectal tumors as well as hereditary nonpolyposis colorectal cancer (HNPCC). The cells that display MSI are thought to be susceptible to increased mutability. MSI has been detected in a wide variety of human tumors, but the influence of this form of genetic instability on disease initiation and progression remains unclear. Using a polymerase chain reaction (PCR)-based method we screened 50 sporadic primary endometrial carcinomas to characterize the prevalence of MSI in these tumors and analyze the correlation of MSI with clinicopathologic parameters in this malignancy. Fifteen cases (30%) displayed low frequency of MSI (MSI-L) showing MSI at one locus in 5 loci examined. Two cases (4%) showed high frequency of MSI (MSI-H) having MSI at 2 or more loci. Taking MSI-L and MSI-H cases together as MSI-positive, statistical analysis of patient age, tumor grade, and stage failed to disclose significant differences or trends between cases with MSI-positive and MSI-negative ( P > 0.05). No significant relationship was observed between patients with MSI and without MSI ( P > 0.05), however, the MSI exhibited only in those cases without evidence of disease at the 24th month after treatment. The difference is statistically significant when compared with patients who are alive with disease or died of disease ( P < 0.01). However, the overall survival curves were not statistically different. We conclude that MSI is present in a subgroup of endometrial cancer.     

DNA flow cytometry in stage IB and II cervical carcinoma

In a retrospective study the prognostic significance of nuclear DNA content was investigated, as measured by flow cytometry, of the tumor specimens from 212 women with nonpretreated FIGO stage IB and II cervical cancer. One-hundred and thirty cases (62%) were found to be diploid, whereas 82 (38%) were aneuploid. Univariate analysis of the follow-up data showed an increased relative risk (RR) for recurrence free survival (RFS) for stage II tumors (RR = 1.87, 95% CI: 1.13–3.10, P = 0.015) and for age (RR = 1.52, 95% CI: 0.66–3.52 and RR = 2.35, 95% CI: 1.19–4.65, P = 0.032). Ploidy showed a relative risk of 1.33 (95% CI: 0.83–2.13, NS). In addition, univariate analysis of overall survival (OS) revealed similar results. For the subgroup of patients with primary surgery ( n = 151), positive pelvic nodes (RR = 5.38, 95% CI: 2.70–10.71, P = 0.0001) and parametrial extension (RR = 2.53, 95% CI: 1.24–5.17, P = 0.011) were significant factors for OS after univariate analysis, the estimated effects on RFS were slightly smaller. Multivariate analysis of RFS for the whole study population showed age, histologic grade and stage with a slightly increased risk, but no effect was significant. Ploidy with an RR of 0.97 (95% CI: 0.58–1.62) seems to have no influence on prognosis. For the subgroup with primary surgery, ploidy again failed statistical significance with an RR of 1.20 (95% CI: 0.58–2.49). Our results suggest that abnormalities of the nuclear DNA content in this homogeneous group of patients are associated with clinical and morphological prognosticators, however, ploidy is not an independent prognostic factor for RFS, or for the whole study population or for the subgroup with primary surgery.     

Adjuvant radiation therapy is not necessary in the management of endometrial carcinoma stage I, low-risk cases

In an attempt to create uniform nationwide guidelines for the management of all stages of endometrial carcinoma, and to limit the use of adjuvant radiation therapy in stage I disease to high-risk patients only, a protocol was developed by the Danish Endometrial Cancer group (DEMCA). From September 1986 through August 1988, 1214 women in Denmark with newly diagnosed carcinoma of the endometrium have been treated according to this protocol. This figure represents all endometrial carcinomas diagnosed in Denmark during this 2-year period. The primary treatment was total abdominal hysterectomy and bilateral salpingo-oophorectomy and no preoperative radiation therapy was delivered. In 1039 cases no macroscopic residual tumor and/or microscopic tumor tissue in the resection margins was found following surgery. Based on surgery and histopathology, these patients were classified as: P-stage I low-risk (grade 1 & 2 and 50% myometrial invasion), P-stage I high-risk (grade 1 & 2 and> 50% myometrial invasion, and grade 3), P-stage II and P-stage III (Group 1). Distribution was as follows: P-I low-risk 641 patients, P-I high-risk 235, P-II 105 and P-III (Group 1) 58 patients. No postoperative radiation therapy was given to P-I low-risk cases. P-I high-risk, P-II, and P-III (Group 1) cases received external radiation therapy. Recurrence rate at 68–92 months follow-up was 45/641 (7%) in P-I low-risk, 36/235 (15%) in P-I high-risk, 30/105 (29%) in P-II, and 27/58 (47%) in P-III (Group 1) cases. Fifteen of 17 vaginal recurrences in P-I low-risk cases were salvaged (mean observation time 61 months).     

