Immunohistochemical comparison of uterine papillary serous and papillary endometrioid carcinoma: clues to pathogenesis.

Twenty-four predominantly papillary carcinomas of the endometrium, 10 serous and 14 endometrioid, were compared using a variety of immunohistochemical antibodies, including p53, estrogen and progesterone receptors, carcinoembryonic antigen, and E-cadherin. These were selected to attempt to find clues to explain the disparate behavior of these two tumor subtypes. We found that 6 of 8 (75%) serous carcinomas had a p53 reactivity score of 300, whereas 90% of endometrioid tumors had a p53 reactivity score of less than 20 (p = 0.0008). Combined estrogen and progesterone hormone reactivity was positive in 13 (100%) of endometrioid lesions compared with 4 of 8 (50%) of serous lesions (p = 0.0117). The significantly greater p53 expression and its significantly diminished hormone receptor expression indicate that papillary serous carcinomas belong to the type II group of endometrial carcinomas that occur in a background of atrophic endometrium, are high grade, present with high stage disease, and have a poor prognosis. In contrast, papillary endometrioid carcinomas, which belong to type I carcinomas, often arise in a background of estrogen-stimulated endometrial hyperplasia, are usually well-differentiated, and have a good prognosis. Early p53 mutations in papillary serous carcinoma as well as in endometrial intraepithelial serous carcinoma may partially explain their proclivity for early intra-abdominal dissemination. Carcinoembryonic antigen expression was similar in both groups and therefore is not useful to characterize possible differences in the cell of origin. The reactivity scores for E-cadherin were also similar in the two tumor subtypes, thus not supporting the hypothesis that decreased cell to cell adhesion molecules might contribute to early dissemination of serous lesions.     

Synchronous ovarian endometrioid adenocarcinoma with a functioning stroma and endometrial endometrioid adenocarcinoma by different loss of heterozygosity findings

Purpose  

Mucinous epithelial ovarian tumors generally have estrogenic stroma, although the frequency of endometrioid adenocarcinoma with functioning stroma is very low. And while synchronous development of carcinomas in the endometrium and ovaries is a fairly common phenomenon, the distinction of a single clonal tumor with metastasis from two independent primary tumors may present a diagnostic challenge. We present a rare case of a 31-year-old woman with endometrioid adenocarcinoma of the ovary with functioning stroma and endometrial endometrioid adenocarcinoma who showed symptoms of virilization. Her preoperative levels of serum testosterone and estradiol were as high as 553 ng/dL and 177 pg/mL, respectively, and her serum gonadotropin levels were suppressed. After surgery, the serum levels of testosterone and estradiol decreased and that of follicle-stimulating hormone increased.     

Comparative immunohistochemical study of endometrioid and serous papillary carcinoma of endometrium.

OBJECTIVE: The aim of this study was to determine whether immunohistochemical analysis of molecular parameters can provide an alternative method for classification of endometrial cancer cases according to their aggressiveness. METHODS: Sixty-four cases of endometrial carcinoma were assigned to three groups: group I--28 cases of endometrioid well and moderately differentiated (G1-G2) carcinoma; group II--14 cases of endometrioid poorly differentiated (G3) carcinoma; group III--22 cases of serous papillary endometrial cancer. Immunohistochemistry was used to determine the existence of estrogen receptors (ER), progesterone receptors (PR), and the expression of bcl-2, p53, HER-2/neu and Ki-67. RESULTS: There was a significant difference in the immunohistochemical profile of the studied molecular parameters comparing the three study groups. The endometrioid G1-G2 cases (group I) were characterized by increased immunoreactivity for ER and PR (85.7% and 78.6%, respectively), increased immunoreactivity for bcl-2 (42.8%) and low expression of p53 (14.3%) and HER-2/neu (14.3%). In contrast to group I cases, the serous papillary endometrial cancer cases (group III) were characterized by immunonegativity for ER, PR and bcl-2 and high immunoreactivity for p53 (81.8%) and HER-2/neu (45.4%). The endometrioid G3 cases (group II) demonstrated an intermediate immunoprofile, characterized by immunonegativity for ER, PR and HER-2/neu, low immunoreactivity for bcl-2 (7.1%) and high expression of p53 (57.1%). The expression of Ki-67 did not differ significantly comparing the different cases of endometrial cancer. CONCLUSION: This study provides evidence that the immunohistochemical analysis of endometrial carcinoma differentiates between different grades and histological types, thus being useful in the distinction of high risk cases.     

