Management of aggressive histologic variants of endometrial carcinoma at the Tom Baker Cancer Centre between 1984 and 1994

OBJECTIVE: The aim of this study was to determine the patient characteristics and outcome of patients with aggressive histologic variants (AV) of endometrial carcinoma, including uterine papillary serous carcinoma (UPSC), uterine clear cell carcinoma (UCCC), and mixed type. METHODS AND MATERIALS: All cases with AV histological type of endometrial carcinoma from January 1984 to December 1994 at the Tom Baker Cancer Centre were identified using the Alberta Cancer Registry. Relevant data from the charts of these patients were entered into a study database (Microsoft Excel) and analyzed for presentation, demography, treatment parameters, and outcome of treatment. All pathology was reviewed at the time of diagnosis. Statistical analysis was performed using the S-plus statistics computer program. Univariate and multivariate analyses were used to assess independent prognostic factors using the Cox proportional hazards model. RESULTS: A total of 103 patients with AV histological type were identified and analyzed; there were 61, 31, and 11 cases of UPSC, CCC, and mixed tumors, respectively. Sixty-three patients had Stage I, 11 had Stage II, 15 had Stage III, and 14 had Stage IV disease. The median age of patients was 67 years with a range of 36 to 86 years. Median follow-up was 60 months with a range of 36 to 156 months. The Cox proportional hazards model showed that lymphvascular space invasion and stage are the two independent prognostic factors affecting recurrence and survival. Forty six percent of all cases underwent surgery alone, 39% underwent treatment which included pelvic RT, and 17% underwent treatment which included chemotherapy. Pelvic recurrence was reduced significantly by radiotherapy in Stages I, II, and III (19% recurrence with no RT vs 7% recurrence with RT, P < 0.005). Chemotherapy improved overall survival, but made little difference in distant relapse rates. CONCLUSIONS: Stage Ia cases treated by surgery alone have a low risk of relapse and need not be offered adjuvant systemic therapy or pelvic radiation. Patients with Ib, Ic, II, and III have significantly lower pelvic failure rates if treated with pelvic radiation, but still have a high distant failure rate. Systemic therapy did not significantly improve distant relapse-free survival, but did extend overall survival. Stage IV patients usually died within 6 months with a few responding to systemic chemotherapy. These results suggest that there is a need for randomized trials for these patients.     

Cervical neuroendocrine carcinoma: a clinical and light microscopic study of 14 cases

Fourteen primary cervical neoplasms with light microscopic features of neuroendocrine carcinoma were studied. Two were of intermediate cell type (IC), resembling the pulmonary atypical carcinoid; seven were small cell type (SC), analogous to pulmonary oat cell carcinoma; two were SC with foci of IC; three were SC with foci of squamous or adenocarcinoma. Four patients were Stage I, five were Stage II, two were Stage III, and three were Stage IV. One patient (Stage I) underwent hysterectomy and has completed radiation therapy. Two patients underwent radical hysterectomy and chemotherapy. One received radiation and chemotherapy; one received only chemotherapy; nine received radical radiation therapy. One patient (Stage I) is alive and well 10.5 years later; one (Stage II) died of other causes 24 months after diagnosis. One other is alive with the disease 12 months postdiagnosis. Eleven died secondary to tumor, four to 33 months (mean 14, median 12.5 months) after diagnosis. There was no significant difference in survival between IC and SC types, either mixed or pure. Cervical neuroendocrine carcinomas are biologically aggressive neoplasms, regardless of histologic type.     

