Clinical and molecular comparison between borderline serous ovarian tumors and advanced serous papillary ovarian carcinomas.

The aim of this study was to characterize the clinical and molecular markers of borderline serous ovarian tumors (BSOT), and to study their expression in the progression from benign lesions to advanced serous papillary ovarian carcinomas (SPOC). The clinical records of 20 patients with BSOT and 22 patients with SPOC were reviewed. Specimens from all these cases and from six benign ovarian serous cystadenomas were evaluated for expression of estrogen receptors (ER), progesterone receptors (PR), p53. HER-2/neu and Ki-67 by immunohistochemical techniques. The mean patient age and the age at menarche differed significantly between the compared groups of BSOT and SPOC (p=0.0006 and p=0.0014, respectively). No difference was observed comparing the other clinical parameters. The immunohistochemical analysis demonstrated a significant increase in the expression of ER (100% vs 72.7%), and a significant decrease in the immunoreactivity for p53 (0% vs 45.4%) and Ki-67 (2% vs 26.8%) in cases of BSOT compared with those of SPOC (p=0.007, p=0.0003 and p=0.012, respectively). No significant difference was demonstrated comparing the expression of PR and HER-2/neu. The immunostaining of benign ovarian serous cystadenoma specimens did not differ significantly from immunoreactivity observed in cases of BSOT. According to immunohistochemical analysis, BSOT had much more in common with benign serous tumors than with SPOC. The main difference between BSOT and SPOC was regarding the overexpression of p53 and Ki-67.     

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.     

Borderline tumors of the ovary: a clinico-pathologic and immunohistochemical study of 54 cases

OBJECTIVE: To study EGF-R, HER-2/neu (p185), p53, Mib-1 (Ki-67), Bax, Bcl-2, ras expression and ploidy in borderline tumors of the ovary by assessing their frequency, and relationship to histologic type, tumor recurrence and survival. METHODS: Fifty-four patients with borderline tumors were followed 3-140 months (median: 38 months). Paraffin-embedded sections were stained using monoclonal antibodies against EGF-R, HER-2/neu (p185), p53, Mib-1 (Ki-67), Bax, Bcl-2, and ras. The immunohistochemical findings were correlated to histologic subtype, tumor recurrence, and survival. RESULTS: Positivity for EGF-R was found in 24% (13/54), in 22% (12/54) p185 was positive, 9% (5/54) of tumors were p53-positive, Mib-1 (Ki-67)-positivity was demonstrable in 46% (25/54). Expression of Bax, Bcl-2, and ras was found in 37% (20/54), 28% (15/54) and in 7% (4/54) of the cases, respectively. CONCLUSION: The data demonstrate expression of EGF-R, p185/HER-2/neu, p53, Mib-1 (Ki-67), Bax, Bcl-2, and ras in a subgroup of patients with ovarian borderline tumors. Further studies to evaluate their prognostic value are warranted.     

Influence of chemotherapy on the expression of p53, HER-2/neu and proliferation markers in ovarian cancer.

OBJECTIVE: Mutated p53 and HER-2/neu play a role in the etiology of ovarian cancer. It is important to know whether the expression of these proteins is affected by platinum-containing chemotherapy. STUDY DESIGN: Together with the cell proliferation markers Ki-67 and PCNA, the expression of p53 and HER-2/neu was assessed before and after chemotherapy. Paraffin-embedded tumor sections from 20 patients with ovarian cancer and four patients with benign disorders of the ovaries (controls) were analyzed. The expression of p53 was determined by the antibodies DO-1 and BP53-12. In addition to HER-2/neu and PCNA specific antibodies, MIB-1 was used to detect Ki-67. RESULTS: The expression of all markers was higher in ovarian cancer patients than in non-malignant controls. MIB-1 showed a significant increase of expression after chemotherapy (P=0.002). HER-2/neu, p53 and PCNA also showed a clear increase after treatment, but this was not statistically significant. HER-2/neu is of prognostic relevance with respect to the response to chemotherapy (P=0.005) and survival (P=0.0002). CONCLUSION: The different markers tested all increase after chemotherapy, but the differences are not statistically significant. Low HER-2/neu expression correlates with good outcome at second look.     