Prognostic significance of hysteroscopic imaging in endometrioid endometrial adenocarcinoma

OBJECTIVE: The aim of this study was to relate hysteroscopic features of endometrioid endometrial adenocarcinoma to stage, grade and overall survival. METHODS: Sixty women with endometrioid adenocarcinoma underwent laparotomy and staging according to current FIGO classification. Before surgery hysteroscopy was performed in all patients to establish the morphology of neoplasia, the extent of endometrial lining involvement, and endocervical spreading. These hysteroscopic parameters were related to overall survival, surgical stage, and grade of disease. RESULTS: First-stage carcinomas were found in 50 patients, second-stage in 4, third-stage in 3, and fourth-stage in 3 patients. Well-differentiated tumors were detected in 32, moderately differentiated in 21, and poorly differentiated in 7 patients. The cumulative 48-month probability of survival was 86.6%. The morphology of adenocarcinomas was unrelated to both their stage and their grade; no relationship to survival was found. The extent of carcinomatous spread within the endometrial cavity was significantly related to stage, grade, and survival. Endometrial lining involvement of less than 50% was associated with 100% survival, 97.1% of first-stage diseases, and 96.6% of low-grade carcinomas. These percentages dropped to 73.1, 65.3 (Fisher's exact test, P = 0.001), and 76.9% (Fisher's exact test, P = 0.035), respectively, when tumoral growth involved more than half of the endometrium. Hysteroscopy detected all carcinomas metastasizing to the cervix; in 8 patients we overdiagnosed endocervical spreading, although histology was negative. From these figures, hysteroscopy showed a sensitivity and specificity in predicting cervical spread of 100 and 87.3%, respectively. CONCLUSIONS: The extent of endometrial lining involvement in patients with endometrioid carcinoma provides preoperative information on the risk of extrauterine spread. We confirm the high accuracy of hysteroscopy in excluding cervical spread.     

The outcome of stage I-II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma

PURPOSE: The aim of this study was to compare survival and recurrence in clinical and surgical stage I-II papillary serous (PS), clear cell (CC), and endometrioid (EM) cancers of the endometrium and examine the prognostic utility of myometrial invasion. METHODS: Clinical, surgicopathologic, and survival data were retrospectively collected on 574 clinical stage I-II endometrial cancer patients, including 53 PS and 18 CC (based on postoperative histology), undergoing hysterectomy at Duke University Medical Center between 1967 and 1990. All staging material was available and reexamined prior to this analysis, and FIGO surgical staging was retrospectively assigned. Prognostic variables examined included age, stage, grade, myometrial invasion, lymph-vascular space invasion (LVSI), and histology. PS and CC histologic subtypes were compared as both common category and discrete categories versus EM, EM grade 1 (EM1), EM grade 2 (EM2), and EM grade 3 (EM3). Statistical analyses were performed using chi(2), Fisher's exact, and Wilcoxon rank sum tests, Cox regression analysis, and Kaplan-Meier survival analysis. RESULTS: PS tumors accounted for 9%, CC for 3%, and EM for 88% of cases. Recurrences were more frequent among PS (38%) and CC (22%) compared with EM (9%) (P < 0.001 and 0.08, respectively), and PS recurred more frequently than EM3 alone (20%) (P = 0.06). Among PS, CC, and EM3 patients with recurrences there were no statistical differences in the proportion that received preoperative or postoperative radiotherapy or chemotherapy. Prognostic factors for shorter survival included age >=60, surgical stage III+IV, presence of LVSI, histology (PS, CC, or EM3), and >=50% myometrial invasion. The estimated 5-year survival of PS+CC patients with <2 mm myometrial invasion is 0.56 compared to 0.93 for EM patients (P < 0. 001). PS + CC tumors confined to the endometrium had a 5-year survival of 0.60 compared to 0.98 and 1.00 for EM and EM3, respectively. The 5-year survival for surgically staged IA patients (0.57) was not different from stages IB and IC combined (0.53) (P = 0.72). The 5-year survival for surgical stage I + II PS + CC patients (0.56) was comparable to that for clinical stage I + II PS + CC patients (0.46) and remained significantly smaller than that for EM patients (0.86) (P < 0.001). CONCLUSION: Recurrences are more frequent among PS and CC tumors compared with EM and among PS compared with EM3. When controlled for surgical stage I-II tumors, 5-year survival for PS + CC patients remains comparable to that of clinical stage I-II patients and below that of EM. Prognostic factors for survival in PS and CC patients include age, stage, and LVSI. PS, CC, and EM3 subtypes together are predictors of poor survival. Thorough extended surgical staging is indicated in PS and CC tumors, and prospective trials of aggressive adjuvant therapies for surgical stage I-II tumors are needed to improve outcome in PS and CC patients.     

Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines

Purpose

The role of the insulin-like growth factor (IGF) system in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR signaling pathways. The aim of the present study was to investigate the anti-proliferative activity of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines.

Methods

Type I (ECC-1, Ishikawa) and Type II (USPC-1, USPC-2) endometrial cancer cell lines were treated with NVP-AEW541 in the presence of IGF-I, and the following parameters were measured: IGF-IR, AKT and ERK phosphorylation, apoptosis, proliferation, cell cycle progression and IGF-IR internalization.

Results

Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated, whereas it abolished AKT and ERK phosphorylation preferentially in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor.

Conclusion

Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer.     

The use of P53, PTEN, and C-erbB-2 to differentiate uterine serous papillary carcinoma from endometrioid endometrial carcinoma

Endometrial adenocarcinoma is the most common pelvic genital malignancy in the western world. The most common subtype of endometrial cancer is endometrioid endometrial carcinoma (EEC), which has a relatively good prognosis. Uterine serous papillary carcinoma (USPC) is also a subtype of endometrial carcinoma. This is an aggressive carcinoma with the majority of patients presenting at stage 3-4 and has a worse prognosis stage for stage when compared with EEC. In addition, the treatment of USPC is more extensive than that of EEC, and therefore definitive diagnosis before surgery ensures the optimum management for the patient. This study aims to determine whether P53, C-erbB-2, and PTEN antibodies have a use in the diagnosis and distinction of these cancers. We created tissue microarrays for 35 cases of EEC and 25 cases of USPC, and then we assessed the immunohistochemical expression of P53, C-erbB-2, and PTEN. There was significantly greater expression of P53 in USPC than that in EEC. However, neither C-erbB-2 nor PTEN showed any significant difference in expression between the two carcinomas. P53 may have a role in the diagnosis of USPC, but neither C-erbB-2 nor PTEN would be useful as part of a diagnostic panel.     

Development of metastatic endometrial endometrioid adenocarcinoma while on progestin therapy for endometrial hyperplasia

BACKGROUND: Conservative treatment with progestins is a reasonable treatment option for endometrial complex atypical hyperplasia and, in the experimental setting, for some women with grade 1 endometrial endometrioid adenocarcinoma. The risk of progression to a high-stage endometrial cancer is quite low, with only two previously reported cases in the English literature. CASE: A 40-year-old woman with endometrial complex atypical hyperplasia diagnosed by dilatation and curettage was managed conservatively with progestin therapy (initially, megesterol acetate; then, a combination oral contraceptive). More than 2 years after her original diagnosis, she developed endometrial endometrioid adenocarcinoma, FIGO grade 2, with lymph node metastasis. The tumor was microsatellite instability-high due to methylation of MLH1 and loss of MLH1 protein. CONCLUSION: Currently, there are no good criteria for predicting which patients with complex atypical hyperplasia/grade 1 endometrioid adenocarcinoma will optimally respond to progestin therapy. There is some evidence that endometrial complex hyperplasia demonstrating loss of MLH1 protein by immunohistochemistry is strongly related to subsequent or concurrent endometrial cancer, especially tumors of higher grade and stage. In a woman with a biopsy diagnosis of endometrial hyperplasia, evaluation of MLH1 protein status by immunohistochemistry may provide useful information when medical management is being considered.     