Persistence of endometrial activity after radiation therapy for cervical carcinoma

Radiation therapy is a proved treatment for cervical carcinoma; however, it destroys ovarian function and has been thought to ablate the endometrium. Estrogen replacement therapy is often prescribed for patients with cervical carcinoma after radiation therapy. A review of records of six teaching hospitals revealed 16 patients who had endometrial sampling for uterine bleeding after standard radiation therapy for cervical carcinoma. Fifteen patients underwent dilatation and curettage, and one patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy when a dilatation and curettage was unsuccessful. Six patients had fibrosis and inflammation of the endometrial cavity, seven had proliferative endometrium, one had cystic hyperplasia, one had atypical adenomatous hyperplasia, and one had adenocarcinoma. Although the number of patients who have an active endometrium after radiation therapy for cervical carcinoma is not known, this report demonstrates that proliferative endometrium may persist, and these patients may develop endometrial hyperplasia or adenocarcinoma. Studies have indicated that patients with normal endometrial glands have an increased risk of developing endometrial adenocarcinoma if they are treated with unopposed estrogen. Patients who have had radiation therapy for cervical carcinoma should be treated with estrogen and a progestational agent to avoid endometrial stimulation from unopposed estrogen therapy.     

子宫内膜癌的分子病理分型及其研究进展

子宫内膜癌是一种在分子水平及组织学上存在显著异质性的恶性肿瘤,不同的病理类型具有不同的生物学行为及组织学特征。与其他组织学亚型的晚期癌症相类似,早期子宫内膜样癌通常采用辅助放射治疗,浆液性子宫内膜癌通常采用化疗。因此,正确的亚型分类是选择合适的辅助治疗方案的关键。目前,临床上子宫内膜癌的分型依旧引用Bokhman分型及世界卫生组织（World Health Organization,WHO）病理类型分型。随着精准医疗及分子诊疗技术的全面推广,传统子宫内膜癌分型方法在子宫内膜癌的个体化治疗、预后评估及相关遗传病筛查上的局限性逐渐凸显。临床上亟需一种优化的分型方法提供确切的理论及实践依据。2013年美国癌症基因组图谱（The Cancer Genome Atlas,TCGA）研究中心通过整合基因组特征的方法确定了子宫内膜癌的分子分型,该分型与Bokhman分型及WHO分型相比,取得了与子宫内膜癌患者预后更强的关联性,为子宫内膜癌的分子诊疗拉开了序幕。     

Screening for endometrial cancer in asymptomatic postmenopausal women with conventional and colour Doppler sonography.

OBJECTIVE: To evaluate endometrial thickness and uterine arterial flow measurement as predictors of endometrial cancer. DESIGN: Prospective study among a cohort of women invited to age-adjusted, population-based breast cancer screening by mammography. SETTING: City of Turku, Finland. POPULATION: 1074 postmenopausal women aged 57-61 years (mean 59 years). METHODS: Conventional and colour Doppler sonography. Endometrial biopsy was taken when the endometrial thickness (double layer) was > or = 4.0 mm, if the uterine artery pulsatility index was < or = 1.0 or if there was a fluid accumulation in the endometrial cavity. MAIN OUTCOME MEASURES: Detection of endometrial cancer in endometrial biopsy. Record linkage with the files of the Finnish Cancer Registry three and a half years after the first ultrasound examination. Major statistical results are based on the analysis of variance and logistic regression models. RESULTS: An endometrial biopsy was taken from 291 women (27%). One woman had endometrial tuberculosis, three an endometrial polyp, 16 endometrial hyperplasia, three endometrial carcinoma (Stage Ib), and one had cervical carcinoma (Stage Ib). One woman was diagnosed as having endometrial cancer Stage Ib two and a half years after screening; she had refused further examination after a positive screen. A second endometrial cancer (Stage Ib) was diagnosed three years after a negative screening result. CONCLUSION: Transvaginal sonography is confirmed to have a very high sensitivity for the detection of early endometrial carcinoma, but the specificity remains low. If endometrial cancer is to be detected at an early stage, further examinations should be carried out when the endometrial thickness is > or = 4.0 mm, especially when the woman has risk factors such as obesity, late menopause or current use of hormonal replacement therapy. Doppler sonography does not improve the detection of premalignant and malignant endometrial lesions compared with normal ultrasound.     