Immunohistochemical staining for Ki-67 and p53 helps distinguish endometrial Arias-Stella reaction from high-grade carcinoma, including clear cell carcinoma.

The distinction of the Arias-Stella reaction from clear cell carcinoma of the endometrium is usually straightforward; however, this differential diagnosis can be difficult when the Arias-Stella reaction occurs outside the setting of pregnancy or in older patients. The differential diagnosis also is problematic when serous or clear cell carcinoma focally arises within an endometrial polyp, as part of "endometrial intra-epithelial carcinoma" (EIC), or in younger patients. The goal of this study was to determine whether immunohistochemical staining can distinguish the Arias-Stella reaction from endometrial high-grade carcinoma, particularly clear cell carcinoma. Cases of endometrial Arias-Stella reaction (n = 27), clear cell carcinoma (n = 11), serous carcinoma (n = 7), and EIC (n = 4) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, estrogen receptor (ER), and progesterone receptor (PR). Composite immunohistochemical scores based on the percentage and intensity of stained cells were calculated, as was the overall positivity (percentage positive cases), using a cutoff value of >/=5% stained cells and at least weak intensity. Appropriate statistical tests were performed. Ki-67 and p53 immunostaining was significantly less in Arias-Stella reaction than in clear cell carcinoma (p < 0.0001 for both) or serous carcinoma/EIC (p < 0.0001 for both), measured by the composite immunohistochemical scores or overall positivity. ER showed a significant difference only between Arias-Stella reaction and clear cell carcinoma; PR showed a significant difference only between Arias-Stella reaction and serous carcinoma/EIC. When clinical or histologic features cannot facilitate the differential diagnosis, immunohistochemical staining for Ki-67 and p53 may help distinguish endometrial Arias-Stella reaction from clear cell carcinoma and other types of high-grade carcinoma.     

Expression of HER-2/neu, epidermal growth factor receptor, vascular endothelial growth factor, cyclooxygenase-2, estrogen receptor, and progesterone receptor in small cell and large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathologic and prognostic study

We studied the immunohistochemical expression of HER-2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), estrogen receptor (ER), and progesterone receptor (PR) in uterine cervical small cell and large cell neuroendocrine carcinomas (SCNECs and LCNECs) from 24 patients seen at The University of Texas M.D. Anderson Cancer Center. The objectives were to determine their expression and prognostic role in survival. Twenty-three cases (95.8%) expressed VEGF. The tumors expressing EGFR, HER-2/neu, and COX-2 were modest in numbers: eight (33.3%), 10 (41.7%), and seven (29.2%), respectively. Only one tumor (4.2%) expressed ER, and only two tumors (8.3%) expressed PR. No significant differences in the expression of these factors were found between SCNECs and LCNECs or between stage I and stage II-III tumors. The median overall survival was 21.1 months (95% confidence interval [CI], 17.2-25.0 months). Only HER-2/neu expression was significantly associated with survival. Patients with negative HER-2/neu expression tumors had significantly shorter survival than those whose tumors were positive, 14.2 months (95% CI, 10.6-17.7 months) versus 33.1 months (95% CI, 0-76.92 months) (P = 0.03). There was a trend toward worse survival in patients with EGFR expression, but this finding was not significant. The combination of negative HER-2/neu expression and positive EGFR expression had the worst impact on survival.     

Expression of cyclooxygenase-2 (COX-2), receptors for estrogen (ER), and progesterone (PR), p53, ki67, and neu protein in endometrial cancer