Combined E-cadherin, α-catenin, and β-catenin expression is a favorable prognostic factor in endometrial carcinoma

Cell adhesion molecules, such as epithelial cadherin (E-cadherin), might be involved in the processes of tumor invasion and differentiation. The aim of this study was to investigate the expression of E-cadherin, alpha-catenin, and beta-catenin in endometrial carcinoma and to determine the prognostic value of these factors. We have investigated the expression of E-cadherin, alpha-catenin, and beta-catenin by immunohistochemistry in 225 endometrial carcinomas. The correlation between the E-cadherin and the catenins and their correlation with several histologic and clinical parameters were analyzed. Negative E-cadherin, alpha-catenin, and beta-catenin expression was observed in 44%, 47%, and 33% of endometrial carcinomas, respectively, and was correlated with histologic FIGO grade 3 (P < 0.001). Negative E-cadherin expression was more often observed in nonendometrioid endometrial carcinomas (NEECs) than in endometrioid carcinomas (75% versus 43%; P= 0.04). Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was an independent positive prognostic factor for survival in patients with grade 1-2 carcinomas (P= 0.02). Negative E-cadherin expression was found to be associated with histologic grade 3 and with NEEC. Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was a significant prognostic factor.     

Elevated platelet count in patients with endometrial carcinoma: correlation with selected prognostic factors and with survival

Platelets may play a role in the metastatic process and, among gynecologic malignancies, thrombocytosis has been reported in cervical and ovarian malignancy. The present study was conducted in order to assess the prevalence of thrombocytosis in endometrial carcinoma and to correlate platelet count with prognostic factors and with survival. The prevalence of preoperative thrombocytosis was assessed in 66 endometrial carcinoma patients and their platelet count was correlated with selected prognostic factors and with projected survival. The prevalence of thrombocytosis ( 400 000 µL⁻¹) was low (one of 66 patients) compared with that in cervical and ovarian carcinoma. Nevertheless, a significant ( P = 0.032) correlation was found between an elevated ( 300 000 µL⁻¹) platelet count and unfavorable grade of differentiation. Patients with an elevated count also had a poorer survival rate and a higher prevalence of older age, high stage and deep myometrial invasion, but this trend did not reach statistical significance. The combination of unfavorable grade and an elevated platelet count had a higher specificity and positive predictive value for deep myometrial invasion than unfavorable grade alone. The prevalence of thrombocytosis in endometrial carcinoma is low. An elevated platelet count may have some prognostic significance, but its ultimate role in endometrial carcinoma remains to be elucidated.     

Lymphadenectomy in high risk endometrial carcinoma stage I and II: no more morbidity and no need for external pelvic radiation

Abstract. Berclaz G, Hänggi W, Kratzer-Berger A, Altermatt HJ, Greiner RH, Dreher E. Lymphadenectomy in high risk endometrial carcinoma stage I and II: no more morbidity and no need for external pelvic radiation.
The objectives of this retrospective study were to analyze the morbidity of surgical staging and to evaluate the omission of external radiotherapy in high-risk patients with stage I and II endometrial carcinoma when the lymph nodes were negative.
From 1988 to 1996, 63 of 117 patients underwent a pelvic and periaortic lymphadenectomy. The decision to perform lymphadenectomy was influenced by patient general health.
Patients with lymphadenectomy had a better physical status ( P < 0.0001). Lymphadenectomy increased mean operative time ( P < 0.0001) and blood loss ( P < 0.01), but there was no increase in postoperative complications. At a median follow-up of 54 months, there was one cuff recurrence in 56 patients. Nineteen high-risk patients without external pelvic radiation had the same disease-free survival rate as 37 low-risk patients ( P = 0.1). In the group without lymphadenectomy, the disease-free survival for 18 high-risk patients and 32 low-risk patients was similar ( P = 0.21).
Surgical staging in properly selected patients does not increase postoperative complications and brachytherapy without external radiotherapy is associated with excellent disease-free survival when the lymph nodes are negative.     

Cervical carcinoma: a hazard model in early stage disease

The 235 patients with stage IB/IIA cervical carcinoma treated by Wertheim's hysterectomy, as a primary procedure, at St Mary's Hospital, Manchester between 1975 and 1989 inclusive, form the basis of this study. Using Cox's regression model, four variables were shown to have independent prognostic significance. These were: (1) lymphatic permeation (adjacent to the tumor); (2) tumor volume; (3) being pregnant at diagnosis and (4) lymph node metastases. A heuristic model was formulated which was based upon these four factors and by using this information it was possible to separate the patients into four distinct prognostic groups. It is suggested that this model may prove useful in identifying those patients at a higher risk of dying of disease and who would benefit from early adjuvant systemic therapy.     

Endometrial carcinoma Stage I-Grade II. Conservative treatment followed by a healthy twin pregnancy

Zuckerman B, Lavie O, Neumann M, Rabinowitz R, Ben-Chetrit A, Voss E, Rosenmann E, Beller U. Endometrial carcinoma Stage I-Grade II. Conservative treatment followed by a healthy twin pregnancy. Int J Gynecol Cancer 1998; 8 : 172–174.
Endometrial cancer treatment is commonly based on hysterectomy as the first step, thus creating infertility. This approach troubles the young patient who desires future pregnancies. Hence, the well-known, yet seldom chosen, high-dose progesterone therapy might offer an adequate alternative treatment for a small, carefully selected group of young, early endometrial cancer patients.
Presented is a 26-year-old multipara diagnosed, on resectoscopy, with Stage I moderately differentiated carcinoma of the endometrium. Treatment included high dose progesterone and residual disease was ruled out at follow-up. Twin gestation was terminated at term by a cesarean delivery of two healthy babies. We suggest that despite this successful case, this treatment should be offered only to selected patients who desire to preserve their fertility, and for whom close follow-up is possible to monitor the response to progestational therapy. In addition, we believe that at the completion of family planning of these patients, protective hysterectomy should be performed.