Morphological and phenotypical features of ovarian metastases in breast cancer patients.

BACKGROUND: Autotransplantation of frozen-thawed ovarian tissue is a method to preserve ovarian function and fertility in patients undergoing gonadotoxic therapy. In oncology patients, the safety cannot yet be guaranteed, since current tumor detection methods can only exclude the presence of malignant cells in ovarian fragments that are not transplanted. We determined the need for a novel detection method by studying the distribution of tumor cells in ovaries from patients with breast cancer. Furthermore, we examined which cell-surface proteins are suitable as a target for non-invasive tumor-specific imaging of ovarian metastases from invasive breast cancer. METHODS: Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 46 women with primary invasive breast cancer and ovarian metastases. The localization and morphology of ovarian metastases were determined on hematoxylin-and-eosin-stained sections. The following cell-surface markers were immunohistochemically analyzed: E-cadherin, epithelial membrane antigen (EMA), human epidermal growth receptor type 2 (Her2/neu), carcinoembryonic antigen (CEA), αvß6 integrin and epithelial cell adhesion molecule (EpCAM). RESULTS: The majority of ovarian metastases (71%) consisted of a solitary metastasis or multiple distinct nodules separated by uninvolved ovarian tissue, suggesting that ovarian metastases might be overlooked by the current detection approach. Combining the targets E-cadherin, EMA and Her2/neu resulted in nearly 100% detection of ductal ovarian metastases, whereas the combination of EMA, Her2/neu and EpCAM was most suitable to detect lobular ovarian metastases. CONCLUSIONS: Examination of the actual ovarian transplants is recommended. A combination of targets is most appropriate to detect ovarian metastases by tumor-specific imaging.

Chemosensitivity of BRCA1-Mutated Ovarian Cancer Cells and Established Cytotoxic Agents.

OBJECTIVE: Serous adenocarcinomas that arise in patients with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 are initially well treatable with platinum/paclitaxel. For recurrent disease in patients with BRCA1 or BRCA2 mutations, olaparib treatment is available. To study additional therapeutic regimens, a better understanding of the cellular and molecular mechanisms of the tumors in in vitro models is important. METHODS/MATERIALS: From a high-grade serous ovarian tumor of a BRCA1 mutation carrier, we established 3 distinct cell line subclones, OVCA-TR3.1, -2, and -3. Immunohistochemical characterization, flow cytometric analyses, chemosensitivity, and somatic mutation profiling were performed. RESULTS: The cell lines expressed AE1/AE3, Pax8, WT-1, OC125, estrogen receptor (ER), and p53, comparable to the primary tumor. Synergism could be shown in the combination treatment eremophila-1-(10)-11(13)-dien-12,8ß-olide (EPD), with cisplatin, whereas combination with olaparib did not show synergism. Eremophila-1-(10)-11(13)-dien-12,8ß-olide, a sesquiterpene lactone, is a novel chemotherapeutic agent. The inherited BRCA1 c.2989_2990dupAA mutation was confirmed in the cell lines. Loss of heterozygosity of BRCA1 was detected in each cell line, as well as a homozygous TP53 c.722C>A mutation. Flow cytometry showed that all cell lines had a distinct DNA index. CONCLUSIONS: Three new isogenic ovarian cancer cell lines were developed from a patient with a germ line BRCA1 mutation. Chemosensitivity profiling of the cell lines showed high tolerance for olaparib. Treatment with EPD proved synergistic with cisplatin. The effects of EPD will be further investigated for future clinical efficacy.

Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer.

Adoptive transfer of tumor-specific T cells, expanded from tumor-infiltrating lymphocytes or from peripheral blood, is a promising immunotherapeutic approach for the treatment of cancer. Here, we studied whether the tumor-draining lymph nodes (TDLN) of patients with human papillomavirus (HPV)-induced cervical cancer can be used as a source for ACT. The objectives were to isolate lymph node mononuclear cells (LNMC) from TDLN and optimally expand HPV-specific CD4+ and CD8+ T cells under clinical grade conditions. TDLN were isolated from 11 patients with early-stage cervical cancer during radical surgery. Isolated lymphocytes were expanded in the presence of HPV16 E6 and E7 clinical grade synthetic long peptides and IL-2 for 22 days and then analyzed for HPV16 specificity by proliferation assay, multiparameter flow cytometry and cytokine analysis as well as for CD25 and FoxP3 expression. Stimulation of LNMC resulted in expansion of polyclonal HPV-specific T cells in all patients. On average a 36-fold expansion of a CD4+ and/or CD8+ HPV16-specific T cell population was observed, which maintained its capacity for secondary expansion. The T helper type 1 cytokine IFNγ was produced in all cell cultures and in some cases also the Th2 cytokines IL-10 and IL-5. The procedure was highly reproducible, as evidenced by complete repeats of the stimulation procedures under research and under full good manufacturing practice conditions. In conclusion, TDLN represent a rich source of polyclonal HPV16 E6- and E7-specific T cells, which can be expanded under clinical grade conditions for adoptive immunotherapy in patients with cervical cancer.