OBJECTIVE: We aimed at investigating by immunohistochemistry the relationship between cyclooxygenase-2 (COX-2) and estrogen (ER), and progesterone (PR) receptors in a single institution series of 90 primary untreated endometrial cancer patients. The simultaneous assessment of p53 protein, ki67, and neu protein has been carried out. METHODS: Immunohistochemistry was performed on paraffin-embedded sections by using rabbit polyclonal antiserum against human COX-2, anti-ER (clone 1D5), and anti-PR (clone 1A6) monoclonal antibodies, anti ki67 (clone MIB-1) and p53 (clone DO-7), and polyclonal antibody anti human c-erbB2/neu. RESULTS: There was no difference in the distribution of COX-2, p53, and neu positive cases according to ER or PR positivity, while the percentage of ki67 positive endometrial tumors was significantly higher in ER negative versus ER positive tumors (54.5% versus 31.6%, P value = 0.044). ER and PR positive tumors showed a statistically significant association with clinicopathological parameters of better clinical outcome. There was no clear association between COX-2 positivity and any of the clinicopathological features. The percentage of ki67, p53, and neu positive tumors was found to be strictly related to more aggressive features. Only advanced stage of disease was found to be a predictor of poor prognosis (P value = 0.034). None of the biological parameters examined was shown to be associated with patient outcome. CONCLUSIONS: We showed that COX-2 expression is not correlated with ER, PR, p53, and neu, thus suggesting that COX-2-mediated activities may follow independent pathways. Our findings provide the rationale to design trials based on the combination of antihormones with inhibitors of COX-2 and neu in recurrent/metastatic endometrial cancer.     

Racial differences in the overexpression of epidermal growth factor type II receptor (HER2/neu): a major prognostic indicator in uterine serous papillary cancer

OBJECTIVE: A difference in survival rates between black and white patients with cancer of the corpus uteri is well established. This study was conducted to determine whether the overexpression of HER2/neu oncogene is associated with poor outcome in uterine serous papillary endometrial cancer, which is a highly aggressive variant of endometrial cancer, and whether a racial difference in the frequency of HER2/neu overexpression may contribute to the disparity in endometrial cancer survival. STUDY DESIGN: Immunohistochemical evaluation was used to examine HER2/neu expression in paraffin blocks from 27 women with stage IA to IV uterine serous papillary endometrial cancer. Univariable analysis was performed and followed by multivariable analysis with Cox's proportional hazard model to evaluate whether HER2/neu expression was associated with poor outcome in uterine serous papillary endometrial cancer. RESULTS: Black patients tended to be younger (P = .02) and have higher HER2/neu expression than white patients (trend P = .02). Seven of 10 black patients (70%) showed heavy (3+) expression, compared with 4 of 17 white patients (24%; P = .04). The association of heavy HER2/neu expression with race persisted after age was controlled through stratification (P = .05). Earlier deaths from uterine serous papillary endometrial cancer were seen among heavy HER2/neu expressers (P = .002), black patients (P = .04), and patients < or = 65 years old (P = .04). However, multivariate Cox regression showed that short survival was associated significantly with heavy HER2/neu expression (P = .02) but not with age (P = .07) or race (P = .35), which indicates that HER2/neu expression accounted for much of the race disparity in survival in this patient population. CONCLUSION: Overexpression of HER2/neu in uterine serous papillary endometrial cancer is an independent variable that is associated with poor outcome, occurs more frequently in black women, and may contribute to racial disparity in survival. HER2/neu expression may guide clinical treatment of patients with uterine serous papillary endometrial cancer and may have implications for the implementation of novel treatment strategies.     

原发性腹膜恶性肿瘤的免疫组化研究及其预后的相关分析

目的探讨原发性腹膜恶性肿瘤p53、Top2α、Ki-67和Her-2/neu的表达及其预测预后的价值。方法对1995年5月至2005年5月在北京大学人民医院治疗的21例原发性腹膜恶性肿瘤患者的石蜡组织标本,用免疫组化技术检测p53、Top2α、Ki-67和Her-2/neu的表达,分析其与化疗疗效和生存时间的关系。结果21例患者Top2α、Ki-67、p53阳性表达率均为52.4%(11/21),8例存在Top2α和Ki-67共表达;Her-2/neu全部呈阴性表达。Top2α与Ki-67表达呈显著的正相关,且均与肿瘤细胞分化等级呈显著正相关。铂类敏感组(10例)和耐药组(8例)p53阳性表达有统计学差异(3例vs7例,P=0.03)。p53阳性表达和阴性表达者的中位无进展生存时间分别为15个月和47个月,两者比较有统计学差异;p53阳性表达对总生存时间以及Top2α、Ki-67阳性表达对中位无进展生存时间和总生存时间均无显著影响。结论原发性腹膜恶性肿瘤组织中存在Top2α、Ki-67与p53的阳性表达,Top2α、Ki-67的表达与肿瘤细胞分化等级呈显著正相关,但对预后可能缺乏显著影响。p53阳性表达者中位无进展生存时间缩短,提示可能对铂类化疗耐药,预后可能较差。     

