MMP-14在卵巢透明细胞癌中的表达及意义

目的:检测膜型-1基质金属蛋白酶(MMP-14)在卵巢透明细胞癌和卵巢浆液性肿瘤中的表达并探讨其临床意义.方法:采用免疫组化的方法检测35例卵巢透明细胞癌、39例卵巢浆液性癌、22例卵巢交界性浆液性肿瘤和24例卵巢浆液性囊腺瘤标本中MMP-14蛋白的表达,探讨其与卵巢透明细胞癌和浆液性肿瘤临床病理因素的关系.结果:MMP-14阳性染色定位于肿瘤细胞;其中透明细胞癌阳性率为94.3％,浆液性癌阳性率为43.5％,二者相比差异显著(P＜0.01).交界性浆液性肿瘤阳性率为45.5％,浆液性囊腺瘤阳性率为8.3％,和浆液性癌相比,差异显著(P＜0.01).MMP-14蛋白的表达与透明细胞癌、浆液性癌的临床分期、淋巴结转移和Ki-67的表达无相关性(P＞0.05).结论:卵巢透明细胞癌中MMP-14蛋白的高表达反应肿瘤有更高的恶性生物学行为并有可能成为卵巢透明细胞癌不良预后的一个指标.     

卵巢透明细胞癌70例临床特点及预后分析

探讨卵巢透明细胞癌的临床、病理特点及预后,回顾性分析我院1982年1月~2001年12月70例原发性卵巢透明细胞癌患者临床资料,对其临床特点与治疗情况进行总结并对预后进行随访,总结其发病规律及临床特点。卵巢透明细胞癌多以腹痛、腹胀和盆腔包块为主要症状(占就诊者80%),70例患者全部进行手术,满意肿瘤细胞减灭术5年生存率(61.5%)与不满意肿瘤细胞减灭术5年生存率(7.69%)差异有统计学意义。术后病理组织证实单纯透明细胞癌42例,透明细胞癌合并其他上皮性癌28例,合并子宫内膜异位症19例。共65例于术后进行了PT、PAC等化疗。在不同方案、不同疗程比较中,发现PT方案、6个疗程以上化疗组有较高的5年生存率,与PAC组、其他化疗方案组差异有统计学意义,P=0.005。卵巢透明细胞癌临床特点不同于其他的卵巢上皮恶性肿瘤,是上皮癌的一种特殊组织类型,其临床分期早,化疗不敏感,即使是早期亦易复发,预后较差,应引起重视。手术尽量行理想的肿瘤细胞减灭术,术后行6个疗程以上的PT方案化疗,可望改善疗效。     

卵巢透明细胞癌70例临床特点及预后分析

探讨卵巢透明细胞癌的临床、病理特点及预后,回顾性分析我院1982年1月～2001年12月70例原发性卵巢透明细胞癌患者临床资料,对其临床特点与治疗情况进行总结并对预后进行随访,总结其发病规律及临床特点.卵巢透明细胞癌多以腹痛、腹胀和盆腔包块为主要症状（占就诊者80%）,70例患者全部进行手术,满意肿瘤细胞减灭术5年生存率（61.5%）与不满意肿瘤细胞减灭术5年生存率（7.69%）差异有统计学意义.术后病理组织证实单纯透明细胞癌42例,透明细胞癌合并其他上皮性癌28例,合并子宫内膜异位症19例.共65例于术后进行了PT、PAC等化疗.在不同方案、不同疗程比较中,发现PT方案、6个疗程以上化疗组有较高的5年生存率,与PAC组、其他化疗方案组差异有统计学意义,P=0.005.卵巢透明细胞癌临床特点不同于其他的卵巢上皮恶性肿瘤,是上皮癌的一种特殊组织类型,其临床分期早,化疗不敏感,即使是早期亦易复发,预后较差,应引起重视.手术尽量行理想的肿瘤细胞减灭术,术后行6个疗程以上的PT方案化疗,可望改善疗效.     

Benign and borderline clear cell adenofibromas of the ovary

The criteria for the diagnosis of benign and borderline clear cell adenofibromas and their biologic behavior were investigated by examination of the clinical and pathologic features of 18 tumors in these categories. Three tumors that showed no significant epithelial atypicality were classified as benign. Twelve tumors that contained glands or small solid nests composed of epithelial cells with nuclear characteristics of low-grade malignancy without invasion of the stromal component of the tumor were designated as borderline. Three predominantly borderline tumors with focal microinvasion of the stromal component were also studied. The 17 patients had nonspecific complaints. Sixteen of the tumors were unilateral without surface involvement; one patient had bilateral borderline tumors. Most of the women were treated by hysterectomy and bilateral salpingo-oophorectomy. Follow-up information was available for 16 of the 17 patients. No recurrences or deaths from tumor occurred in 14 patients (2 benign, 10 borderline, 2 microinvasive). One patient with a borderline adenofibroma had questionable lung metastasis 4 years after presentation, and another patient who had a microinvasive tumor had a pelvic recurrence 3.3 years postoperatively.     