Exploring Morphologic and Molecular Aspects of Endometrial Cancer Under Progesterone Treatment in the Context of Fertility Preservation.

OBJECTIVE: The standard treatment of early-stage (FIGO [International Federation of Gynecology and Obstetrics] I) endometrioid endometrial cancer (EEC) is hysterectomy with bilateral salpingo-oophorectomy. An alternative approach for younger women with low-grade EEC who wish to preserve fertility may be hormonal treatment. Previous studies have suggested that progesterone may elicit its antitumor effect in EEC by interacting with the Wingless (Wnt) and/or phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Therefore, we explored whether common activating genetic alterations in Wnt and PI3K/Akt signaling correlated with nonresponsiveness to progesterone therapy for low-grade EEC. In addition, we investigated whether benign morphology under progesterone treatment is accompanied by the absence of genetic changes. METHODS: We analyzed molecular alterations in the Wnt and PI3K/Akt signaling in 84 serial endometrial samples from 11 premenopausal patients with progesterone receptor-positive low-grade EEC conservatively treated with progesterone and correlated these with histological and clinical follow-up. RESULTS: There were 6 responders and 5 nonresponders to progesterone treatment. The response rate to progesterone treatment was 55%, and the relapse rate was 83%. All responders had alterations in both the Wnt and PI3K/Akt pathway before treatment. In the nonresponder group, tumors inconsistently showed alterations in none, 1, or both pathways. Normalization of the endometrium morphology under progesterone treatment is accompanied by the absence of the genetic changes found in the specimen before treatment. CONCLUSIONS: We found that activating molecular alterations in either Wnt or PI3K/Akt signaling pathways did not predict resistance to progesterone treatment. It seems that morphological response goes along with disappearance of the established mutations. This exploratory study suggests that Wnt or PI3K/Akt status is unable to predict response to progesterone treatment in patients with EEC.

Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV-induced vulvar neoplasia.

Human papilloma virus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) is infiltrated by myeloid cells but the type and role of these cells is unclear. We used triple immunofluorescent confocal microscopy to locate, identify and quantify myeloid cells based on their staining pattern for CD14, CD33 and CD163 in a cohort of 43 primary and 20 recurrent uVIN lesions, 21 carcinomas and 26 normal vulvar tissues. The progressive course of uVIN is characterized by an increase in both intraepithelial and stromal mature M1 and M2 macrophages. While the M2 macrophages outnumber M1 macrophages in healthy controls and uVIN, they are matched in number by M1 macrophages in cancer. Importantly, uVIN patients with a dense intraepithelial infiltration with mature CD14+ macrophages (irrespective of M1 or M2 type) displayed approximately a six times higher risk to develop a recurrence and a high number of these cells constituted an independent prognostic factor for recurrence. In addition, a dense intraepithelial CD14+ cell infiltration was associated with high numbers of intraepithelial CD4+ Tregs and low numbers of stromal CD8+TIM3+ T cells. Patients with low numbers of intraepithelial CD14+ cells and high numbers of stromal CD8+TIM3+ cells showed the best recurrence-free survival. These data clearly show the importance of the local immune response in HPV-induced vulvar neoplasia and may be of help in predicting the prognosis of patients or their response to immunotherapy.

Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence-free survival.