Expression of steroid receptors, Ki-67, and epidermal growth factor receptor in tamoxifen-treated endometrium.

Endometrial specimens of 34 (25 premenopausal and 9 postmenopausal) breast cancer patients receiving tamoxifen were immunohistochemically examined using estrogen receptor (ER), progesterone receptor (PR), Ki-67, and epidermal growth factor receptor (EGFR) antibodies. Proliferative (n = 6), secretory (n = 9), and postmenopausal (n = 6) endometria served as controls. The ER and PR expressions of the glandular cells in tamoxifen-treated patients did not differ from those of the glandular cells in the control women regardless of menopausal status. The Ki-67 index of glandular cells in tamoxifen-induced amenorrheic women was found to be lower than that of the proliferative glandular cells in the control women (p < 0.03), whereas the Ki-67 index of glandular cells in the tamoxifen-treated postmenopausal patients was higher than that of the glandular cells in the control women (p < 0.02). No EGFR overexpression was found in the glandular cells of the tamoxifen-treated premenopausal patients, but expression of EGFR was high in glandular cells of the tamoxifen-treated postmenopausal patients associated with a high Ki-67 index. In competition with ovarian estrogen secretion, tamoxifen may have an antiestrogenic effect on the endometrium, but tamoxifen probably has an estrogenic effect in the absence of ovarian estrogen secretion. This estrogenic effect of tamoxifen may be associated with an EGFR autocrine system.     

Overexpression of p53 and HER-2/neu and c-myc in primary fallopian tube carcinoma

Primary fallopian tube carcinoma is a rare form of female cancer and the genetic basis of its carcinogenesis remains unclear. Eighteen cases of primary fallopian tube adenocarcinoma were studied. Immunohistochemical staining for p53, HER-2/neu and c-myc genes were performed. Overexpression of p53 was detected in 12 cases (67%), HER-2/neu in 16 cases (89%), and c-myc in 11 cases (61%). The potential relevance of overexpression of the three genes with clinicopathological features was examined, but no significant correlation was found. The high incidence of p53, HER-2/neu and c-myc overexpression in fallopian tube adenocarcinoma suggests these genes may play a role in its tumorigenesis.     

Significantly greater expression of ER, PR, and ECAD in advanced-stage low-grade ovarian serous carcinoma as revealed by immunohistochemical analysis.

A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.     

Correlation of mammographic appearance and molecular prognostic factors in high-grade breast carcinomas

The aim of our study was to evaluate the association between the mammographic appearance and the biologic characteristics of high-grade breast carcinomas. Three hundred and twenty patients with breast carcinomas were studied. Histological examination showed 83 (26%) high-grade ductal carcinomas. Immunohistochemistry was carried out by using antibodies against estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, p53 and cathepsin D. In 60/83 high-grade carcinomas we studied the mammographic appearance. Asymmetric density with poorly defined margins without microcalcifications was the major mammographic finding in 49/60 (approximately 82%) high-grade ductal carcinomas. HER-2/neu positivity (68.7%) and p53 positivity (48.2%) were statistically correlated with asymmetric density with poorly defined margins without microcalcifications in high-grade carcinomas. We observed loss of ER and PR receptors in 50%, whereas loss of PR receptors was observed in 65% of high-grade breast carcinomas. Cathepsin D (> 20%) was detected in 38.5% of high-grade carcinomas. Our findings suggest a significant relationship between mammographic appearance and biologic markers in high-grade breast carcinomas.     

