Infiltrating adenomyosis of the cervix with features of a low-grade stromal sarcoma: a case report and a literature review.

Adenomyosis is a common, non-neoplastic, chronic gynecologic disorder that is detected in 5% to 70% of hysterectomy specimens. It is characterized by the presence of ectopic endometrial glands and stroma within the myometrium, and it occurs mostly in late reproductive age women. Adenomyosis has a propensity to present in the uterine fundus and is rarely seen in the cervix. At present, the most reliable way to diagnose adenomyosis is by pathologic examination of the hysterectomy specimens. Herein, we report a case of infiltrating adenomyosis in the cervix with unusual clinical and pathologic findings.

Gestational choriocarcinoma metastasis to the extraocular muscle: a case report.

This case report describes a biopsy-proven metastasis of gestational choriocarcinoma to the medial rectus muscle. Patient evaluation and follow up included comprehensive ophthalmologic history and examination, external and fundus photography, immunohistochemistry preparations of the medial rectus muscle specimen, MRI, ultrasound of the abdomen and pelvis, comprehensive blood tests, and CT scans of the chest, abdomen, and pelvis. The tissue specimen was obtained via a medial perilimbal conjunctival peritomy. MRI revealed a mass intrinsic to the right medial rectus muscle. Immunohistochemical staining confirmed gestational choriocarcinoma metastasis in medial rectus muscle biopsy. The patient showed general and orbital improvement following 7 subsequent cycles of chemotherapy. In conclusion, gestational choriocarcinoma may metastasize to the orbit in addition to the previously reported ocular site, the choroid. A chemotherapy regimen of etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine can effectively treat the intraorbital component of the disease.

Prognostic significance of mucinous differentiation of endometrioid adenocarcinoma of the endometrium.

Using Surveillance, Epidemiology, and End Results database we identified 43,882 (97.0%) women with endometrioid adenocarcinomas and 1,374 (3.0%) with mucinous adenocarcinomas. Women with mucinous tumors were older (P < .0001), more often white (P = .04), and more often to present at advanced stage (P = .001). Survival was similar for both histologies; the hazard ratio for cancer-specific survival for mucinous compared to endometrioid tumors was 0.90 (95% CI, 0.74-1.09) while the hazard ratio for overall survival was 0.95 (95% CI, 0.85-1.07). Five-year survival for stage I mucinous tumors was 89.9% (95% CI, 87.6-91.9%) compared to 89.0% (95% CI, 88.6-89.4%) for endometrioid tumors.

Unmet needs in ovarian cancer: dividing histologic subtypes to exploit novel targets and pathways.

Ovarian cancer (OC) carries a poor prognosis; however, accumulating molecular data for the major histologic subtypes may lead to subtype-specific treatment paradigms. The present review discusses what is currently understood about the major molecular and histologic subgroups of OC. Areas specifically addressed include hormonal pathways, tumor protein p53 (TP53) and AT rich interactive domain 1A (SWI-like; ARID1A) mutation, and the breast cancer 1/2, early onset (BRCA1/2) mutation/poly (ADP-ribose) polymerase 1 (PARP1), phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PI3KCA)/v-akt murine thymoma viral oncogene homolog 1 (AKT1)/mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2) pathways. This molecular characterization only very recently has impacted clinical research efforts to develop targeted therapies for both common and rare OC subtypes. This targeted strategy is illustrated by ongoing low-grade serous, clear-cell, and mucinous subtypeexclusive clinical trials evaluating agents based on common molecular abnormalities among patients (i.e., PARP1 inhibitors for BRCA1/2 mutation-positive OC). This report also reviews the published clinical trial efficacy data for investigational therapies within specific subgroups, and summarizes the currently active clinical trials evaluating these agents (e.g., temsirolimus, sunitinib, TP53 immunotherapy, olaparib, iniparib, veliparib). Available data suggest that histologic profiles and molecular tumor markers are valuable resources for identifying patients who may benefit from these specific agents, and future research should focus on targeting molecules and signaling pathways that are most commonly altered in each subtype.

NOTCH2 expression is decreased in epithelial ovarian cancer and is related to the tumor histological subtype.