Cytogenetic and molecular findings in 75 clear cell renal cell carcinomas

Cytogenetic analysis of 75 clear cell renal cell carcinomas (RCC) from adult patients revealed abnormal karyotypes in 59 (79%) tumors. Among structural abnormalities, the most frequent were deletions and unbalanced translocations leading to loss of 3p (found in 68% of karyotypically abnormal tumors), followed by rearrangements of chromosomes 5 (in 37%) and 1 (in 20%). Fifteen unbalanced interchromosomal rearrangements and one reciprocal translocation have not been hitherto reported in clear cell RCC. The most common numerical aberrations were trisomy 7, seen in 44% of tumors, and loss of chromosome Y, detected in 48% of RCCs diagnosed in male patients. In 25 tumors, loss of heterozygosity (LOH) analysis was performed using five polymorphic markers spanning region 3p13-p25. LOH was identified in 10 RCCs with 3p loss detected cytogenetically and 4 karyotypically aberrant tumors without cytogenetic rearrangements of 3p; no LOH was found in 3 tumors with 3p loss seen at the cytogenetic level. Overall, 3p loss was detected by cytogenetic and/or LOH analyses in 75% of RCCs with abnormal karyotype studied. The presence or absence of 3p loss did not correlate with tumor size, nodal involvement, tumor grade or its ability to metastasize. However, karyotypes of metastasizing tumors contained more aberrations than those of non-metastasizing RCCs (5.5 versus 2.9 aberrations per tumor, respectively), and -14/14q-, -17 and -10 were significantly more frequent in metastasizing tumors, suggesting that these aberrations might contribute to the progression of RCC. One patient had t(X;1)(p11.2;p34) as a sole abnormality in the stemline. This is the sixth case with this translocation reported to date. Together with our case, all but 1 RCC with t(X;1)(p11.2;p34) had morphology with a clear cell component, which contrasts these RCCs from tumors harboring t(X;1)(p11.2;q21) that largely had papillary morphology.     

Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy

BACKGROUND: A retrospective review of treatment results comparing women with clear cell carcinoma of the ovary (CCC) with a group with serous adenocarcinoma of the ovary (SAC) was conducted. METHODS: Between 1988-1998, 662 patients with epithelial ovarian carcinoma were identified through the medical records department and the tumor registry at 4 institutions. After the central pathologic review, 101 patients with pure or dominant (>/= 90%) CCC (15.3%) were entered into the current study. Two hundred thirty five patients with pure SAC were selected as a group for comparison. All patients underwent staging laparotomy followed by platinum-based chemotherapy. Distribution of the International Federation of Gynecology and Obstetrics (FIGO) disease stage, response to chemotherapy, and prognosis for patients with CCC were compared with the same values in patients with SAC. RESULTS: Patients with CCC were significantly more likely to have FIGO Stage I disease than were patients with SAC (48.5% vs. 16.6%). A high recurrence rate was noted in those patients with Stage IC CCC (37%). In those patients with Stage IC disease, the survival rates for patients with CCC were lower than those for patients with SAC. The 3-year and 5-year survival rates for Stage III CCC patients were significantly lower compared with Stage III SAC patients. The response rate to platinum-based chemotherapy in patients with CCC was significantly lower than that in patients with SAC. CONCLUSIONS: CCC is an intriguing histologic type of epithelial ovarian cancer that demonstrates a clinical behavior distinctly different from that of SAC.     

Mechanisms of cisplatin resistance in clear cell carcinoma of the ovary

Resistance of clear cell carcinoma (CCC) of the ovary to platinum-based chemotherapy is associated with a poor prognosis. However, the mechanism underlying the resistance of CCC to platinum has not yet been understood. We conducted the present study to clarify the mechanism of cisplatin (CDDP) resistance in CCC cells. Eleven CCC and 5 serous adenocarcinoma (SAC) cell lines were used in this study. The IC(50) to CDDP ranged from 1.3 to 18.0 microM for CCC cells and from 2.2 to 13.0 microM for SAC cells. There was no correlation between multidrug resistance-associated protein expression and the sensitivity to CDDP in CCC cells. In contrast, the doubling time for CCC cells was significantly longer than that for SAC cells (61.4 vs. 29.8 h). A significant reverse correlation between the S-phase fraction and the response to CDDP was observed (r = 0.647, p < 0.05). The present study suggests that the resistance of CCC to CDDP may be caused by low cell proliferation.     