Long-term survival after paclitaxel plus platinum-based combination chemotherapy for extraovarian peritoneal serous papillary carcinoma: is it different from that for ovarian serous papillary cancer?

The purpose of this study was to compare the effect of paclitaxel plus platinum-based chemotherapy in the treatment of extraovarian peritoneal serous papillary carcinoma (EPSPC) and ovarian serous papillary cancer (OSPC). Only the patients treated with initial surgery plus postoperative adjuvant chemotherapy and having FIGO stage IIIC disease with omental and/or peritoneal involvement were analyzed. Thirty-two patients with EPSPC and 43 with OSPC were included in this study. The median age, mean CA-125, and volume of ascitis were higher in patients with EPSPC. There was no significant difference between the two groups with respect to other prognosticators. The median overall survival (OS) durations were 30 months (95% CI 24.8-35.3) in patients with EPSPC and 28 months (95% CI 21.1-34.9) in those with OSPC (P= 0.35). The 3-year OS rates in the patients and controls were 28% and 31%, respectively (P= 0.84). In patients with EPSPC, only optimal cytoreduction was significantly related to progression-free survival and OS durations as a prognostic factor. In the EPSPC group, 65.5% of the patients (19/29) had lymphatic involvement, compared to 88.4% (38/43) in the OSPC group (P= 0.02). As an adjuvant therapy, the paclitaxel plus platinum-based combination regimen had similar effects on survival in the EPSPC and OSPC groups.     

原发性腹膜恶性肿瘤的治疗及预后分析

目的 探讨原发性腹膜恶性肿瘤的临床治疗方案及预后相关因素。方法 对1995年5月—2004年4月在北京大学人民医院治疗的24例原发性腹膜恶性肿瘤患者的临床病理资料进行回顾性分析。结果 24例患者中,腹膜浆液性乳头状腺癌15例(中、高分化9例,低分化6例),腹膜混合型上皮性癌6例,腹膜恶性苗勒管混合瘤3例。全部患者均施行肿瘤细胞减灭术,其中满意的肿瘤细胞减灭术(残留灶直径＜2cm)3例,不满意的肿瘤细胞减灭术(残留灶直径≥2cm)21例。术后给予以铂类为主的联合化疗,其中13例行紫杉醇 顺铂或卡铂(TP)方案化疗,9例行顺铂 阿霉素 环磷酰胺(PAC)方案化疗。初次化疗缓解率为80％,其中完全缓解率为55％,部分缓解率为25％。患者的中位数生存时间为42个月(22～62个月),其中腹膜浆液性乳头状腺癌、恶性苗勒管混合瘤、混合型上皮性癌患者的中位数生存时间分别为44、13和19个月,前两者比较,差异有统计学意义(P＜0．05),而后者分别与前两者比较,差异均无统计学意义(P＞0．05);接受,TP和PAC方案化疗患者的平均生存时间分别为75、28个月,两者比较,差异有统计学意义(P＜0．05)。结论 原发性腹膜恶性肿瘤的治疗,应尽量首选恰当的肿瘤细胞减灭术,基本术式为双侧附件及大网膜切除术,过分强调减瘤的彻底性可能不利于患者的预后;术后应给予以铂类为主的联合化疗,TP方案可能优于PAC方案。病理类型及化疗方案是预后的影响因素。     

ER, PR and Ki-67 expression status in granulomatous and chronic non-specific endometritis

AIM: To study the changes in the histological pattern, distribution and intensity of sex steroid receptors (estrogen and progesterone) and cell proliferation by Ki-67 expression by semi-quantitative scores in granulomatous and chronic non-specific endometritis in the premenstrual phase. METHODS: A retrospective study was conducted on 20 cases of granulomatous endometritis, 10 of chronic non-specific endometritis and 30 age matched (2 years) controls with no endometrial lesions. Morphological changes were noted on histological examination and semi-quantitative scoring of Estrogen Receptor (ER), Progesterone Receptor (PR) and Ki-67 expression was done by immunohistochemistry. RESULTS: There was significantly higher ER, PR and Ki-67 expression in endometrial glandular and stromal cells in inflamed endometria as compared with the controls (all P-values < 0.02) regardless of the character of the inflammation. The cases with morphology not conforming to the secretory phase at which biopsy was taken had significantly higher ER, PR and Ki-67 expression in both endometrial and stromal cells indicating a lag in the endometrial maturation (all P-values < 0.02). Interestingly, all parameters except PR expression in glandular cells had a significantly higher expression even in cases with secretory morphology indicating disturbances in local milieu. CONCLUSION: Endometrial inflammation interferes with local expression of ER, PR and Ki-67. This may contribute to infertility regardless of other factors and other endometrial dysfunctional states.     

