Trastuzumab with carboplatin/paclitaxel for treatment of advanced stage and recurrent uterine papillary serous carcinoma: A cost-effectiveness analysis.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a variant of endometrial cancer that is aggressive and associated with poor outcomes. We sought to evaluate the cost effectiveness of carboplatin/paclitaxel alone versus carboplatin/paclitaxel with trastuzumab among patients with Her2/neu-positive advanced or recurrent UPSC. METHODS: We designed a Markov model in TreeAge Pro 2019 software to simulate management of a theoretical cohort of 4000 patients with Her2/neu-positive advanced or recurrent uterine papillary serous carcinoma (UPSC) followed for four years. In the carboplatin/paclitaxel with trastuzumab strategy, we included the cost of testing for Her2/neu status. We obtained all model inputs from the literature and a societal perspective was assumed. Outcomes included progression-free survival, progression, UPSC-specific mortality, cost, and quality-adjusted life years (QALYs). The intervention was considered cost effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were used to determine the robustness of the results. RESULTS: In our theoretical cohort of 4000 women, treatment with the addition of trastuzumab resulted in 637 fewer deaths and 627 fewer cases of progression compared with treatment with carboplatin/paclitaxel alone. Treatment with trastuzumab was associated with an additional cost of $144,335,895, but was associated with an increase of 2065 QALYs. The ICER was $69,903 per QALY, which was below our willingness-to-pay threshold. Sensitivity analysis demonstrated that this treatment strategy was cost-effective until the cost of 6 months of treatment surpassed $38,505 (baseline input: $27,562). CONCLUSION: We found that the addition of trastuzumab to carboplatin/paclitaxel was a cost-effective treatment strategy for patients with advanced/recurrent Her2/neu-positive UPSC.

Prohibitin: targeting peptide coupled to ovarian cancer, luteinization and TGF-ß pathways.

BACKGROUND: Ovarian epithelial tumor (OET) is a silent disease of late diagnosis and poor prognosis. Currently treatment options are limited and patient response to treatment is difficult to predict so there is a serious need to delineate the real pathogenesis to predict tumour prognosis. Prohibitin (PHB) is an evolutionarily protein that regulates the cell cycle. TGF-ß has been shown to be a positive and negative regulator of cellular proliferation and differentiation. The present study provides an overview on the role played by PHB1, TGF-ß and LH in ovarian cancer. METHODS: The study was conducted on 60 patients with ovarian tumors (benign, borderline and malignant) and 20 healthy volunteers. LH and TGF-ß serum levels were measured by ELISA. Expression of prohibitin and LHR-mRNA were assessed by IHC and TaqMan® real time gene expression assay, respectively. RESULTS: Serum levels of LH and TGF-ß were significantly decreased among borderline and malignant groups. There was significant over-expression of LHRmRNA in malignant group. Prohibitin expression was significantly increased in malignant ovarian tissue. Strong negative correlations were found between LHR mRNA expression and serum LH levels, and between IHC score of prohibitin and serum levels of LH among patients with borderline ovarian tumors. CONCLUSION: Steady decline of LH and TGF-B serum levels, from benign cystadenoma to borderline tumor to carcinoma, suggests their inhibitory role against OET cell growth. Increased PHB1 expression in OET suggests its proliferative activity that can be regulated by luteinisation and/or TGF-ß. Furthermore increased LHR mRNA tissue expression can provide hope for using LH in treatment of some types of ovarian cancers.

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats.

Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFß1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy.

Vaginal fold prolapse in a dog with pyometra and ovarian papillary cystadenocarcinoma.