Cyclin E amplification and overexpression in clear cell adenocarcinoma of the ovary

OBJECTIVE: The purpose of this study is to compare DNA, mRNA and protein levels of the cyclin E between clear cell (CC) and serous (SC) ovarian carcinomas, and evaluate the relationship between cyclin E and p53 status. METHOD: We examined the DNA, mRNA and protein levels of cyclin E and the protein level of p53 in 44 CCs and 39 SCs using microdissected tissues. RESULTS: Relative cyclin E mRNA expression was significantly higher in CC (3.62, 95% CI, 2.24-4.99) than in SC (1.75, 95% CI, 1.05-2.45; p = 0.0098). The percentage of positive nuclear staining of cyclin E was significantly higher in CC (48.3, 95% CI, 40.4-56.1) than SC (25.3, 95% CI, 17.4-33.3; p = 0.0001). The mRNA and protein expression of cyclin E was significantly correlated (r = 0.66, p < 0.0001). However, the correlation between relative DNA copy number and relative mRNA expression was not significant (r = -0.063; p = 0.66). Percentage of positive nuclear staining of cyclin E was significantly higher in p53 positive cases (51.8, 95% CI, 40.0-63.5) than p53 negative cases (36.2, 95% CI, 28.2-44.2; p = 0.028). CONCLUSIONS: Cyclin E expression is significantly higher in CC than in SC. Cyclin E expression is significantly related with p53 positivity.     

Long-term follow-up and prognostic factor analysis in clear cell adenocarcinoma of the ovary

BACKGROUND AND OBJECTIVES: There were a few reports of a large number of patients with clear cell adenocarcinoma (CCA) of the ovary because of the low incidence of CCA. This study compared the clinical factors affecting long-term survival of patients with CCA to those with serous cystadenocarcinoma (SCA). METHODS: One hundred and seventy-eight CCA and 311 SCA patients treated between 1987 and 2000 were retrospectively evaluated. Differences in survival rates were calculated using log-rank test and Cox's proportional hazards analysis was used to identify independent prognostic factors. RESULTS: The ratio of stage I was significantly higher than that of SCA. There was no significant difference of 8-year survival rate in each stage between CCA and SCA. However, the patients with stage IIIb or IIIc CCA showed significantly worse prognosis than those with SCA. Positive peritoneal or ascitic cytology, the presence of residual tumor, more than 100 ml ascites were demonstrated to have the significant impact on survival by univariate analysis. Multivariate analysis demonstrated that stage, more than 100 ml ascites, and the presence of residual tumor were significant prognostic factors of CCA overall survival. CONCLUSIONS: Distribution of stage and substage differed between CCA and SCA in this study. Thus, substaging is quite important for comparison of prognoses between histologies, and CCA showed poorer prognoses than serous adenocarcinoma in stages IIIb and IIIc.     

Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas

Background

Piwi-interacting RNAs (piRNAs) are small RNAs of 27–30 nucleotides mapping to transposons or clustering in repeat genomic regions. Preliminary studies suggest an important role in cancerogenesis. This study is the first one investigating their prognostic impact in clear cell renal cell cancer (ccRCC) patients.

Methods

Three piRNAs (piR-30924, piR-57125, and piR-38756) selected on the basis of initial piRNA microarray analyses were determined using RT-qPCR in non-metastatic (n = 76) and metastatic (n = 30) ccRCC tissue at the time of nephrectomy in comparison to normal renal tissue (n = 77) and tissue from distant ccRCC metastases (n = 13). Primary clinical end points were recurrence-free and overall survival.

Results

piR-57125 showed lower expression in metastatic than in non-metastatic tumors, whereas the expression of piR-30924 and piR-38756 increased in metastatic tumors. The higher expression of piR-30924 and piR-38756 as well as the lower expression of piR-57125 in metastatic primary tumors were significantly associated with tumor recurrence and overall survival. Multivariate Cox regression analyses revealed both piR-30924 and piR-57125 as independent prognostic predictors. This impact was even more pronounced in non-metastatic patients.

Conclusions

This study demonstrates that the expression levels of these piRNAs in primary non-metastatic and metastatic ccRCC tissue can serve as potential prognostic biomarkers in combination with clinicopathological factors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0180-3) contains supplementary material, which is available to authorized users.     