Papillary serous carcinoma--a less radio-sensitive subtype of endometrial cancer

OBJECTIVE: To explore factors that determine the response of endometrial cancer to radiation therapy. Such factors may influence treatment outcome and yield predictive information about individual patients and their tumors. METHODS: A retrospective study of the complete pathologic response (pCR) rates in the hysterectomy specimens of patients, who had undergone pre-operative radiotherapy for > or = Stage II biopsy-proven endometrial carcinoma, was performed. 62 patient records were reviewed with respect to patient characteristics, tumor stage, histological grade and subtype, radiation technique and dose, and presence or absence of pCR in the post-operative hysterectomy specimen. RESULTS: 24 of 62 specimens exhibited a pCR. The only significant factor with respect to pCR was presence of uterine papillary serous carcinoma (UPSC). None of the seven cases of UPSC displayed a pCR (P = 0.036 Fischer's exact test), despite not differing from the non-UPSC cases in any other tumor, treatment, or patient factors. No factors were found that separated non-UPSC cases with a pCR from those without. CONCLUSIONS: These data suggest an intrinsic radioresistance within UPSC, which may have implications for future treatment strategies. UPSC has documented genetic aberrations that may account for this, although its true radiosensitivity has yet to be quantitated directly. Future studies should focus on the molecular basis of its response to radiation. The reasons for the heterogeneous response of non-UPSC has yet to be elucidated and should also be investigated.     

Intraperitoneal chromic phosphate P 32 suspension therapy of malignant peritoneal cytology in endometrial carcinoma

Malignant peritoneal cytology in patients with endometrial carcinoma is a poor prognostic feature, identifying patients at high risk for early intra-abdominal recurrence. Between 1977 and January, 1983, 65 women with endometrial carcinoma who had malignant peritoneal cytology were treated with adjuvant intraperitoneal radioactive chromic phosphate P 32 suspension. Fifty-three patients (80%) were clinical Stage I, nine (14%) were Stage II, and three (7%) were clinical Stage III. Life-table estimates of disease-free survival were 89% for clinical Stage I patients and 94% for surgical Stage I patients beyond 24 months. One patient developed an intraperitoneal recurrence, four had simultaneous intraperitoneal and extraperitoneal recurrences, and six developed recurrences outside of the peritoneal cavity. Few significant acute complications occurred after therapy with radioactive chromic phosphate P 32 suspension. Chronic intestinal morbidity that required surgical correction was encountered in five of 17 patients (29%) who received adjuvant pelvic radiation, compared to none of the 48 patients (0%) who received only radioactive chromic phosphate P 32 suspension (p less than 0.001). Intraperitoneal instillation of radioactive chromic phosphate P 32 suspension is effective therapy for patients with malignant peritoneal cytology from endometrial carcinoma. Caution should be exercised when radioactive chromic phosphate P 32 suspension and external radiation therapy are combined.     

Invasive Vulvar Carcinoma in Two Women Infected with Human Immunodeficiency Virus

This report presents two HIV-infected women who developed invasive squamous cell carcinoma of the vulva. One patient was diagnosed with Stage II vulvar cancer 4 years after surgical excision of VIN. This patient underwent a hemivulvectomy and external-beam radiation therapy, but has subsequently developed recurrent vulvar cancer. The other patient was diagnosed with stage IV invasive vulvar cancer 1 year after the diagnosis of VIN and died of invasive vulvar cancer 11 months later. VIN should be considered a serious condition in HIV-infected women and clinicians should be careful to examine the vulva and perianal region in all HIV-infected women.     

Carcinoma of the cervix, FIGO Stage IB: treatment failures

All patients with carcinoma of the cervix, FIGO Stage IB, treated at the University of Minnesota Hospitals during a 10-year period were reviewed. Of the 220 patients 31 (14.0%) developed recurrent disease and did not survive. Thirteen patients had pelvic wall recurrences, with concurrent cervical involvement. No patient had a resectable pelvic recurrence. Hysterectomy was subsequently performed on 10 of the 172 patients who received radiation therapy. Carcinoma was not present in any of the operative specimens although two patients with adenocarcinoma later died of metastatic cancer. Median time of recurrence was 9 months, with median survival following recurrence of 6 months. Cervical cytology was not of value in the early diagnosis of recurrent disease. The 5-year adjusted actuarial survival rate for patients with adenosquamous carcinoma was significantly lower than that for patients with squamous cell carcinoma. The median age of patients not surviving with adenosquamous carcinoma was significantly lower than that for patients not surviving with squamous cell carcinoma. Patients with invasive carcinoma presumably confined to the cervix may have disseminated disease. It is essential such selected patients receive primary treatment that includes systemic therapy.     