CASE DESCRIPTION: A 7-year-old 42-kg (92.4-lb) sexually intact nulliparous female Italian Mastiff was examined because of a history of vaginal prolapse during diestrus. CLINICAL FINDINGS: A physical examination revealed vaginal fold prolapse. Abdominal ultrasonography revealed an enlarged uterus with hypoechogenic content, corpora lutea in the ovaries, and a cyst in the right ovary. Hematologic abnormalities included leukocytosis, neutrophilia, mild anemia, and low Hct. Progesterone and estradiol concentrations were 9.36 ng/mL and 30.42 pg/mL, respectively, in serum and 72.72 ng/mL and 792 pg/mL, respectively, in the ovarian cystic fluid. TREATMENT AND OUTCOME: Ovariohysterectomy was performed; the prolapsed tissue was repositioned by external manipulation and maintained in situ by temporary apposition of the vulvar lips with a retention suture. Anatomic and histologic examinations of the excised tissues revealed pyometra and papillary cystadenocarcinoma in the right ovary. The vaginal hyperplasia completely regressed at 35 days after surgery; 5 months after surgery, the dog's general condition was considered good. CLINICAL RELEVANCE: Findings in this case were indicative of a hormonally active ovarian papillary cystadenocarcinoma in a female dog in diestrus. Hormone production by the cystadenocarcinoma was the predisposing factor that induced pyometra, mucosal hyperplasia, and vaginal fold prolapse in the dog. On the basis of these concurrent disorders, ovariohysterectomy was an appropriate treatment.

Follicle-stimulating hormone induced epithelial-mesenchymal transition of epithelial ovarian cancer cells through follicle-stimulating hormone receptor PI3K/Akt-Snail signaling pathway.

PURPOSE: It has previously been shown that follicle-stimulating hormone (FSH) and its receptor contribute to epithelial ovarian cancer (EOC) development. Epithelial-mesenchymal transition (EMT) is the early event of metastasis in cancer. Therefore, the aim of this study was to investigate the roles of FSH and the FSH receptor (FSHR) in EMT of EOC. METHODS: Ovarian cancer cells treated with various doses of FSH were used to investigate the effect of FSH on EMT. Small interfering RNA-mediated FSHR depletion or reexpression of FSHR by acute transfecting pcDNA-hFSHR plasmid was performed to determine the role of FSHR in FSH-induced EMT. Moreover, LY294002, a potent and specific cell-permeable inhibitor of phosphatidylinositol 3-kinases (PI3K), was selected to pretreat ovarian cancer cells to confirm whether PI3K/Akt signaling is involved in this event. RESULTS: In the current study, FSH was found to induce the phenotypes of EMT including migration and invasion in EOC cells. Elevated FSHR levels promoted EMT, migration, and invasion, whereas small interfering RNA-mediated FSHR knockdown inhibited these processes. Moreover, the inhibition of FSH-induced PI3K/Akt signaling pathway attenuated Snail expression and the EMT process. CONCLUSIONS: Collectively, the findings of the current study indicate that FSH induced the EMT of ovarian cancer cells through the FSHR-PI3K/Akt-Snail signaling pathway.

Syringocystadenocarcinoma papilliferum in situ: report of a case with late recurrence.

Syringocystadenocarcinoma papilliferum (SCACP) is an extremely rare cutaneous neoplasm with apocrine differentiation. Only 27 cases have been reported up-to-date, 8 of them described as carcinomas in situ. Two cases with local recurrence and 3 cases with regional lymph node metastases have been documented. The authors present the case of a 32-year-old female with a SCACP in situ on the scalp that recurred 8 years after the excision of the primary tumor. No SCACP with late recurrence have been previously reported. This case highlights the need for a long-term follow-up in patients with this type of carcinoma.

Photodynamic detection and management of intraperitoneal spreading of primary peritoneal papillary serous carcinoma in a man: report of a case.