Human papillomavirus-induced usual-type vulvar intraepithelial neoplasia (uVIN) are infiltrated by immune cells but apparently not cleared. A potential explanation for this is an impaired T cell effector function by an immunesuppressive milieu, coinfiltrating regulatory T cells or the expression of coinhibitory molecules. Here, the role of these potential inhibitory mechanisms was evaluated by a detailed immunohistochemical analysis of T cell infiltration in the context of FoxP3, Tbet, indoleamine 2,3-dioxygenase, programmed cell death 1, T cell immunoglobulin mucin 3 (TIM3), natural killer cell lectin-like receptor A (NKG2A) and galectins-1, -3 and -9. Paraffin-embedded tissues of primary uVIN lesions (n=43), recurrent uVIN lesions (n=20), vulvar carcinoma (n=21) and healthy vulvar tissue (n=26) were studied. We show that the vulva constitutes an area intensely surveyed by CD8+, CD4+, Tbet+ and regulatory T cell populations, parts of which express the examined coinhibitory molecules. In uVIN especially, the number of regulatory T cells and TIM3+ T cells increased. The expression of the coinhibitory markers TIM3 and NKG2A probably reflected a higher degree of T cell activation as a dense infiltration with stromal CD8+TIM3+ T cells and CD3+NKG2A+ T cells was related to the absence of recurrences and/or a prolonged recurrence-free survival. A dense coinfiltrate with regulatory T cells was negatively associated with the time to recurrence, most dominantly when the stromal CD8+TIM3+ infiltration was limited. This notion was sustained in vulvar carcinoma's where the numbers of regulatory T cells progressively increased to outnumber coinfiltrating CD8+TIM3+ T cells and CD3+NKG2A+ T cells.

HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8⁺ T lymphocytes.

HLA-E is a nonclassical HLA class I molecule, which differs from classical HLA molecules by its nonpolymorphic, conserved nature. Expression and function of HLA-E in normal tissues and solid tumors is not fully understood. We investigated HLA-E protein expression on tissue sections of 420 ovarian and cervical cancers and found equal or higher levels than normal counterpart epithelia in 80% of the tumors. Expression was strongly associated with components of the antigen presentation pathway, e.g., transporter associated with antigen processing (TAP), endoplasmic reticulum aminopeptide (ERAP), ß2 microglobulin (ß2m), HLA classes I and II, and for ovarian cancer with tumor infiltrating CD8(+) T lymphocytes (CTLs). This association argues against the idea that HLA-E would compensate for the loss of classical HLA in tumors. In situ detection of HLA-E interacting receptors revealed a very low infiltrate of natural killer (NK) cells, but up to 50% of intraepithelial CTLs expressed the inhibiting CD94/NKG2A receptor. In cervical cancer, HLA-E expression did not alter the prognostic effect of CTLs, most likely due to very high infiltrating CTL numbers in this virus-induced tumor. Overall survival of ovarian cancer patients, however, was strongly influenced by HLA-E, because the beneficial effect of high CTL infiltration was completely neutralized in the subpopulation with strong HLA-E expression. Interestingly, these results indicate that CTL infiltration in ovarian cancer is associated with better survival only when HLA-E expression is low and that intratumoral CTLs are inhibited by CD94/NKG2A receptors on CTLs in the tumor microenvironment.

If the Mountain Does Not Come to Mohammad: The Significance of Guest Operations for Early Stage Ovarian Cancer.

Background: In women with early ovarian cancer (EOC), comprehensive surgical staging is known to enhance ovarian cancer outcomes and requires specific surgical competence. Given that centralization of care remains a topic of continuing debate, a system of "guest operations" was introduced in the midwestern part of The Netherlands. During a guest operation a gynecologic oncologist participates in oncology surgery performed in the community hospital. Objective: This study was conducted to examine the effects of the presence of a gynecologic oncologist on the quality of staging, treatment, and survival in patients with EOC. Materials and Methods: All patients with a pathologically confirmed diagnosis of EOC between January 2000 and December 2009 were selected from a regional cancer registry. Surgical accuracy was checked on the basis of each patient's file, operative notes, and pathology report. Results: A total of 130 patients were included, of whom 15 were treated in the Leiden University Medical Center (LUMC) and 115 in eight regional community hospitals. If a gynecologic oncologist attended the operation, surgical staging was more often adequately performed, 81.1% versus 32.1% when a gynecologic oncologist was not present (p<0.001). Adherence to protocol was observed in 76.9% of operations when a gynecologic oncologist had been present, compared to 49.5% of patients who were treated by a general gynecologist alone (p=0.004). The 5-year disease-free survival was borderline significantly in favor of optimally staged patients, 75.1% in those who were not staged optimally versus 90.9% who were staged optimally (p=0.058). Conclusions: Guest operations deserve a distinguished place among the treatment modalities available to patients with EOC, because surgery by the most specialized and experienced surgeons contributes to better care. (J GYNECOL SURG 30:265).