BACKGROUND: Notch family members function as both oncogenes and tumor suppressors. NOTCH2 is down-regulated in colon cancer, and reduced expression is associated with a less differentiated, more aggressive phenotype, and reduced overall survival. NOTCH2 has also been shown to have pro-apoptotic and growth suppressive effects in thyroid carcinoma, and carcinoid tumors. The expression pattern of NOTCH2 in ovarian cancer is unknown. METHODS: An immunohistochemical analysis using a polyclonal antibody to the NOTCH2 intracellular domain was performed on a total of 119 ovarian carcinomas, and 7 serous borderline tumors, arranged onto tissue arrays. Normal ovarian and fallopian tube epithelium were used as controls. Specimens were scored as low or high NOTCH2 expression. The score distributions for the subtypes were analyzed with the chi square test. RESULTS: Fifty two of 61 (85.2%) papillary serous, eight of 13 (61.5%) clear cell, and 23 of 30 (76.7%) endometrioid, demonstrated negative or lower NOTCH2 expression than normal fallopian tubal epithelium or ovarian surface epithelium. In contrast, 10 of 15 (66.7%) mucinous carcinomas had a high level of NOTCH2 expression and consistently demonstrated intense polarized staining (P<.001). The apical expression of NOTCH2 protein present in the normal fallopian tube epithelium and many borderline tumors was absent in the high grade carcinomas, most notably in papillary serous. CONCLUSION: Decreased NOTCH2 expression is associated with the poorly differentiated serous epithelial ovarian carcinoma histology. Further studies are needed to assess the functional role of NOTCH2 in ovarian cancer and its effect on prognosis.

Preoperative enoxaparin is safe to use in major gynecologic surgery for prophylaxis of venous thromboembolism: a retrospective cohort study.

OBJECTIVE: To evaluate the safety of preoperative enoxaparin in patients undergoing major gynecologic oncology surgery. METHODS: We identified a retrospective cohort group of patients undergoing major gynecologic oncology surgery from June 2002 to June 2004. Exclusion criteria included laparoscopic surgery, inferior vena cava filter, history of venous thromboembolism, and current anticoagulation for prior venous thromboembolism. All patients received prophylaxis with sequential pneumatic compression devices and early ambulation. We identified patients who received (preoperative and postoperative) enoxaparin (20-40 mg) and compared them to patients who received no additional prophylaxis other than pneumatic compression alone. Patient outcomes including estimated blood loss, blood transfusions, operative time, and length of hospital stay were collected. Statistical analysis was performed using the χ Wilcoxon rank sum tests. This study was approved by the institutional review board. RESULTS: We identified 122 patients who met our study criteria; there were 63 patients who received preoperative enoxaparin and 59 patients who received no additional prophylaxis. Both groups were similar in age, body mass index, race, comorbidities, cancer diagnosis, and surgical procedure. There was no significant difference between the enoxaparin group and the sequential pneumatic compression devices-only group regarding transfusion rates (29% and 27%; P = 0.86), operating time (150 and 140 minutes; P = 0.16), blood loss greater than 500 cc (35% and 37%; P = 0.79), and length of stay (5 vs 6 days). CONCLUSION: The use of preoperative enoxaparin is not associated with increased blood loss, transfusion requirements, operative time, or hospital stay among patients having major gynecologic surgery.

Prognostic significance of adenocarcinoma histology in women with cervical cancer.

OBJECTIVES: We performed a population-based analysis to determine the effect of histology on survival for women with invasive cervical cancer. METHODS: The Surveillance, Epidemiology and End Results database was used to identify women with stage IB-IVB cervical cancer treated from 1988 to 2005. Patients were stratified by histology (squamous, adenocarcinoma, and adenosquamous). Clinical characteristics, patterns of care, and outcomes were analyzed using multivariable logistic regression and Cox proportional hazards models. RESULTS: A total of 24,562 patients were identified including 18,979 (77%) women with squamous cell carcinomas, 4103 (17%) with adencarcinomas, and 1480 (6%) with adenosquamous tumors. Women with adenocarcinomas were younger, more often white, and more frequently married than patients with squamous cell tumors (p<0.0001 for all). Patients with adenocarcinomas were more likely to present with early-stage disease (p<0.0001). At diagnosis, 26.7% of women with adenocarcinomas had stage IB1 tumors compared to 16.9% of those with squamous cell carcinomas. Among women with early-stage (IB1-IIA) tumors, patients with adenocarcinomas were 39% (HR=1.39; 95% CI, 1.23-1.56) more likely to die from their tumors than those with squamous cell carcinomas. For patients with advanced-stage disease (stage IIB-IVA) women with adenocarcinomas were 21% (HR=1.21; 95% CI, 1.10-1.32) more likely to die from their tumors than those with squamous neoplasms. Five-year survival for stage IIIB neoplasms five-year survival was 31.3% (95% CI, 29.2-33.3%) for squamous tumors vs. 20.3% (95% CI, 14.2-27.1%) for adenocarcinomas. CONCLUSION: Cervical adenocarcinomas are more common in younger women and white patients. Adenocarcinoma histology negatively impacts survival for both early and advanced-stage carcinomas.