HER-2/neu amplification and overexpression in endometrial carcinoma.

HER-2/neu is a proto-oncogene associated with poor prognosis in women with breast and ovarian carcinoma. The significance of HER-2/neu in endometrial carcinoma is less clearly established. The authors compared HER-2/neu gene amplification using fluorescence in situ hybridization and protein overexpression using immunohistochemistry with survival in patients with endometrial carcinoma. Fluorescence in situ hybridization and immunohistochemical staining were performed on 72 formalin-fixed, paraffin-embedded endometrial carcinoma specimens. Vysis combination HER-2/neu and centromere 17 probe mixture was applied to isolated tumor cell nuclei. A minimum of 200 nuclei were scored for each specimen using standard signal enumeration criteria. A specimen was considered amplified with 5% or greater amplified nuclei. Tissue sections were immunostained with polyclonal antibody against p185erb-2 transmembrane glycoprotein. Immunohistochemical reactivity was scored on a three-tiered scale. HER-2/neu gene amplification and protein overexpression were detected in 15 of 72 (21%) and 12 of 72 (17%) of the specimens, respectively, with 2 cases of normal copy overexpression and 5 cases of amplification without overexpression. Both amplification and overexpression were associated with higher grade tumors. Amplification was associated with clear cell and serous subtypes (p = 0.002), and overexpression with only clear cell type (p = 0.006). Using the proportional hazards model of survival, amplification was found to have significant negative predictive value beyond stage, grade, and cell type (p = 0.002). HER-2/neu gene amplification as detected by fluorescence in situ hybridization in archival material has significant prognostic value.     

The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study

OBJECTIVE: The prognostic and predictive relevance of HER-2/neu dysregulation in epithelial ovarian cancer is controversial. The purpose of our study was to document HER-2/neu expression patterns and their correlation with clinicopathologic parameters and survival in a large and biologically homogenous Caucasian patient collective. METHODS: Expression of HER-2/neu in ovarian cancer tissue was assessed by immunohistochemistry. Immunohistochemical staining was performed according to established protocols. Results were correlated to clinical data. RESULTS: HER-2/neu overexpression was detected in 6.9% (25/361) of the tumor samples and was significantly associated with tumor stage (P = 0.03), but not with lymph node involvement (P = 0.5), tumor grade (P = 0.3), histological type (P = 0.6), residual tumor (P = 0.4), serum CA-125 before therapy (P = 0.2), and patient age (P = 0.8). We found no significant influence of HER-2/neu overexpression on overall and disease-free survival independent of FIGO stage, tumor grade, and residual tumor mass. In a subset of 73 suboptimally debulked patients, women with response to first-line chemotherapy (complete remission [CR] + partial remission [PR]) and no response to first-line chemotherapy (stable disease [SD] + progressive disease [PD]) showed significantly different rates of HER-2/neu overexpression (0% [0/51] vs. 14% [3/22]; P = 0.02). CONCLUSIONS: Tumor overexpression of HER-2/neu in women with advanced ovarian cancer is rare and provides no prognostic information in addition to that provided by established clinicopathologic parameters. This multicenter study, however, indicates that HER-2/neu overexpression is a predictive factor for the response to first-line chemotherapy in suboptimally debulked patients.     