As a peritoneal surface malignancy, primary peritoneal papillary serous carcinoma (PPPSC) almost always occurs in women. Our search of the literature found only two previous case reports of men with PPPSC, both with very short survival. We report the case of a 63-year-old man with PPPSC, treated effectively with cytoreductive surgery and docetaxel-based hyperthermic intraperitoneal chemotherapy following six cycles of docetaxel-based laparoscopic neoadjuvant intraperitoneal and cisplatin-based systemic chemotherapy. Furthermore, we detected intraoperative intraperitoneal spreading of the tumor after the oral administration of 5-amino levulinic acid (5-ALA). The patient remains in good health without ascites 18 months after his diagnosis. Thus, primary peritoneal papillary serous carcinoma should be managed by intraperitoneal chemotherapy combined with peritonectomy procedures. Moreover, the intraoperative detection of the intraperitoneal spreading of the tumor after administering oral 5-ALA shows that this is an exciting and promising diagnostic technique, which needs to be confirmed by further studies.

Decreased expression of 14-3-3σ is predictive of poor prognosis for patients with human uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) morphologically resembles ovarian serous carcinoma and is categorized as a type II endometrial cancer. UPSC comprises about 10% of all types of endometrial cancer and has an aggressive clinical course and a poor prognosis. The 14-3-3σ gene was originally discovered as a p53-inducible gene; its expression is induced by DNA damage in a p53-dependent manner, which leads to G2 arrest and repair of damaged DNA. Moreover, it has been reported that expression of 14-3-3σ is frequently lost in various types of human cancer, including ovarian cancer. We therefore examined the association between 14-3-3σ expression determined by immunohistochemistry and clinical outcomes of 51 patients with UPSC. UPSC was considered positive for 14-3-3σ when > 30% of tumor cells were stained with a specific antibody. Of these patients, 29 (58.7%) showed positive immunoreactivity for 14-3-3σ and 22 (41.3%) had decreased 14-3-3σ staining. Decreased immunoreactivity for 14-3-3σ was associated with stage (P = 0.001) and lymphovascular space involvement (P = 0.005). Moreover, decreased 14-3-3σ expression was an independent risk factor for reduced overall survival (P = 0.0416) in multivariate analysis. Direct bisulfite sequencing was performed to evaluate the methylation status of the 27 CpG islands in the promoter region and first exon of the 14-3-3σ gene. These CpG islands were hypermethylated in 30% of 14-3-3σ-positive UPSC and 80% of 14-3-3σ-negative UPSC, although the difference was not statistically significant. These findings suggest that decreased expression of immunoreactive 14-3-3σ may be a predictor of poor prognosis in patients with UPSC.

Clear cell papillary cystadenocarcinoma of the epididymis: a case report and immunohistochemistry of markers for renal cell carcinoma.

Neoplasms of the epididymis are uncommon, and malignant tumors are extremely rare. We report a case of clear cell papillary cystadenocarcinoma of the epididymis presenting with a long history of painless scrotal mass on the left side. Immunohistochemical markers for clear cell renal cell carcinoma (RCC) were examined to distinguish between clear cell papillary cystadenocarcinoma of the epididymis and metastatic clear cell renal cell carcinoma. The present case was positive for cytokeratin-7, PAX2, vinculin, vimentin and carbonic anhydrase IX. Expression of CD10 was focally observed. In contrast, no immunoreactivities for α-methylacyl-CoA racemase, RCC marker, glutathione S-transferase α or C-KIT were detected. The immunophenotypic profile of clear cell papillary cystadenocarcinoma of the epididymis closely resembles that of clear cell papillary RCC, although the immunohistochemical markers tested in this study are useful to make a differential diagnosis between clear cell papillary cystadenocarcinoma of the epididymis and metastatic clear cell RCC.

Borderline serous papillary tumour of the testis: a case report and review of the literature.

Borderline serous tumour of the testis and paratestis is an uncommon entity. We report a case of borderline serous tumour of a 59-year-old male, who presented with a right testicular swelling which was clinically suspicious of carcinoma. Radical orchidectomy was performed and a cystic lesion was identified in the testis. Macroscopically the tumour was composed of a unilocular cyst with excrescences in the inner surface. The histological features were identical to the ovarian counterpart of borderline serous papillary tumour. The excrescences were formed by stratified columnar epithelium, which exhibited mild nuclear pleomorphism and mitotic activity, with a fibrovascular core and scattered psammoma bodies. There was no lymphovascular or stromal invasion. The lesion was surrounded by a dense fibrous wall. On immunohistochemistry, the lining epithelial cells expressed cytokeratin AE1/AE3 but not carcinoembryonic antigen or calretinin. Following the removal of the tumour, the patient was followed up and no recurrence or metastasis has occurred to date. This case highlights the need for clinicians and pathologists to be aware of this rare entity and to develop the best approach for patient management.