Lymph node positivity in cervical cancer

From January 1962 until July 1978, 44 patients with invasive cervical cancer at exploratory surgery were found to have positive lymph nodes. Forty-three of these patients received radiation as definitive therapy after the discovery of lymph node metastasis. One patient had a positive left scalene biopsy as well and was treated only with chemotherapy. Thirty-three of the patients were clinically Stage IB. Two patients were Stage IIA, while 7 were IIB. There was 1 individual staged as IIIB. One patient was unstageable because of carcinoma found at operation for benign disease. Histologically, 35 of the 44 had squamous cell carcinoma. Five patients had adenocarcinoma, while 2 were adenosquamous. One patient was noted to be glassy cell type, and 1 patient had small cell undifferentiated carcinoma. Evaluation of the 44 operative specimens comparing clinical stage to highest positive node revealed that 32 patients (73%) had external iliac/obturator node involvement. Twenty-five of these were clinically Stage I disease. Twelve patients (27%) had involvement above the external iliac/obturator level and 8 of these were clinically Stage I. It is evident that a number of patients who are thought to have early disease clinically may have more advanced disease surgically and pathologically. Using the actuarial method of Berkson and Gage, the 5-year survival rate of the entire 44 operated patients was 52%. For comparison with other studies, we have additionally divided the patients into: (1) 22 who had completed hysterectomies and lymph node dissections followed by radiotherapy; (2) 22 who had lymph node sampling followed by radiation or chemotherapy alone. The actuarial survival of the first group was 71%. The survival of the second group, which included clinical Stages I, II, and III and one unstageable patient, was 34%.     

Invasive cervical cancer treated initially by standard hysterectomy

Ninety-two patients with invasive cervical cancer initially treated by standard hysterectomy were evaluated for features related to survival. The cell type included squamous cell (64) and adenocarcinoma (28). Posthysterectomy therapy included radiation therapy (78), pelvic lymphadenectomy (3), and radical parametrectomy (1). Hysterectomy was initially performed for the following indications: invasive lesion missed on cone biopsy, 17; hemorrhage at cone biopsy, 2; bleeding, 16; abnormal cytology, 13; presumed endometrial cancer, 9; known cancer, 7; pelvic relaxation, 5; planned therapy, 3; fibroids, 3; adnexal mass, 2; chronic discharge, 1; pyometra, 1; postpartum endometritis, 1. The cumulative 5-year survival for all patients was 68%, for squamous cell 80%, and for adenocarcinoma 41% (P = 0.0001). On postoperative evaluation 84 patients had presumed Stage I and 7 had parametrial involvement (Stage II). Patients with Stage I disease were then examined separately by cell type. Fifty-seven patients with squamous cell disease had cumulative 5-year survival of 85%. Radiation therapy in the immediate postoperative period produced a survival of 88%, compared to observation only with a 69% survival (P = .10). Patients with squamous cell disease and more than 50% cervical invasion had a 75% survival compared to a 96% survival for those with less than 50% (P = .02). The presence of disease at the surgical margins, grade, age, and increase in radiation therapy did not influence survival. Twenty-seven patients with presumed Stage I adenocarcinoma had a cumulative 5-year survival rate of 42%. Survival was significantly influenced by tumor grade (P = .018) and the amount of postoperative radiation therapy (P = .03), while age, amount of residual tumor, and presence of tumor at surgical margins did not influence survival. Patients with invasive squamous cell carcinoma treated by standard hysterectomy and postoperative radiation therapy have a prognosis similar to those treated initially by either radical surgery or radiation therapy. Patients with adenocarcinoma appear to have a significantly decreased survival when compared to patients with squamous cell disease and their prognosis is related to tumor grade and the amount of postoperative pelvic radiation.     