透明细胞肉瘤病理与临床特点

目的　了解透明细胞肉瘤的病理与临床特点。方法　复习中国医学科学院肿瘤医院1973 年至1998 年收治的6 个病例及复习文献,对其病理及临床特点、治疗方法及疗效、预后因素等做一总结。结果　透明细胞肉瘤来源于原始神经外胚层细胞,由在胚胎形成过程中迷走于肌腱和肌筋膜中的神经脊细胞发展而来,具有特征性的染色体改变,即t(12;22)(q1314;q1213) 等;病变与肌腱及肌筋膜关系密切;易出现区域淋巴结转移;手术切除后易局部复发。治疗原则应为手术加术后大野放射治疗并采用多次缩野技术,区域淋巴结应给予手术清扫或放射治疗。5 年生存率为37 % ～67% 。影响预后的因素有肿瘤大小及是否伴有坏死。结论　透明细胞肉瘤是一类有自身特征的肿瘤,治疗上应有别于其他软组织肉瘤     

Clonal divergence and genetic heterogeneity in clear cell renal cell carcinomas with sarcomatoid transformation

BACKGROUND: Approximately 5% of clear cell renal cell carcinomas contain components with sarcomatoid differentiation. It has been suggested that the sarcomatoid elements arise from the clear cell tumors as a consequence of clonal expansions of neoplastic cells with progressively more genetic alterations. Analysis of the pattern of allelic loss and X-chromosome inactivation in both the clear cell and sarcomatoid components of the same tumor allows assessment of the genetic relationship of these tumor elements. METHODS: The authors of the current study examined the pattern of allelic loss in clear cell and sarcomatoid components of renal cell carcinomas from 22 patients who had tumors with both components. DNA samples were prepared from formalin-fixed, paraffin-embedded renal tissue sections using laser-capture microdissection. Five microsatellite polymorphic markers for putative tumor suppressor genes on 5 different chromosomes were analyzed. These included D3S1300 (3p14), D7S522 (7q31), D8S261 (8p21), D9S171 (9p21), and TP53 (17p13). In addition, X-chromosome inactivation analysis was performed in 14 tumors from female patients. RESULTS: The clear cell components showed loss of heterozygosity (LOH) at the D3S1300, D7S522, D8S261, D9S171, and TP53 loci in 18% (4/22), 18% (4/22), 50% (10/20), 15% (3/20), and 20% (4/20) of informative cases, respectively. LOH in the sarcomatoid components was seen at the D3S1300, D7S522, D8S261, D9S171, and TP53 loci in 18% (4/22), 41% (9/22), 70% (14/20), 35% (7/20), and 20% (4/20) of informative cases, respectively. Six cases demonstrated an LOH pattern in the clear cell component that was not seen in the sarcomatoid component. Different patterns of allelic loss were seen in the clear cell and sarcomatoid components in 15 cases. Clonality analysis showed the same pattern of nonrandom X-chromosome inactivation in both clear cell and sarcomatoid components in 13 of the 14 cases studied. One case showed a random pattern of X-chromosome inactivation. CONCLUSION: X-chromosome inactivation analysis data suggest that both clear cell and sarcomatoid components of renal cell carcinomas are derived from the same progenitor cell. Different patterns of allelic loss in multiple chromosomal regions were observed in clear cell and sarcomatoid components from the same patient. This genetic heterogeneity indicates genetic divergence during the clonal evolution of renal cell carcinoma.     

Gene expression in ovarian cancer reflects both morphology and biological behavior,distinguishing clear cell from other poor-prognosis ovarian carcinomas

Biologically and clinically meaningful tumor classification schemes have long been sought. Some malignant epithelial neoplasms, such as those in the thyroid and endometrium, exhibit more than one pattern of differentiation, each associated with distinctive clinical features and treatments. In other tissues, all carcinomas, regardless of morphological type, are treated as though they represent a single disease. To better understand the biological and clinical features seen in the four major histological types of ovarian carcinoma (OvCa), we analyzed gene expression in 113 ovarian epithelial tumors using oligonucleotide microarrays. Global views of the variation in gene expression were obtained using PCA. These analyses show that mucinous and clear cell OvCas can be readily distinguished from serous OvCas based on their gene expression profiles, regardless of tumor stage and grade. In contrast, endometrioid adenocarcinomas show significant overlap with other histological types. Although high-stage/grade tumors are generally separable from low-stage/grade tumors, clear cell OvCa has a molecular signature that distinguishes it from other poor-prognosis OvCas. Indeed, 73 genes, expressed 2- to 29-fold higher in clear cell OvCas compared with each of the other OvCa types, were identified. Collectively, the data indicate that gene expression patterns in ovarian adenocarcinomas reflect both morphological features and biological behavior. Moreover, these studies provide a foundation for the development of new type-specific diagnostic strategies and treatments for ovarian cancer.     