Cystic papillary pattern in pancreatic ductal adenocarcinoma: a heretofore undescribed morphologic pattern that mimics intraductal papillary mucinous carcinoma.

INTRODUCTION: The prototypic pancreatic ductal adenocarcinoma shows small-caliber glands that are placed within an exuberant desmoplastic stromal reaction. A number of histologic patterns have been described, and the majority of these patterns are genetically and biologically related to conventional ductal adenocarcinomas. In this report we describe our experience with a heretofore undescribed histologic pattern of pancreatic adenocarcinoma that mimics intraductal papillary mucinous carcinoma, both morphologically and radiologically. METHODS: We identified 10 cases of pancreatic adenocarcinoma with large-caliber malignant glands and an intraluminal papillary pattern. The demographic, clinical, radiologic, and outcome data were recorded. In addition to a review of the histologic features we also performed elastin stains, immunohistochemistry for selected oncogenes and tumor suppressor genes including SMAD4. Immunohistochemical staining for MUC proteins was also performed. RESULTS: The median age of the patients was 67 years, and there were 6 women and 4 men. Grossly, the cut surface in 6 of these cases showed an admixture of solid and cystic areas. The papillary cystic architecture was intimately mixed with areas of conventional adenocarcinoma, the latter characterized by invasive small-caliber tubular structures. None of the tumors showed a pure papillary cystic pattern; however, in 8 cases, this was the predominant pattern (>50% of the tumor). The cysts and papillae were lined predominantly by tall columnar hypermucinous epithelium. Elastin fibers were not identified around these dilated malignant cysts and glands. The intratumoral stroma was paucicellular and hyalinized. Seven of the 10 tumors were negative for SMAD4. The lack of pericystic elastin fibers and loss of SMAD4 in the majority of cases argue against these lesions representing an intraductal papillary mucinous neoplasm. All 10 tumors stained for MUC1; focal MUC2 reactivity was noted in 1 case. The majority of cases were positive for MUC5AC (9/10) and MUC6 (8/10). Seven patients died of their disease, whereas 1 patient is alive with widely metastatic disease. Two patients were lost to follow up. CONCLUSIONS: The adenocarcinoma described herein is a unique morphologic pattern of pancreatic ductal adenocarcinoma. The biology and genetics (as estimated by immunohistochemistry) are no different from that of conventional ductal adenocarcinoma but are distinctly different from that of an intraductal papillary mucinous carcinoma, its closest morphologic mimic.

Diagnostic implications of p16 expression in serous papillary endometrial cancer.

OBJECTIVE: The purpose of this study was to examine whether the degree of expression of the p16 protein in serous papillary endometrial cancer bears a prognostic significance. The secondary objective was to establish the value of p16 immunohistochemical staining as an adjunct to diagnosis. STUDY DESIGN: Archived paraffin blocks holding specimens from the uteri of 31 serous papillary and 31 endometrioid endometrial carcinoma patients were recut and restained for p16 and p53. RESULTS: Overexpression of p16 was found in 78% of the serous papillary patients versus 36% of the endometrioid patients. p16 was not found to be an independent prognostic factor in serous papillary endometrial carcinoma. CONCLUSIONS: Although p16 was not found to have prognostic significance in serous papillary endometrial carcinoma, it may be valuable as a diagnostic adjunct in histologically ambiguous tumors.

Expression of αV-integrins in uterine serous papillary carcinomas; implications for targeted therapy with intetumumab (CNTO 95), a fully human antagonist anti-αV-integrin antibody.

