Lymphovascular invasion as a criterion for adjuvant chemotherapy for FIGO stage I-IIa clear cell carcinoma, mucinous, low grade serous and low grade endometrioid ovarian cancer.

BACKGROUND: The aim of this study was to evaluate the impact of lymphovascular space invasion (LVSI) on overall survival (OS) and recurrence-free survival (RFS) in patients managed for stage I-IIa clear cell carcinoma, mucinous, low-grade serous and low-grade endometrioid ovarian cancer MATERIAL AND METHODS: Retrospective multicentre study of the research group FRANCOGYN between January 2001 and December 2018. All patients managed for stage I-IIa clear cell carcinoma, mucinous /low grade serous and endometrioid ovarian cancer and for whom the presence of histological slides for the review of LVSI was available, were included. Patient's characteristics with LVSI (LVSI group) were compared to those without LVSI (No LVSI group). A cox analysis for OS and RFS analysis were performed in all population. RESULTS: Over the study period, 133 patients were included in the thirteen institutions. Among them, 12 patients had LVSI (9%). LVSI was an independent predictive factor for poorer Overall and recurrence free survivals. LVSI affected OS (p < 0.001) and RFS (p = 0.0007), CONCLUSION: The presence of LVSI in stage I-IIa clear cell carcinoma, mucinous /low grade serous and endometrioid ovarian cancer has an impact on OS and RFS and should put them at high risk and consider the option of adjuvant chemotherapy.

Clear Cell Carcinoma of the Abdominal Wall as a Rare Complication of General Obstetric and Gynecologic Surgeries: 15 Years of Experience at a Large Academic Institution.

The objective of this article was to report the clinicopathological characteristics, treatment modalities, and outcomes of patients with clear cell carcinoma (CCC) of the abdominal wall. Medical records of six patients diagnosed with CCC of the abdominal wall between May 2003 and May 2018 at the National Taiwan University Hospital were reviewed. All patients had prior obstetric or gynecologic surgeries. The primary clinical presentation was enlarging abdominal masses at previous surgical scars. Four patients underwent initial/primary surgeries with/without adjuvant chemotherapy. One patient received neoadjuvant chemotherapy followed by surgical intervention and adjuvant chemotherapy, the other received chemotherapy and sequential radiotherapy without any surgical intervention. Two of four patients undergoing initial/primary surgeries had disease recurrence and the remaining two cases without initial surgery experienced disease progression during primary treatment. Inguinal lymph nodes were the most frequent sites of recurrence. In conclusion, previous obstetric or gynecologic surgery can be a risk factor for CCC of the abdominal wall. Complete resection of abdominal wall tumor and suspected intra-abdominal lesions with hysterectomy and bilateral inguinal lymph nodes dissection may be the primary treatment. Adjuvant chemotherapy would be considered for potential benefits. For patients without bilateral inguinal lymph nodes dissection, careful inguinal lymph node palpation during postoperative surveillance is necessary. More cases are still needed to elucidate the clinical management of this disease.

Recent concepts of ovarian carcinogenesis: type I and type II.

Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC) arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT). With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs) of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the "tubal peritoneal junction" (TPJ), undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.

Increased steroid receptor RNA activator protein (SRAP) accompanied by decreased estrogen receptor-beta (ER-ß) levels during the malignant transformation of endometriosis associated ovarian clear cell carcinoma.

The modulating attributes of steroid receptor RNA activator protein (SRAP) on steroid receptors have been shown in some types of tumor cells. There is compelling evidence to suggest that this molecule may play a critical role in the development of the tumor. However, little has been reported on its expression in endometriosis associated ovarian clear cell carcinoma (EAOCCC). In order to investigate the role of SRAP and estrogen receptors (ERs) in EAOCCC, we have analyzed the distribution of these proteins in the malignant transformation tissues and endometrioma tissues by immunohistochemistry. Our results revealed that the positive ratio of ER-ß expression was gradually reduced during the malignant transformation from endometriosis to atypical endometriosis to clear cell carcinoma. Conversely, during the process, a gradual increase in SRAP expression was observed. Furthermore, there is a negative relationship between the expressions of these two molecules. Overall an increase in SRAP and a reduction in ER-ß expression might be associated with malignant transformation of EAOCCC.

Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic cancer. Clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) of the ovary have been associated with endometriosis, thus indicating that endometriosis has been believed to increase the risk of developing EOC. The aim of our review was to identify and synthesize the most current information on CCC with regard to molecular and pathophysiological distinctions. METHOD: This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis and endometriosis-associated ovarian cancer (EAOC). In this review, we focus on the functions and roles of redox-active iron in CCC carcinogenesis. RESULTS: The iron-induced reactive oxygen species signals can contribute to carcinogenesis via 3 major processes: step 1, by increasing oxidative stress, which promotes DNA mutagenesis, histone modification, chromatin remodeling, and gene products activation/inactivation thus contributing to EAOC initiation; step 2, by activating detoxification and antiapoptotic pathways via the transcription factor hepatocyte nuclear factor 1ß overexpression, thereby contributing to CCC promotion; and step 3, by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of cancer cells via estrogen-dependent (EAC) or estrogen-independent (CCC) mechanisms, thus supporting tumor progression and metastasis. CONCLUSIONS: These aspects of reactive oxygen species biology will be discussed in the context of its relationship to EAOC carcinogenesis.

A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients.

Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.

Targeting annexin A4 to counteract chemoresistance in clear cell carcinoma of the ovary.

IMPORTANCE OF THE FIELD: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancies in Western countries. Among the four major histological subtypes of EOC, clear cell carcinoma (CCC) of the ovary is highly resistant to platinum-based chemotherapy and is consequently associated with poor patient prognosis in advanced stages. AREAS COVERED IN THIS REVIEW: An overview of the clinical characteristics of ovarian CCC; the role of annexin family proteins in tumor development and progression; the role of annexin A4 in enhancing cellular drug resistance; recent studies linking annexin A4 overexpression to chemoresistance in tumors of ovarian CCC. WHAT THE READER WILL GAIN: Insight into the emerging role for annexin A4 in enhancing chemoresistance in ovarian CCC. TAKE HOME MESSAGE: Annexin A4 enhances cancer cell chemoresistance and is overexpressed in tumors of patients with ovarian CCC. Targeting of annexin A4 may represent a future strategy to counteract resistance to chemotherapy in ovarian CCC.

ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells.

Epithelial polarization modulates gene expression. The transcription factor zonula occludens 1 (ZO-1)-associated nucleic acid binding protein (ZONAB) can shuttle between tight junctions and nuclei, promoting cell proliferation and expression of cyclin D1 and proliferating cell nuclear antigen (PCNA), but whether it also represses epithelial differentiation is unknown. Here, during mouse kidney ontogeny and polarization of proximal tubular cells (OK cells), ZONAB and PCNA levels decreased in parallel and inversely correlated with increasing apical differentiation, reflected by expression of megalin/cubilin, maturation of the brush border, and extension of the primary cilium. Conversely, ZONAB reexpression and loss of apical differentiation markers provided a signature for renal clear cell carcinoma. In confluent OK cells, ZONAB overexpression increased proliferation and PCNA while repressing megalin/cubilin expression and impairing differentiation of the brush border and primary cilium. Reporter and chromatin immunoprecipitation assays demonstrated that megalin and cubilin are ZONAB target genes. Sparsely plated OK cells formed small islands composed of distinct populations: Cells on the periphery, which lacked external tight junctions, strongly expressed nuclear ZONAB, proliferated, and failed to differentiate; central cells, surrounded by continuous junctions, lost nuclear ZONAB, stopped proliferating, and engaged in apical differentiation. Taken together, these data suggest that ZONAB is an important component of the mechanisms that sense epithelial density and participates in the complex transcriptional networks that regulate the switch between proliferation and differentiation.

The reduction in pigment epithelium-derived factor is a sign of malignancy in ovarian cancer expressing low-level of vascular endothelial growth factor.