Self-reported sexual, bowel and bladder function in cervical cancer patients following different treatment modalities: longitudinal prospective cohort study.

OBJECTIVE: Conventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients. METHODS: Self-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire. RESULTS: Included were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina). CONCLUSIONS: In the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.

Randomized comparison of near-infrared fluorescence lymphatic tracers for sentinel lymph node mapping of cervical cancer.

OBJECTIVE: Near-infrared fluorescence imaging using indocyanine green (ICG) has recently been introduced as a novel technique for sentinel lymph node (SLN) mapping in early-stage cervical cancer. Although preclinical research has shown that ICG adsorbed to human serum albumin (ICG:HSA) improves its performance, the need for HSA has not yet been confirmed in cervical cancer patients. The current randomized study aims to determine whether ICG:HSA offers advantages over using ICG alone. METHODS: Eighteen consecutive early-stage cervical cancer patients scheduled to undergo pelvic lymphadenectomy were included. Prior to surgery, 1.6 mL of 500 µM ICG:HSA or 500 µM ICG alone was injected transvaginally in 4 quadrants around the tumor. The Mini-FLARE imaging system was used for intraoperative NIR fluorescence detection and quantitation. RESULTS: SLNs were identified intraoperatively in 78% of the patients. Patient and tumor characteristics were equally distributed over both treatment groups. No significant difference in signal-to-background ratio (9.3 vs. 10.1, P=.72) or average number of detected SLNs (2.9 vs 2.7, P=.84) was found between the ICG:HSA group and the ICG alone group, respectively. CONCLUSIONS: In conclusion, this double-blind, randomized trial showed no advantage of ICG:HSA over ICG alone for the SLN procedure in early-stage cervical cancer. Further optimization is required to improve the intraoperative detection rate.

Lymphadenectomy in ovarian cancer: standard of care or unnecessary risk.

PURPOSE OF REVIEW: The clinical significance of lymphadenectomy in ovarian cancer is controversial. In early ovarian cancer (EOC), it is the extent of the procedure that is the main focus of debate. In advanced disease [advanced ovarian cancer (AOC)], the issue is whether or not lymphadenectomy independently impacts survival. This review summarizes the current standard of care as it relates to the role of lymphadenectomy in ovarian cancer. RECENT FINDINGS: Lymphadenectomy in EOC is a diagnostic procedure in as much as it is an integral and mandatory part of a complete surgical staging. The required extent of the procedure, however, remains uncertain. It has been suggested that at least 10 nodes from different, predefined retroperitoneal sites should be the minimum number removed. Lymphadenectomy in AOC is of potential therapeutic value. The only published randomized clinical trial (RCT) showed no overall survival benefit after radical/systematic lymphadenectomy, although there was an impact on 6-month disease-free survival. Conversely, retrospective studies, a meta-analysis and a re-analysis of three RCTs in AOC do suggest an overall survival benefit for radical/systematic lymphadenectomy. SUMMARY: This review concludes with the recommendation that lymphadenectomy in EOC is a mandatory part of surgical staging and that a minimum of 10 nodes should be harvested from different retroperitoneal sites. In AOC, lymphadenectomy can be considered when intraperitoneal cytoreduction has been complete or when there are bulky nodes.

Molecular mechanisms of epidermal growth factor receptor overexpression in patients with cervical cancer.