FIGO Stage I endometrial carcinoma: evaluation of lung metastases and follow-up

PURPOSE: The aim of our study was to evaluate the incidence of lung metastases in the follow-up of women submitted to surgery for endometrial carcinoma, in particular for FIGO Stage I which is the lowest risk stage for this metastatic site. METHODS: The study was conducted on 210 patients affected by FIGO Stage I endometrial cancer in the years 1990 to 2005 distributed as follows: 35 patients with Stage IA (limited to the endometrium), 150 patients with Stage IB (invasion up to and including half the myometrial thickness), 25 patients with Stage IC (invasion greater than half the myometrial thickness). They underwent follow-up. RESULTS: Only one patient out of the group studied has developed lung metastasis six years after surgery. She was staged as FIGO IB (T1b Mx G1). CONCLUSION: We are still following the cases and evaluating the biological behavior of this specific endometrial carcinoma and its reaction to further therapies. We are also looking for possible clinical characteristics in disagreement with those reported in the literature, which would thus make it necessary to reconsider the prognosis and therapy of this stage of disease.     

Stage II endometrial carcinoma

Fifty-one patients with FIGO Stage II endometrial carcinoma are presented. Sixteen patients were treated by external pelvic radiation therapy followed by radical hysterectomy. Eighteen patients were treated by external pelvic and intracavitary radiation therapy followed by simple hysterectomy. Seventeen patients were excluded from this study. Complications in the two major groups were compared. Questions regarding tumor differentiation, residual carcinoma in the surgical specimen, and the need for radical hysterectomy in Stage II endometrial carcinoma are discussed.     

Carcinomas of the female genital tract occurring after pelvic irradiation: a report of 15 cases.

The concept of postradiation sarcoma is widely appreciated, however carcinomas arising in previously irradiated fields, the putative "postradiation carcinoma," are less well understood. Fifteen patients who developed gynecological malignancies after pelvic radiation therapy were studied. Five of these patients had HPV-related tumors both pre- and post- irradiation. Ten were irradiated for cervical cancer, one for endometrial carcinoma, one for vulvar carcinoma, one for colon cancer and 2 for benign conditions. The mean and median latent periods from the initiation of radiation therapy to the development of the second malignancy were 22.8 and 19 years, respectively (22.4 and 19.5 years, respectively, for non-HPV-related cancers; 24 and 18 years for HPV-related cancers). The "postradiation" malignancies included 2 ovarian carcinomas, 5 vaginal carcinomas (3 invasive, 2 in situ), 4 endometrial carcinomas, one cervical carcinoma, one vulvar carcinoma, one distal urethral carcinoma, and one pelvic carcinoma of unclear primary site. Gynecological carcinomas may occur many years after pelvic irradiation. Although the evidence for a causative role is circumstantial, these tumors appear to have a similar latent period as postradiation sarcomas.     

Analysis of outcome of Stage I-III endometrial cancer treated with systematic operation omitting paraaortic lymphadenectomy

PURPOSE: The aim of this study was to assess the outcomes of endometrial cancer patients treated with systematic surgery omitting paraarotic lymphadenectomy. PATIENTS AND METHODS: We retrospectively analyzed a consecutive series of 84 endometrioid-type endometrial cancer patients at FIGO Stage I, II or III without grossly metastatic paraaortic lymphadenodes, who underwent surgery at our institute. RESULTS: Sixty-five patients (77%) underwent primary surgery with pelvic lymphadenectomy while the remaining 19 patients underwent surgery without lymphadenectomy due to severe medical complications or age greater than 70 years. The patients with high risk for recurrence were treated mainly by adjuvant irradiation therapy of the whole pelvis. The median follow-up period was 44 months. The 5-year overall survival (OS) rate was 92%, 92% and 65% for FIGO Stage I, II and III, respectively. Recurrence was detected in eight of the 82 optimally operated patients (9.8%). Out of the eight recurrent patients, five patients had a recurrent tumor at extra-pelvic sites (chest or abdomen), two patients had a recurrent tumor only in a paraaortic lymph node, and one patient had a recurrent tumor only in the vagina. Thus, the recurrence rate was relatively low, with 2.4% relapse at the paraarotic lymph nodes, and 5-year OS rate appeared to be favorable. However, all the six recurrent patients who underwent adjuvant radiation therapy had distant recurrence. CONCLUSIONS: These findings indicate that omission of paraarotic lymphadenectomy may be acceptable for endometrial cancer patients without gross metastasis at this site. However, the high rate of distant recurrence after whole pelvic irradiation strongly indicates an urgent need to develop potent systemic adjuvant therapy, potentially by chemotherapy or chemoradiation therapy.     

Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging

From January 1981 to December 1987, 82 patients with carcinoma of the ovary, Stages 1A, 1B, and 1C (cytology negative) (FIGO 1988), were enrolled in this study following accurate surgical staging. No patient received adjunctive therapy and all were followed from 2 to 6 years with a mean duration of follow-up of 4 years. Sixty-eight patients were eligible for review--thirty-nine Stage 1A, six Stage 1B, and twenty-three Stage 1C (twenty-one with tumor rupture, two with excrescences). The mean age was 48.8 years. Three patients had a recurrence of their disease (one death). Forty patients in this series were Stage 1A or 1B (well or moderately well differentiated, no excrescences, no rupture). Only 1 patient in this group (with clear cell carcinoma) has recurred, suggesting that this patient population can be followed without adjunctive therapy. Adhesions or rupture in this series did not affect outcome. Clear cell tumors may have an ominous prognosis despite apparent local disease.     

The effect of radiation therapy on brain metastases from endometrial carcinoma: a retrospective study

OBJECTIVE: The objective of this study was to investigate the effectiveness of radiation therapy as a treatment for brain metastases from endometrial carcinoma. METHODS: Between July 1985 and November 1999, 10 patients with brain metastases from endometrial carcinoma were treated at the Cleveland Clinic. We reviewed the patient and tumor characteristics at the time of the primary diagnosis and the brain metastases diagnosis. For the 8 patients who received radiation therapy with or without surgery, we analyzed the treatment results with regard to survival and local control of the metastases. RESULTS: Brain metastases from endometrial carcinoma were commonly accompanied by uncontrolled local-regional disease and systemic metastases. Multiple brain lesions developed in 7 of 10 patients. Two patients were treated with surgery alone and had a median survival of 2.75 months (4 and 1.5 months) after the brain metastases diagnosis. Three patients were treated with surgery and radiation therapy and lived for a median survival of 15 months (range 11.5 to 15.5 months). The 5 patients who were treated with radiation therapy without surgery had a median survival of 2.4 months (range 0.25 to 6 months). Patients with multiple brain metastases had a shorter survival than patients with a single metastasis. CONCLUSION: Overall survival after brain metastases development in patients with endometrial carcinoma was poor. Although the number of patients was small, radiation therapy alone resulted in poor survival. Combination treatment with surgery and radiation therapy may improve survival for selected patients.     

Preoperative radiation therapy in clinical stage II endometrial carcinoma.

From 1980 to 1987, 30 patients with FIGO clinical Stage II carcinoma of the endometrium were treated with 5000 cGy preoperative pelvic radiation therapy at Thomas Jefferson University Hospital. Patients with gross cervical disease received additional intracavitary irradiation with a tandem and ovoids for a combined total dose of 7000 cGy to point A. All patients then underwent exploratory laparotomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO). The 5-year actuarial survival for the entire group was 69%. The 5-year actuarial survival for the 8 patients with papillary serous, clear cell, and undifferentiated small cell carcinoma was 38%, with most patients failing in the upper abdomen. The 5-year actuarial survival for the remaining 22 patients was 82%. The only local failure occurred in the patient with an undifferentiated small cell carcinoma. Although preoperative pelvic radiation therapy together with TAH/BSO appears to offer excellent local control in all patients with Stage II endometrial carcinoma, additional treatment options should be considered for patients with papillary serous and clear cell histologies because of the poor survival and high failure rate in the upper abdomen.