Surgical resection in the treatment of stages I-II of small cell lung carcinoma (SCLC)

From 1981 to 1986, 17 patients with resected small cell lung carcinoma (SCLC) staged as I or II according to the new TNM classification were recruited for a prospective study to evaluate the effectiveness of surgery and postoperative chemotherapy (plus locoregional radiotherapy only when a nonradical resection was accomplished) in the treatment of early stages of the disease. Six patients received full protocol chemotherapy (6 courses) and 8 a mean of 79.1% of the planned courses. Three patients received non adjuvant treatment. Locoregional radiotherapy for residual disease was administered in 2 cases. One patient died for myelosuppression due to chemotherapy and 10 for recurrences of cancer, all within the 20th postoperative month. Metastases accounted 80% of overall recurrences. Six patients were alive and tumor-free at 18, 22, 39, 44, 47 and 51 months from resection. Actuarial observed 3-year survival was 32%.     

Exploratory study of effective chemotherapy to clear cell carcinoma of the ovary

Although clear cell carcinoma of the ovary is considered to be a tumor with poor prognosis, the clinical characteristics has not been defined. The aim of this study was to evaluate the response of clear cell carcinoma of the ovary to first and second-line chemotherapy and explore effective chemotherapy. Fifty-three patients with clear cell carcinoma of the ovary were enrolled between 1988 and 1997 at our department. Since taxol was not available in Japan at that time, cisplatin-based combination chemotherapy has been exclusively used as a standard first-line chemotherapy. Retrospective analyses of clinical characteristics and the response to first or second-line chemotherapy were performed. Median age was 52 years (range 27-71 years). Tumors were 34% (18/53) stage I, 19% (5/53) stage II, 38% (20/53) stage III, and 9% (5/53) stage IV. All patients with I or II stage disease had optimal cytoreduction. Out of 25 patients with III or IV stage disease 20% (5/25) had negative residual tumor, 36% (9/25) had <2 cm residual tumor, and 44% (11/25) had >/=2 cm residual tumor. All patients received postoperative platinum-based chemotherapy. Of 23 patients with measurable residual tumor 8.7% (2/23) completely and 13% (3/23) partially responded to first-line chemotherapy consisting of cisplatin, adriamycin and cyclophosphamide (CAP) or cisplatin and cyclophosphamide (CP) by CT scan or second look laparotomy. Presence of endometriosis was 55% (29/53) but was not a prognostic factor. Although overall response rate of ovarian clear cell carcinoma to first-line chemotherapy by CAP or CP was about 22%, EP or EJ consisting of etoposide and cisplatin or carboplatin used as a second-line chemotherapy showed 29% response rate, while CPT-P consisting of CPT-11 and cisplatin showed 40% response rate. Clear cell carcinomas were frequently present at early stage, with association of endometriosis and with poor overall prognosis. Although patients with advanced ovarian clear cell carcinoma seemed to have better response to CPT-P than conventional platinum-based chemotherapy, further studies are required with larger number of patients to draw firm conclusions.     

Hypermethylation of the 5'CpG island of the FHIT gene in clear cell renal carcinomas

FHIT is a tumour suppressor gene which is frequently inactivated in different types of cancer. Both genetic (mutations, deletions, chromosomal rearrangements) and epigenetic (aberrant methylation of the 5'CpG island) alterations of the FHIT gene have been reported in various malignancies. Yet little is known about the mechanism of FHIT inactivation in clear cell renal carcinomas. Since genetic alterations were not frequently observed in DNA corresponding to the FHIT gene in renal tumours, to elucidate the mechanism of FHIT gene silencing we examined 22 paired samples of clear cell renal carcinoma and non-malignant renal tissue for the methylation of the FHIT 5'CpG island by methylation-specific PCR. Hypermethylation of the FHIT 5'CpG island was detected in 54.5% (12/22) of clear cell renal carcinomas. Bisulfite sequencing of the FHIT 5'CpG island confirmed the results obtained by methylation-specific PCR for selected samples. We showed here that expression of the FHIT gene is inversely correlated with hypermethylation of the FHIT 5'CpG island in the selected samples. Our results suggest that hypermethylation of the FHIT 5'CpG island may be responsible for inactivation of the FHIT gene in clear cell renal carcinomas.