The epidermal growth factor receptor is overexpressed in 70-90% of cervical cancers. Previously, we have shown that epidermal growth factor receptor overexpression independently predicts poor prognosis in cervical cancer patients, which makes it a potential therapeutic target. The aim of this study was to systematically analyze the molecular mechanism leading to epidermal growth factor receptor overexpression in cervical cancer. All experiments were performed on archival paraffin-embedded material. In 166 cervical cancer patients, cytoplasmic, membrane and phosphorylated epidermal growth factor receptor protein expression were studied in association with patient survival. Membrane epidermal growth factor receptor overexpression was associated with poor disease-specific survival (P=0.027). This association was particularly present in human papillomavirus 16-positive patients (P=0.029). We analyzed whether epidermal growth factor receptor overexpression was caused by gene amplification using fluorescence in situ hybridization. Epidermal growth factor receptor gene copy number was linked to chromosome 7 ploidy, as no gene amplification could be detected when corrected for chromosome 7 centromeric signals. Chromosome 7 aneuploidy was associated with membrane epidermal growth factor receptor overexpression (P=0.013). Additional mutation analysis was performed by sequencing pure, flow-sorted tumor cells, but no mutations were detected. Furthermore, human papillomavirus 16 E5 and E6 oncogene mRNA expression was measured, using quantitative real-time polymerase chain reaction, to determine the association between the human papillomavirus and epidermal growth factor receptor overexpression. High human papillomavirus 16 E5 and E6 mRNA expression were associated with decreased survival (P=0.045 and 0.047, respectively). High human papillomavirus 16 E6 mRNA expression was associated with membrane epidermal growth factor receptor overexpression (P=0.013). This is the first study performed on cancer patient material showing that chromosome 7 aneuploidy and high human papillomavirus 16 E6 mRNA expression lead to membrane epidermal growth factor receptor overexpression in cervical cancer.

Patterns of parametrial involvement in radical hysterectomy specimens of cervical cancer patients.

A tumor in the parametria, either continuous with or separate from the primary malignancy, is an unfavorable prognostic factor in cervical cancer. The incidence of a parametrial tumor localized in blood or lymph vessels, or in tissue, and the relationship of these involvement patterns with pathologic characteristics and prognosis were investigated. Seventy-nine of 763 surgically treated cervical cancer patients (10%) had a tumor in the parametria in hysterectomy specimens. The available patient material was reviewed to discriminate between continuous and discontinuous parametrial tumor growth. The involvement pattern for discontinuous growth was specified on the basis of immunohistochemical staining with different specific markers. Fifty percent of the parametrial tumor involvement found postoperatively was caused by continuous extension of the primary process into the parametria. In the other 50%, the parametrial tumor was separate from the primary process. In this discontinuous group, we found a frequent presence of tumor in the lymph nodes and/or lymph vessels (together 79%) and even a rare appearance of tumor in the blood vessels (14%). A tumor was further found in unspecified vessels in 2 patients (5%), and as isolated foci in 6 patients (14%). Fourteen patients (33%) had more than 1 involvement pattern. Positive pelvic lymph nodes were more frequent in the discontinuous group. The involvement pattern was no independent predictor of overall survival. Parametrial blood vessel involvement was related to the development of distant metastases. The majority (79%) of parametrial involvement in the discontinuous group is caused by lymphatic metastases. Parametrial blood vessel involvement might be an independent predictor for the development of distant metastasis.

Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer.

Cervical carcinoma is the second most frequent cancer type in women worldwide. Both inflammatory cells and stromal cells are important for tumor progression. Stromal cells produce growth factors and extracellular matrix and provide an adequate environment for angiogenesis. Versican, a member of the extracellular matrix, has been shown to have a role in tumor progression. The aim of this study was to investigate versican expression, and its association with tumor-infiltrating inflammatory cell subsets and with clinicopathological parameters in human cervical cancers. We have studied the expression of versican in 149 cervical cancers using immunohistochemistry and mRNA in situ hybridization. Versican was predominantly expressed in the stroma (myofibroblasts). Using quantitative real-time-PCR, V0 was found to be the most prominent isoform. High stromal versican expression was significantly associated with a low number of tumor-infiltrating T cells (P=0.018) and particularly a low number of CD8-positive T cells (cytotoxic T cells; P=0.002). Stromal versican expression was significantly higher in patients with an infiltration depth >14 mm (P=0.004) and in patients with parametrial invasion (P=0.044). Stromal versican expression was not associated with survival. Our results suggest that versican expression in the stromal compartment of cervical cancers results in reduced numbers of intraepithelial CD8-positive T cells and enhanced local invasion.

Lymph node sampling and taking of blind biopsies are important elements of the surgical staging of early ovarian cancer.