OBJECTIVE: Uterine serous papillary carcinoma (USPC) is an aggressive variant of endometrial cancer characterized by an innate resistance to chemotherapy and poor prognosis. In this study, we evaluated the expression of αV-integrins in primary USPC cell lines and the in vitro ability of intetumumab (CNTO 95), a fully human monoclonal antibody against αV-integrins, to inhibit USPC cell adhesion and migration. MATERIALS AND METHODS: The surface expression of integrins belonging to the αV-family, including αVß3, αVß5, and αVß6, was evaluated in 6 primary USPC cell lines using flow cytometry analysis. To test the ability of intetumumab to inhibit USPC cell adhesion and migration, adhesion assays in the presence of vitronectin and migration assays through an 8.0-µm pore polycarbonate membrane also were performed. RESULTS: We found high expression of the αV-subunit on the cell surface of all 6 primary USPC cell lines tested (100% positive cells; mean fluorescence intensity range, 13.1-39.5). When the expression of single heterodimeric integrins was evaluated, αVß3, αVß5, and αVß6 were expressed on 37.5%, 32.0%, and 16.3% of cells (mean fluorescence intensity range, 6.5-16.2, 9.2-32.5, and 6.2-11.5, respectively). Importantly, in functional assays, low doses of intetumumab were effective in inhibiting adhesion (0.15 µg/mL, P = 0.003) and migration (1.25 µg/mL P = 0.02) of primary USPC cell lines. CONCLUSIONS: The αV-integrins are overexpressed on the cell surface of primary USPC cell lines. Intetumumab may significantly inhibit USPC cell adhesion and migration pathways and may therefore represent a novel treatment option for patients harboring this rare but highly aggressive variant of endometrial cancer.

HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes.

The AT-hook transcription factor HMGA2 is an oncogene involved in the tumorigenesis of many malignant neoplasms. HMGA2 overexpression is common in both early and late-stage high-grade ovarian serous papillary carcinoma. To test whether HMGA2 participates in the initiation of ovarian cancer and promotion of aggressive tumor growth, we examined the oncogenic properties of HMGA2 in ovarian surface epithelial (OSE) cell lines. We found that introduction of HMGA2 overexpression was sufficient to induce OSE transformation in vitro. HMGA2-mediated OSE transformation resulted in tumor formation in the xenografts of nude mice. By silencing HMGA2 in HMGA2-overexpressing OSE and ovarian cancer cell lines, the aggressiveness of tumor cell growth behaviors was partially suppressed. Global gene profiling analyses revealed that HMGA2-mediated tumorigenesis was associated with expression changes of target genes and microRNAs that are involved in epithelial-to-mesenchymal transition (EMT). Lumican, a tumor suppressor that inhibits EMT, was found to be transcriptionally repressed by HMGA2 and was frequently lost in human high-grade serous papillary carcinoma. Our findings show that HMGA2 overexpression confers a powerful oncogenic signal in ovarian cancers through the modulation of EMT genes.

Immunohistochemical profile of paratesticular serous papillary adenocarcinoma and tunica vaginalis facilitates distinction from malignant mesothelioma.

Testicular and paratesticular tumors resembling mullerian epithelium of the ovary are extremely uncommon. This study reports a case of paratesticular serous papillary adenocarcinoma (SPA) in an 87-year-old man that was misdiagnosed as malignant mesothelioma (MM) and is 37 years older than previous cases, highlighting that SPA does not occur exclusively in young patients as described. Immunohistochemistry revealed expression of pankeratin, CAM 5.2, CK7, CK903, Ber-EP4, vimentin, S100, and CEA and virtually no expression of CK5/6, CK20, calretinin, thrombomodulin, or glypican 3. Expression of adjacent nonneoplastic tunica vaginalis mesothelium was assessed in this patient and additional specimens. Profiles of paratesticular SPA and MM were summarized and compared with paratesticular mesothelium. Nontumoral stromal and entrapped mesothelial expression were 2 diagnostic pitfalls in this case that have not been previously described. Based on these data, a panel of markers and the use of sections containing nonneoplastic mesothelium to facilitate interpretation is recommended.