Paclitaxel poliglumex for ovarian cancer.

INTRODUCTION: Despite an 80% initial response rate to the standard primary regimen of carboplatin and paclitaxel, most women with ovarian cancer will experience recurrence with incurable disease within five years and will be treated with several successive palliative regimens. Consequently, a significant need exists for chemotherapeutic agents, which are not only clinically efficacious, but have acceptable side-effect profiles. Paclitaxel poliglumex (PPX) is a recently developed taxane in which paclitaxel is conjugated to poly(l-glutamic acid), which renders it water soluble, reduces hypersensitivity reactions and preferentially targets it to the tumor. AREAS COVERED: This review covers pre-clinical pharmacokinetic data and key Phase I and II clinical trial results in ovarian cancer. EXPERT OPINION: While PPX is active in ovarian cancer, it is unclear at present whether it offers significant benefit in terms of its side-effect profile or outcomes over a standard taxane-based regimen as first-line therapy, or what role it will have in maintenance therapy as studies are ongoing.

Alternate molecular genetic pathways in ovarian carcinomas of common histological types.

We evaluated alterations in p53, PIK3CA, PTEN, CTNNB1 (beta-catenin), MLH1, and BRAF among common histological subsets of epithelial ovarian tumors to characterize patterns of alterations of different molecular pathways. There were 12 clear cell, 26 endometrioid, and 51 serous carcinomas evaluated by direct DNA sequencing for mutations in p53, PIK3CA, PTEN, BRAF, and CTNNB1. Methylation-specific polymerase chain reaction (PCR) assessed MLH1 promoter methylation status. Quantitative PCR identified PIK3CA amplification in 22 EC/CC and 94 SC. p53 mutations were identified in 25 (49%) of 51 SC, 11 (42%) of 26 EC, and 1 (8.3%) of 12 CC neoplasms and were more common in grade 3 EC (P = .045) and advanced-stage EC/CC (P = .007). PIK3CA mutations were identified in 3 (25%) of 12 CC, 3 (12%) of 26 EC, and 0 of 51 SC. PTEN mutations were significantly more common in EC (8/26, 31%) compared with CC (0/12; P = .04) and SC (2/51, 4%; P = .002). CTNNB1 mutations were identified, 6 (23%) EC and no CC or SC (P = .008). Both PTEN and CTNNB1 mutations were more common in low-grade EC/CC, whereas PIK3CA mutations occurred only in grade 3 cancers. PTEN and PIK3CA mutations were more common in p53 wild-type tumors (P = .003). PIK3CA amplification occurred in fewer EC/CC (0/22) versus SC (19/94, 20%; P = 0.02) and were slightly more common in p53 wild-type compared with p53 mutant SC (P = .08). Of 26 EC, 22 (85%) had a mutation in one of the genes studied compared with 4 33% of 12 CC (P = .003). Women with EC/CC had significantly better overall survival (P = .0008), and this remained significant after accounting for stage (P=.04). Mutations in p53 or in PTEN/PIK3CA are alternative pathways in ovarian carcinogenesis. Activation of PIK3CA occurs by gene amplification in SC but via somatic mutation of PIK3CA or PTEN in EC and CC. PIK3CA mutations are associated with high-grade tumors, whereas PTEN and CTNNB1 mutations are associated with low-grade tumors. Mutations in p53, PIK3CA, PTEN, and CTNNB1 account for most EC tumors; most CC remain unexplained. EC/CC histology is a favorable prognostic factor.