芳香化酶蛋白及性激素受体等在子宫内膜病变组织中的表达变化及意义

目的探讨芳香化酶蛋白、雌激素受体（ER）、孕激素受体（PR）及细胞增殖相关核抗原Ki67在子宫内膜病变组织中的阳性表达率及其在子宫内膜病变的诊断和治疗中的价值。方法采用免疫组化链霉菌抗生物素蛋白-过氧化物酶链接（SP）法,检测148例子宫内膜病变患者（观察组,其中子宫内膜增殖症30例,轻、中、重度子宫内膜非典型增生各10例,子宫内膜腺癌88例）及30例因患宫颈原位癌行子宫全切除术患者的正常子宫内膜组织（对照组,其中增殖期及分泌期子宫内膜各15例）中芳香化酶蛋白、ER、PR及Ki67的阳性表达率。结果（1）观察组子宫内膜增殖症、子宫内膜非典型增生组织芳香化酶蛋白、ER、PR、Ki67的阳性表达率与对照组增殖期内膜比较,差异无统计学意义（P〉0．05）;（2）观察组子宫内膜腺癌组织芳香化酶蛋白阳性表达率为64％（56／88）,与子宫内膜非典型增生（23％,7／30）、子宫内膜增殖症（13％,4／30）及对照组（0／15）比较,差异均有统计学意义（P〈0．01）;（3）芳香化酶蛋白的阳性表达率与子宫内膜腺癌的临床分期（Ⅰ期61％、Ⅱ期77％、Ⅲ期70％、Ⅳ期67％）、肿瘤细胞分化级别（高分化64％,中分化74％,低分化58％）、有无淋巴转移（转移59％,无转移67％）无明显相关性（P〉0．05）。（4）子宫内膜腺癌组织中ER、PR、Ki67的阳性表达率分别为22％（19／88）、19％（17／88）、41％（36／88）,与对照组分别比较,差异均有统计学意义（P〈0．01）。结论子宫内膜良性病变组织与正常内膜组织中,芳香化酶蛋白表达无明显差异;子宫内膜腺癌组织中芳香化酶蛋白的过度表达,可作为诊断子宫内膜腺癌的指标之一。     

A significance of immunohistochemical determination of steroid receptors, cell proliferation factor Ki-67 and protein p53 in endometrial carcinoma

OBJECTIVES: The aim of the study was to preoperatively predict the biologic behavior of the endometrial carcinoma using immunohistochemical analysis of the p53 protein and Ki-67 expression, and estrogen receptor (ER) and progesterone receptor (PR) status, in the material obtained by fractional curettage. METHODS: One hundred and thirty-six patients with primary endometrial carcinoma were included in the study. In all 136 patients, the fractional curettage was performed before the hysterectomy, and the diagnosis of endometrial carcinoma was confirmed pathohistologically after the surgical procedure on the hysterectomy specimens. The significance of the prognostic factors was assessed using univariate and multivariate analyses. The cutoff values of the percentage of ER, PR, p53, and Ki-67 positive cells in terms of survival probability determination were obtained as the values of the highest chi-square test, using proportional-risk regression method. A multivariate Cox regression analysis was performed to estimate the influence of several clinical, pathohistologic, and immunohistochemical covariates to patients' survival. Survival curves were determined by the Kaplan-Meier product-limit method based on the most recent clinical status. RESULTS: According to the histologic type of the tumor, fractional curettage specimens revealed 111 histologically favorable types (81.6%) and 25 unfavorable types (18.4%). The data indicate that ER, PR, Ki-67, and p53 levels of the hysterectomy specimens and those of the preoperative specimens were in fairly good agreement. The patients with the most favorable tumor grade (G I) had significantly better prognosis when the percentage of p53 positive cells was less than 15%. In the group of patients with histologic grade II, the survival was affected by ER expression (more than 30% of positive cells) and p53 levels (less than 15% of positive cells). None of the parameters was predictive in the group of patients with histologic grade III. CONCLUSIONS: We found that determination of immunohistochemical parameters (ER, PR, and p53) on well-differentiated and moderately differentiated endometrial carcinoma of favorable histologic type obtained by curettage enables the recognition of the patients with favorable prognosis, who should not be treated by radical surgery.