LRP16基因在子宫内膜样腺癌中的表达及意义

目的:探讨LRP16在子宫内膜样腺癌(EEC)中的表达及与临床病理的相关性。方法:用免疫组化法检测76例EEC患者癌组织标本中LRP16和雌激素受体α(ERα)的表达水平。结果:LRP16核阳性率为67.11%(51/76),LRP16浆阳性率为96.05%(73/76),浆核均阳性占64.47%(49/76);ERα阳性占51.32%(39/76),阴性占48.68(37/76)。ERα阴性患者中LRP16核阳性率(86.49%,32/37)明显高于ERα阳性患者(48.71%,19/39)(P<0.01),且LRP16在胞核中表达与EEC患者的手术病理分期无显著相关性(P>0.05)。在胞浆中分布的LRP16与ERα表达无关(P>0.05),但胞浆中的LRP16与EEC的手术病理分期呈明显的负相关(P<0.01),与组织学分级则无显著相关性(P>0.05)。在LRP16核浆均阳性的病例中,ERα阴性患者(81.08%,30/37)的比例明显高于ERα阳性患者(48.72%,19/39)(P<0.01);且LRP16在核浆中均有表达与EEC患者的手术病理分期及组织学分级无显著相关性(P>0·05)。在EEC肿瘤细胞中核、浆分布的LRP16着色强度呈负相关(P<0.05)。结论:LRP16在EEC细胞中均有表达,但其亚细胞分布与ERα状态密切相关,LRP16在胞浆中的表达可能提示预后良好。     

Fractal analysis of surface growth patterns in endometrioid endometrial adenocarcinoma

Objective: A fractal is a shape made of parts similar to the whole in some way. The objective of this study was to determine whether surface growth patterns in endometrioid endometrial adenocarcinoma are fractal, and the mean fractal dimension differs according to histologic grades and depth of myometrial invasion. Methods: After the images of photographs of 120 resected uteri with endometrial cancers were digitized, the fractal dimensions of surface of tumors were measured using a fractal analysis software. Results: The mean fractal dimensions of surface growth patterns in G1, G2, and G3 adenocarcinoma were 2.318, 2.303, and 2.383, respectively. These values were significantly greater than the topological dimension of a surface (= 2). The value was significantly higher in G3 than in G2 (p = 0.03). And although not statistically significant, the value of G3 was greater than G1 (p = 0.10) and than (G1 and G2) group (p = 0.06). No significant difference nor tendency was found in the fractal dimension of the surface of the tumor according to depth of invasion. Conclusion: This study shows that the surface of endometrioid endometrial adenocarcinoma has a fractal structure, and the mean fractal dimension may differ according to histologic grades. Our report proposes a new way of looking at endometrial cancer pathology. We believe that fractal geometry gives insights into tumor morphology and becomes a useful tool for analyzing complex and irregular tumor growth patterns mathematically.     

Opposite alterations of DNA methyltransferase gene expression in endometrioid and serous endometrial cancers

OBJECTIVE: To examine the DNA methyltransferase (DNMT) mRNA and protein levels in endometrioid and serous cancers and to study the relationship between DNA methyltransferase expression and endometrial cancer development. METHODS: Normal endometrium, Grade I and Grade III endometrioid carcinoma tissues and cell lines, as well as serous cancer tissues, were analyzed for DNMT expression. Real-time PCR and Western blot techniques were employed to measure the mRNA and protein levels of the four DNA methyltransferases, DNMT1, DNMT2, DNMT3A, and DNMT3B. Immunohistochemistry was performed to detect alterations in DNMT nuclear localization and spatial organization patterns. RESULTS: While DNMT2 and DNMT3A expression appear to be normal, two- to fourfold increase in DNMT1 and DNMT3B were found in both Grade I and Grade III endometrioid cancers. In addition, the poorly differentiated cell lines expressed relatively higher DNMT levels than well-differentiated cells. In contrast to endometrioid carcinomas, serous cancers expressed substantially lower levels of DNMT1 and DNMT3B than normal controls, with four- and twofold reduction observed in DNMT1 and DNMT3B mRNA levels, respectively. Western blot analysis confirmed opposite expression patterns of DNMT1 and DNMT3B protein in endometrioid and serous cancers. Immunohistochemistry showed normal nuclear localization of DNMT1 and DNMT3B in Type I and Type II cancer specimens as well as cell cultures. CONCLUSION: Two opposite DNMT expression patterns were identified in endometrioid and serous cancers. The concerted upregulation in maintenance and de novo DNA methyltransferases in endometrioid carcinomas is consistent with a tendency for gene-specific hypermethylation observed in this histologic subtype, and may be implicated in tumor suppressor silencing. In contrast, the downregulation of maintenance and de novo DNA methyltransferases in serous cancers suggests that these tumors may contain hypomethylated genomic DNA, which has been associated with a higher mutation rate and is consistent with the known pathogenesis of serous-specific phenotypes. Taken together, the data suggest that divergent DNA methylation pathways may be implicated in the development of Type I and Type II endometrial cancers.     