Diagnostic pitfalls in syringocystadenocarcinoma papilliferum: case report and review of the literature.

We report the first case, to our knowledge, of syringocystadenocarcinoma papilliferum with p63-verified squamous differentiation and extensive dermal invasion accompanying in situ components. An 86-year-old woman presented with a neoplasm on the neck, and the intralesional heterogeneity typical of these neoplasms led to an initial diagnosis on needle biopsy favoring squamous cell carcinoma. Excision illustrated diverse morphology, raising a broad differential diagnosis, including more common extracutaneous malignancies, such as breast, gastrointestinal, and ovarian primary tumors. Fortuitous sectioning revealed a focal connection to the skin surface with evidence of apocrine differentiation allowing final diagnosis as syringocystadenocarcinoma papilliferum. Our literature review shows the histologic and immunohistochemical features of syringocystadenocarcinoma papilliferum are not well defined outside of their clear morphologic overlap with syringocystadenoma papilliferum. We describe our findings and diagnostic pitfalls to help pathologists encountering this unusual apocrine neoplasm.

[Clinical significance of Her-2/neu status in patients with uterine papillary serous carcinoma].

OBJECTIVE: The purpose of this study was to evaluate gene amplification by chromogenic in situ hybridization (CISH) and the protein expression of Her-2/neu gene in patients with uterine papillary serous carcinoma (UPSC) and to determine its prognostic value. METHODS: Thirty-six patients with confirmed pathologic diagnosis of UPSC in Cancer Hospital of Fudan University from Jan. 1996 to Jan. 2006, were analysed retrospectively. CISH was performed to assess Her-2/neu gene amplification, and protein expression was evaluated by immunohistochemistry (IHC). The prognostic factors were analyzed by log-rank test or Cox proportional hazard model. RESULTS: Among 36 cases with UPSC, 13 patients (36.1%) showed moderate staining (++) to strong staining (+++) for Her-2/neu protein, while amplification of the Her-2/neu gene by CISH was observed in 4 of the 36 (11.1%) cases. Her-2/neu protein over-expression was significantly associated with advanced surgical stage and worse prognosis by univariate analysis (P=0.030 and P=0.002, respectively), while the multivariate analysis shown that only Her-2/neu protein over-expression and deep myometrial invasion were associated with a poor prognosis (P<0.05). In 13 patients with Her-2/neu protein over-expression, the mean survival period with chemotherapy was shorter than those without chemotherapy (20 vs. 42 months, P=0.370). CONCLUSION: Her-2/neu protein over-expression is significantly associated with advanced surgical stage UPSC and poor survival outcome, and might reduce the chemotherapy sensitivity.

Expression of soluble interleukin-6 receptor in malignant ovarian tissue.

OBJECTIVE: The objective of the study was to investigate interleukin-6 receptor (IL6R) isoforms and sheddases in the ovarian tumor microenvironment. STUDY DESIGN: Expression of IL6R and sheddases was measured in tissue samples of papillary serous ovarian carcinomas and benign ovaries by real-time polymerase chain reaction and immunohistochemistry. Murine xenograft samples were tested by enzyme-linked immunosorbent assay to discriminate and evaluate tumor and host contributions of IL6R. RESULTS: IL6R expression was increased in malignant ovarian tumors and localized to epithelial cells. Expression of a soluble splice variant of IL6R was increased in malignant tumors, as were the sheddases for the full-length isoform. An in vivo xenograft model showed that host IL6R expression is also increased and regulated by tumor-associated inflammation. CONCLUSION: IL6R is overexpressed in epithelial ovarian malignancies because of increases in a soluble IL6R variant, in the sheddases for full-length IL6R and host IL6R expression. Soluble IL6R may be an efficacious target for reducing IL6-mediated ovarian tumor progression.