BACKGROUND: Angiogenesis is a critical factor in the progression of solid tumors and metastasis. The aim of this study was to characterise the roles of angiogenic and anti-angiogenic factors on ovarian cancer. METHODS: The expression levels of vascular endothelial growth factor (VEGF, angiogenic factor) and pigment epithelial growth factor (PEDF, anti-angiogenic factor) were measured by real-time polymerase chain reaction and Western blotting in ovarian tumors. Microvessel density (MVD) was evaluated by the total microvessel length in high-power field of tumor tissue preparations. RESULTS: MVD correlated with tumor malignancy. The tissues with the highest expression levels of VEGF (VEGF-H) were malignant tumors. The VEGF expression levels in some malignant tumors (VEGF-L) were as low as that in benign tumors. Therefore, the expression of PEDF was examined. The PEDF expression levels in VEGF-L malignant tumors were significantly lower than those in benign tumors. On the other hand, the PEDF expression levels in VEGF-H malignant tumor tissues were not significantly different from those in benign tumors. CONCLUSION: The reduction in PEDF expression levels may be, in part, responsible for tumor malignancy in VEGF-L ovarian tumors. Furthermore, PEDF may be a useful marker of malignancy in VEGF-L ovarian tumors.

Tight junction formation in epithelial ovarian adenocarcinoma.

BACKGROUND: Epithelial cells are characterised by their ability to form polarised cell sheets with barriers between two tissue compartments. Epithelial tightness and apical/basolateral orientation are maintained through adherens and tight junctions (TJs). Alterations in junction formation and function could promote tumorigenesis via increased access to growth factors and cytokines. The etiology and development of epithelial ovarian cancer (EOC) are far from understood. The ovarian surface epithelium (OSE), regarded as progenitor cells of EOC, form weak functional TJs in culture without expressing typical junction proteins. However, these integral membrane epithelial proteins, E-cadherin, claudin-3 and claudin-4, are often found in EOC. METHODS: To clarify whether EOC can form functional TJs, 4 different ovarian cancer cell lines of various histology were analysed for their expression of TJ (claudin-1, claudin-3, claudin-4 and zonola occludens-1 (ZO-1)) and adherens junction (AJ) (E-cadherin and N-cadherin) proteins, and the ability to build up trans-epithelial resistance (TER) in culture was measured. RESULTS: We found expression for all cell-junction proteins with a typical honeycomb-staining pattern in the serous adenocarcinomas indicating proper junction formation. Clear-cell and endometrioid adenocarcinomas showed a different expression pattern. By measuring TER, including Ca(2+) switch experiments, functional TJs were shown to build up only in serous adenocarcinomas. CONCLUSION: Serous adenocarcinomas formed functional TJs in vitro. The presence of claudin-4 might be essential for the function of TJs in ovarian cancer.

Proliferative activity of early ovarian clear cell adenocarcinoma depends on association with endometriosis.

OBJECTIVE: To investigate differences in the biological characteristics of ovarian clear cell adenocarcinoma based on the presence/absence of endometriosis and tumor proliferative activity. METHODS: Stage I ovarian clear cell adenocarcinoma patients were divided into groups with and without endometriosis, and immunohistochemical expression of proliferating cell nuclear antigen was determined in surgical specimens. Then xenograft models of human ovarian clear cell adenocarcinoma with or without human ectopic endometrium were created in severe combined immunodeficiency mice, and tumor growth was assessed from the wet weight and the bromodeoxyuridine uptake. Furthermore, a xenograft model of human endometriosis was made with or without ovarian clear cell adenocarcinoma and cytokine production was investigated. RESULTS: The proliferating cell nuclear antigen labeling index was significantly lower in the tumors of patients with endometriosis compared to the tumors of patients without endometriosis. In tumor-bearing mice, the tumor weight and bromodeoxyuridine uptake were both significantly lower when ovarian clear cell adenocarcinoma was associated with endometriosis than in its absence. Release of transforming growth factor-beta1 and interleukin-6 from the ectopic human endometrium was greater in the presence of clear cell adenocarcinoma than without it, and transforming growth factor-beta1 levels showed a significant difference. CONCLUSION: The proliferative activity of early ovarian clear cell adenocarcinoma seems to depend on the association of this cancer with endometriosis. When endometriosis is associated with ovarian clear cell adenocarcinoma, there is a change of its cytokine production that may inhibit tumor growth.

Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer.

The development of hereditary von Hippel-Lindau (VHL) disease and the majority of sporadic kidney cancers are due to the functional inactivation of the VHL gene. The product of the VHL gene, pVHL, in association with elongins B and C, cullin 2, and Rbx1 form an E3 ubiquitin-ligase complex VEC that targets the alpha subunits of hypoxia-inducible factor (HIF) for ubiquitination. Ubiquitin-tagged HIF-alpha proteins are subsequently degraded by the common 26S proteasome. pVHL functions as the substrate-docking interface that specifically recognizes prolyl-hydroxylated HIF-alpha. This hydroxylation occurs only in the presence of oxygen or normoxia. Thus, under hypoxia, HIF-alpha subunits are no longer subjected to degradation and are thereby able to dimerize with the common and constitutively stable beta subunits. The heterodimeric HIFs upregulate a myriad of hypoxia-inducible genes, triggering our physiologic response to hypoxia. Inappropriate accumulations of HIF-alpha in VHL disease are believed to contribute to the pathogenesis via the upregulation of several of these HIF target genes. Our current molecular understanding of the roles of HIF and pVHL in the development of VHL-associated clear-cell renal cell carcinoma (CC-RCC) is the focus of this review.

Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma.

Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the approximately 12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1 beta (HNF-1 beta). We validated up-regulation of HNF-1 beta in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1 beta, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1 beta expression in CCC using RNA interference. The reduction of HNF-1 beta expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1 beta is not only an excellent CCC-specific molecular marker but also a molecular target for therapy of ovarian CCC.

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.

Remarkable suppressive effect of consecutive low-dose cisplatin therapy on advanced ovarian clear cell adenocarcinoma.

Ovarian clear cell adenocarcinoma (OCCA) is known to be less responsive to cisplatin and most other anti-cancer drugs and to have a poorer prognosis than other ovarian cancers. We report a rare case of stage IIIc OCCA in a patient who has been treated postoperatively with cisplatin alone and continues to survive after 7.5 years. In this case, 25 mg/m2/day of cisplatin was administered for 5 consecutive days every 4 weeks. After remission, intermittent administration of cisplatin every 3 to 4 months was performed 8 times. This case suggests that induction and intermittent chemotherapy using consecutive low-dose cisplatin administration may be a useful treatment for OCCA.

[Cancer of the kidney in adults. Apropos of 60 cases]. / Le cancer du rein de l'adulte. A propos de 60 cas.

The authors report a series of 60 cases of renal cancer observed over a 10-year period. Patients consisted of 35 women (58%) and 25 men (42%), with a mean age of 52 years (range: 21-72 years). The clinical features were polymorphic, dominated by loin pain (76%), haematuria (75%), a lumbar mass (46%), alteration of the general state (30%). The diagnosis was established by ultrasonography in 58 patients and CT scan in 38 patients. The mean tumour diameter was 11.5 cm (5-25 cm) and two cases presented bilateral tumours. The tumour was located in the upper pole in 40% of cases and was mid-renal in 30% of cases. The time to diagnosis ranged from 2 months to 3 years. Staging reflected the advanced stage of the cancer. Treatment was surgical for 53 patients (88%). A lumbar incision was generally performed (83%). The surgical procedure consisted of nephrectomy and regional or hilar lymph node dissection. Nephrectomy was simple for 27% of patients, radical for 69% of patients and partial for 4% of patients. The postoperative course was marked by one death due to pulmonary embolism, and a stercoral fistula in 2 patients. Histological examination of the specimen showed clear cell adenocarcinoma in 92% of cases. The tumour weight was often considerable, with a maximum of 3.750 kg. The lymph nodes removed were invaded in 50% of cases. The mean follow-up was 46 months (12 to 120 months). Follow-up was normal at 3 years for 23 patients (43%) and at 10 years for 4 patients (8%). Tumour recurrence in the renal compartment was observed in 3 patients after 3 years. Asynchronous metastases occurred in 10 patients (23%). The mean interval to metastases was 20 months (4 to 36 months).