Primary peritoneal papillary serous adenocarcinoma: Clinical and management aspects

From January 1, 1984 to April 30, 1990, 38 patients were surgically found to have an intraabdominal disease resembling epithelial ovarian cancer. This diagnosis was confirmed in 31 patients; the remaining 7 met the criteria of primary peritoneal papillary serous carcinoma. Five of these were diagnosed retrospectively and two during surgery. The mean age at diagnosis was 61.2 years. Tumor histology revealed papillary serous carcinoma in six and mixed (papillary serous and papillary clear cell carcinoma) in one patient. Optimal debulking was achieved in three of seven cases (42.8%). Cisplatin-based combination chemotherapy was administered to all in the study group. Complete response was obtained in four patients, with one surviving for 76 months. The median survival in these patients was 34.5 months (range 6–76 months). Currently, three patients with complete response are alive with clinically undetectable disease. CA-125 assays were available in three cases and blood levels corroborated the clinically determined status of the disease. Tumor steroid hormone receptor status was determined in one case and revealed low levels of estrogen and progesterone receptors. To the best of our knowledge, the usefulness of CA-125 in the diagnosis, management, follow-up, and determination of tumor steroid hormone receptor status, mixed papillary serous and clear cell subtype histological patterns for primary peritoneal papillary serous carcinoma are first described in this report. It seems that this neoplasm may be treated and followed up as in epithelial ovarian cancer, obtaining long-term survival; however, the biologic behavior and management problems of this relatively new entity deserve further clinical experience.     

Primary peritoneal papillary serous adenocarcinoma: clinical and management aspects

From January 1, 1984 to April 30, 1990, 38 patients were surgically found to have an intraabdominal disease resembling epithelial ovarian cancer. This diagnosis was confirmed in 31 patients; the remaining 7 met the criteria of primary peritoneal papillary serous carcinoma. Five of these were diagnosed retrospectively and two during surgery. The mean age at diagnosis was 61.2 years. Tumor histology revealed papillary serous carcinoma in six and mixed (papillary serous and papillary clear cell carcinoma) in one patient. Optimal debulking was achieved in three of seven cases (42.8%). Cisplatin-based combination chemotherapy was administered to all in the study group. Complete response was obtained in four patients, with one surviving for 76 months. The median survival in these patients was 34.5 months (range 6-76 months). Currently, three patients with complete response are alive with clinically undetectable disease. CA-125 assays were available in three cases and blood levels corroborated the clinically determined status of the disease. Tumor steroid hormone receptor status was determined in one case and revealed low levels of estrogen and progesterone receptors. To the best of our knowledge, the usefulness of CA-125 in the diagnosis, management, follow-up, and determination of tumor steroid hormone receptor status, mixed papillary serous and clear cell subtype histological patterns for primary peritoneal papillary serous carcinoma are first described in this report. It seems that this neoplasm may be treated and followed up as in epithelial ovarian cancer, obtaining long-term survival; however, the biologic behavior and management problems of this relatively new entity deserve further clinical experience.     

Cytogenetic abnormalities in serous papillary adenocarcinoma of the ovary

PURPOSE OF INVESTIGATION: Epithelial ovarian tumors are usually mucinous or serous type, affecting nearly 1% of women during their lifetime. They may be regarded as benign, borderline or invasive according to pathological examination. Karyotypes of the tumor provide critical information about both the genetic predisposition and the stage of the tumor. We aimed to investigate the correlation between karyotype findings and the stage of the serous papillary tumors of the ovary. METHODS: Tissue cultures were set up from 15 serous papillary adenocarcinoma samples of different stages and examined cytogenetically. RESULTS: The most common chromosome abnormalities included both numerical and structural abnormalities of chromosomes 1, 3,6,7,8, 11, 21, 22 and X. CONCLUSION: Karyotypes became more complex, as expected, with the later stages.