BACKGROUND: The purpose of this study was to determine the effect of lymph node sampling and taking of blind biopsies as part of the surgical staging procedure for early ovarian cancer on disease-free survival (DFS) and overall survival (OS) in patients who received no adjuvant chemotherapy. METHODS: In the EORTC ACTION Trial, 448 patients with early ovarian carcinoma were randomized between November 1990 and March 2000-224 patients to observation and 224 to adjuvant platin-based chemotherapy. Only patients allocated to observation were included for the current study. Analyses were performed in a subgroup of 75 optimally staged patients (group A), 46 patients in whom all staging steps were performed except para-aortic or pelvic lymph node sampling (group B), and 14 patients who fulfilled all staging criteria but in whom no blind peritoneal biopsies were taken (group C). The study group did not differ in stage distribution, cell type, or tumor grade. RESULTS: Significantly improved 5-year DFS (P = 0.03) and 5-year OS (P = 0.01) were found in group A (optimally staged) versus group B (no lymph node sampling). A significant difference was also shown in 5-year DFS (P = 0.02) and 5-year OS (P = 0.003) between group A and group C (no blind biopsies). Recurrences occurred in 11 (14.6%) of 75 patients in group A, 16 (34.8%) of 46 patients in group B, and 5 (35.7%) of 14 in group C. The 5-year DFS in group A was 79% versus 61% and 64% in groups B and C, respectively. The 5-year OS decreased from 89% in group A to 71% in group B and 65% in group C. CONCLUSIONS: In this study, statistically significant differences were found in patients in whom para-aortic and pelvic lymph node sampling and taking of blind peritoneal biopsies were undertaken compared with patients in whom these staging steps had been omitted. These findings support the relevance of lymph node sampling and the taking of blind peritoneal biopsies in the surgical staging of early ovarian cancer.

Power Doppler area in the diagnosis of endometrial cancer.

OBJECTIVE: To evaluate the diagnostic accuracy of power Doppler area (PDA) in the detection of endometrial cancer in women with postmenopausal bleeding. DESIGN: Prospective diagnostic study. SETTING: University hospital. POPULATION: Seventy-four consecutive women presenting with postmenopausal bleeding and a total endometrial thickness of more than 4 mm. METHODS: The PDA was measured by pelvic ultrasound. Endometrial cancer and hyperplasia with complex atypia were considered abnormal. MAIN OUTCOME MEASURES: A receiver operating characteristic curve was constructed and area under curve (AUC) calculated as well as positive and negative likelihood ratios (LR+ and LR-). RESULTS: Eighteen women (24%) had abnormal results of their histological specimen. The AUC of the PDA was 0.88 (95% confidence interval [CI], 0.80-0.98). The LR+ and LR- of the PDA were, respectively, 14.5 (95% CI, 4.69-44.9) and 0.23 (95% CI, 0.09-0.55). In women with total endometrial thickness of 4 to 10 mm, the AUC, LR+, and LR- were, respectively, 0.91 (95% CI, 0.78-1.00), 23.9 (95% CI, 3.29-175.0), and 0.34 (95% CI, 0.13-0.86). CONCLUSIONS: The PDA is an effective measure in the diagnosis and exclusion of endometrial cancer.

Nerve sparing in radical surgery for early-stage cervical cancer: yes we should!

Radical hysterectomy with pelvic lymphadenectomy is considered to be the cornerstone in the treatment of early-stage cervical cancer. Although survival in early-stage cervical cancer is up to 95%, long-term morbidity with regard to bladder, bowel, and sexual function is considerable. Damage to the pelvic autonomic nerves may be the cause of these long-term complications following radical hysterectomy. Some authors have presented surgical techniques to preserve the autonomic nerves (ie, the hypogastric nerves and the splanchnic nerves) without compromising radicality. Safety, efficacy, and the surgical techniques of nerve-sparing radical hysterectomy are presented, and data confirm that whenever the decision is made to perform a radical hysterectomy, nerve-sparing techniques should be considered.

Abdominal scar recurrences of cervical cancer: incidence and characteristics: a case-control study.