Common polymorphisms in TP53 and MDM2 and the relationship to TP53 mutations and clinical outcomes in women with ovarian and peritoneal carcinomas.

The importance of somatic TP53 mutations and germline TP53 codon 72 genotype in the survival of women with epithelial ovarian cancer is controversial. Recent data suggest that a promoter polymorphism in the MDM2 gene may influence age of cancer onset in a gender-specific fashion. We sought to determine the relationship between somatic TP53 mutations, germline genotypes at TP53 codon 72 and MDM2 SNP309, and overall survival and response to chemotherapy in a large series of patients with ovarian and peritoneal carcinomas. Of the 188 cancers, 103 (54.8%) had a TP53 mutation, of which 71% were missense mutations and 29% were null mutations. TP53 mutation status and mutation type (null vs. missense) did not influence response to therapy or overall survival. Women with the codon 72 Pro/Pro had a decreased overall survival (median, 29 months) compared with women with one or two arginine alleles (median, 49 months; P=0.04). Somatic mutation or deletion was equally common for either codon 72 allele. Age of diagnosis was not influenced by codon 72 but showed a trend for younger age in women with somatic TP53 mutations and the MDM2 G/G genotype.

Common polymorphism in interleukin 6 influences survival of women with ovarian and peritoneal carcinoma.

OBJECTIVES: The IL6 -174 promoter polymorphism impacts serum cytokine levels through transcriptional regulation. The objective of our study was to determine if -174 IL6 genotype influences survival in ovarian cancer. METHODS: The IL6 -174 polymorphism was assessed by direct DNA sequencing in lymphocyte DNA from 160 women with invasive ovarian, or peritoneal cancers. IL6 levels were measured in ascites and plasma in a subset of cases using colorimetric sandwich ELISA procedure. Overall survival was calculated according to the method of Kaplan and Meier. Cox regression analysis was used to evaluate the significance of individual variables in multivariate analysis. Chi-square or Fishers Exact was used to assess the significance of contingency tables. RESULTS: The IL6 -174 genotype frequencies of CC (19%), CG (50%), and GG (31%) were in Hardy-Weinberg equilibrium and were similar to published frequencies in Caucasian controls. There were no associations with IL6 -174 genotype and age, stage or optimal cytoreduction. Stage had a significant impact on survival (p=0.003). The IL6 -174 GG genotype was significantly associated with longer overall survival (median 131 months) compared to CC or CG (median 28 months, p=0.0007). In cox regression analysis using the covariates genotype (p=0.006) and stage (p=0.02), both were independently significant. Furthermore, there was no association found between IL6 levels in ascites or plasma, and genotype, stage, or overall survival. CONCLUSIONS: The IL6 -174 GG genotype has a strong, independent, and favorable impact on survival for women with ovarian, and peritoneal carcinoma.

Aggressive prenatal care results in successful fetal outcomes in CF women.

BACKGROUND: The impact of pre-pregnancy pulmonary and nutritional status in pregnancy outcomes of women with cystic fibrosis (CF) is not clearly defined. METHODS: A chart review of CF women who attended the University of Washington Medical Center (UWMC), Seattle WA. from January 1989 until May 2004. RESULTS: There were 43 pregnancies resulting in 36 live births among 25 of 189 CF women. In the subset of CF women receiving their obstetric care at the UWMC whose FEV1 was < 50% predicted, infant weight was lower than in women with a higher FEV1 (2.9 kg+/-0.4 (range 2.2-3.3 kg) versus 3.4+/-0.8 kg (range 2.5-5.1 kg)) p = 0.05 although the gestational ages were the same (37+/-2 weeks (range 33-39 weeks) versus to 38+/-2 weeks (range 35-40 weeks) p = 0.17). Infant weight and gestational age of women whose initial BMI was < 20 kg/m2 was no different from women with a normal initial BMI (3.0+/-0.4 kg, range 2.2-3.4 kg versus 3.3+/-0.8 kg, range 2.6-5.1 kg p = 0.29, and 37.7+/-2.4 weeks, range 33-39 weeks versus 37.2+/-2.1 weeks, range 34-40 weeks). CONCLUSIONS: CF women with severe pulmonary impairment tend to have lower weight babies but it remains difficult to determine prospectively which CF women will tolerate pregnancy well. Aggressive antepartum management is recommended for all CF women.