BACKGROUND: Tumor recurrence in the surgical scar after radical hysterectomy for cervical cancer has been reported, but the incidence is unknown. Facts about patient and tumor characteristics and follow-up are lacking. The objective of this study was to analyze the incidence and characteristics of cervical cancer scar recurrences. METHODS: All patients who were surgically treated for cervical cancer in our center between 1984 and 2007 were reviewed for scar recurrences. For each case, 5 random controls were selected. Clinical characteristics were compared between the cases and controls. RESULTS: Eleven (1.3%) of 842 patients developed a scar recurrence. Mean time between surgery and scar recurrence was 16 months (range, 2-45 months). For 8 patients (73%), the scar recurrence was the first disease recurrence. Five patients (45%) died, and 2 (18%) were lost to follow-up. Mean time between scar recurrence and death was 9 months. Ninety-one percent of the cases had recurrent disease besides the scar recurrence during follow-up. The case group had a higher percentage of advanced FIGO (International Federation of Gynecology and Obstetrics) stage and postoperatively found involvement of parametria or resection margins and tumor diameter greater than 4 cm, whereas lymph nodes were more often involved in the control group. CONCLUSIONS: The incidence of scar recurrences after primary surgery for cervical cancer was 1.3%. Time to development was variable, and prognosis was poor. Besides higher FIGO stage and concurrent unfavorable pathological characteristics, we found no outstanding characteristics of patients with scar recurrence. Scar recurrences go hand in hand with recurrent disease at other locations and seem a manifestation of tumors with extensive metastatic potential.

Nerve-sparing radical hysterectomy: local recurrence rate, feasibility, and safety in cervical cancer patients stage IA to IIA.

UNLABELLED: To clarify the debate about the possible threat of sparing the pelvic autonomic nerves in radical hysterectomy for cervical cancer to radicality, comparative studies of nerve-sparing and conventional surgery are necessary. The aim of his study was to analyze and compare local recurrence rate, feasibility, and safety of nerve-sparing and non-nerve-sparing radical hysterectomy. METHODS: In a cohort study with 2 years of follow-up, 246 patients with cervical cancer of stages IA to IIA were analyzed: 124 in the non-nerve-sparing group (1994-1999) and 122 in the group where nerve-sparing was the intention-to-treat (2001-2005). Local recurrence rate, local recurrence-free survival, feasibility, and safety were analyzed and compared. RESULTS: The clinical characteristics of the treatment groups were comparable. Sparing the nerves unilaterally or bilaterally was possible in 80% of cases of the nerve-sparing group. Local recurrence rates in the non-nerve-sparing (4.9%) and nerve-sparing (8.3%) group were not significantly different. Mean local recurrence-free survival within 2 years were 22.7 and 22.0 months, respectively. Univariate and multivariate regression analyses showed that nerve-sparing treatment was not a significant prognostic factor for local recurrence. With respect to perioperative and postoperative parameters, operating time and blood loss were less in the nerve-sparing group and mortality was equal (1 patient); the postoperative course of the nerve-sparing group was similar to the state-of-the-art of conventional radical hysterectomy. CONCLUSIONS: On the basis of the results of our study, we consider the nerve-sparing technique for cervical cancer stages IA to IIA feasible and safe.

High human papillomavirus oncogene mRNA expression and not viral DNA load is associated with poor prognosis in cervical cancer patients.

PURPOSE: Cervical cancer is now known to be caused by infection with an oncogenic type of the human papillomavirus (HPV). However, little is known about the continued role of HPV once cancer has been established. Here, we describe the quantitative relation between HPV DNA copy number and mRNA expression of the viral oncogenes (E6 and E7) and the prognostic value of both measures in cervical cancer patients. EXPERIMENTAL DESIGN: We studied the number of viral DNA copies and the level of HPV E6/E7 mRNA expression in 75 HPV 16-positive or HPV 18-positive International Federation of Gynecology and Obstetrics stage Ib and IIa cervical cancer patients. Measurements were done with quantitative PCR. DNA copy number analysis was done on pure tumor cell samples enriched with flow sorting. mRNA expression data were compensated for the percentage of tumor cells included. RESULTS: The number of viral DNA copies was not predictive of survival in cervical cancer patients. In contrast, high HPV E6/E7 mRNA expression was strongly related to an unfavorable prognosis (P = 0.006). In a multivariate Cox model for overall survival, including all known prognostic variables and stratified for HPV type, the level of E6/E7 mRNA expression was an independent prognostic indicator, second only to lymph node status. No correlation was observed between DNA copy number and the level of HPV E6/E7 mRNA expression, which reflects that not all DNA copies are equally transcriptionally active. CONCLUSIONS: Cervical cancer patients with high HPV E6/E7 oncogene mRNA expression have a worse survival independently from established prognostic factors.