Pierandrea De Iaco

FDG-PET/CT in advanced ovarian cancer staging: Value and pitfalls in detecting lesions in different abdominal and pelvic quadrants compared with laparoscopy

INTRODUCTION AND AIM Ovarian carcinoma (OC) is a common cancer in the Western Countries, and an important cause of death in patients suffering with gynaecologic malignancies. The majority of patients present with advanced disease at the time of diagnosis. Treatment with debulking surgery followed by chemotherapy is the standard approach while chemotherapy is contemplated when surgery is not possible. A correct pre-operative staging is important to ensure a most appropriate management. Laparoscopy (LPS) is the standard diagnostic tool for the assessment of intraperitoneal infiltration but is invasive and requires general anaesthesia. FDG-PET/CT is increasingly used for staging different types of cancer, and the aim of this study is to assess the value of FDG-PET/CT in staging advanced OC and its sensitivity to detect lesions in different quadrants of the abdominal-pelvic area compared to laparoscopy. MATERIALS AND METHODS From September 2004 till April 2008, 40 patients with high suspicion of OC were referred to our hospital for diagnostic LPS to explore the possibility of optimal debulking surgery. Those who were not suitable for surgery were referred for chemotherapy. Before chemotherapy, the patients underwent an FDG-PET/CT scan. The findings in 9 quadrants of abdominal-pelvic area (total 360 quadrants) for PET/CT and LPS were recorded and compared. RESULTS In 14/360 areas (3.8%), surgical evaluation was not possible because of presence of adhesions, thus the number of areas explored by laparoscopy was 346. Tumour was found in 308 quadrants (38 quadrants free of disease). PET/CT was positive in all 40 patients with true negative results in 26/346 quadrants (7.5%), and true positives results in 243/346 quadrants (70.2%). False positive and negative PET/CT results were found in 12/346 and 65/346 quadrants, respectively. False positive PET/CT findings were evenly present in all quadrants. False negative PET/CT findings were present in 31/109 (28.4%) upper abdominal quadrants (epigastrium and diaphragmatic areas). Final analysis showed a sensitivity and specificity for PET/TC of 78.9 and 68.4% respectively with a positive predictive value of 95.3%. A significant difference was noted between mean SUVmax associated with lesions smaller or larger than 0.5 cm (p=0.006). CONCLUSION Our results suggest that PET/CT may prove a useful tool for pre-surgical staging of ovarian cancer with a sensitivity and specificity of 78 and 68%, respectively. However, it may be used in combination with laparoscopy for better results. PET/CT showed an adequate correlation between SUVmax values and laparoscopy findings of lesions>5mm, but a high rate of false negative results in lesions<5mm such as in carcinomatosis. PET/CT should be used carefully in early stage disease, with low risk of peritoneal infiltration, because of high rate of false positive results, to avoid unnecessary therapy procedures.

A multicentric trial (Olympia–MITO 13) on the accuracy of laparoscopy to assess peritoneal spread in ovarian cancer

OBJECTIVE The objective of the study was to prospectively evaluate the accuracy of laparoscopy performed in satellite centers (SCs) to describe intraabdominal diffusion of advanced ovarian cancer (AOC). STUDY DESIGN Patients with a clinical/radiological suspicion of AOC were included in the protocol. SCs were selected among those surgeons, spending a short intensive training period at the coordinator center (CC) to learn the application of staging laparoscopy (S-LPS) in AOC. All women underwent S-LPS at the SCs, and the surgical procedure was recorded and blindly reviewed at the CC. Calculating specificity, positive and negative predictive values, and the accuracy for each parameter with respect to the CC assessed the diagnostic performance of S-LPS. The Cohens kappa was used to test the interobserver agreement of each parameter. RESULTS One hundred sixty-eight cases were considered eligible for the study. A per-protocol analysis was performed on 120 cases. The worst laparoscopic assessable feature was mesenteric retraction, whereas the remaining variables ranged from 99.2% (peritoneal carcinomatosis) to 90% (bowel infiltration). All but 1 SC (SC number 4) reached an accuracy rate of 80% or greater for both single parameters and overall score. The Cohens kappa and the P value for overall predicitive index value were 0.685 and .01, respectively, but improved to 0.773 and .388 after removing the SC number 4 from the analysis. CONCLUSION S-LPS allows an accurate and reliable assessment of intraperitoneal diffusion of disease in AOC patients in trained gynecological oncology centers.

Vaginal cuff dehiscence after hysterectomy: a multicenter retrospective study

OBJECTIVE This study estimates the incidence of vaginal cuff dehiscence resulting from different approaches to hysterectomy. STUDY DESIGN This multicentric study was carried out retrospectively. We retrospectively analyzed 8635 patients; 37% underwent abdominal hysterectomy, 31.2% vaginal hysterectomy, and 31.8% laparoscopic hysterectomy. All the hysterectomies were considered, vaginal evisceration was registered and analyzed for time of onset, trigger event, presenting symptoms, details of prolapsed organs and type of repair surgery. Continuous variables were compared using the one-way analysis of variance between groups as all data followed a Gaussian distribution, as confirmed by the Kolmogorov-Smirnov test. Differences among subgroups were assessed using the Tukey-Kramer multiple comparisons test. Categorical variables were compared with two tailed Chi-square tests with Yates correction or Fishers exact test, as appropriate. Pearsons linear correlation was used to verify linear relationships between the dehiscence interval and patients age at surgery. RESULTS Thirty-four patients (0.39%) experienced vaginal evisceration. The laparoscopic route was associated with a significantly higher incidence of dehiscence (p<0.05). No differences were found between the 6027 patients (69.8%) who had closure of the vaginal cuff and the 2608 (30.2%) who had an unclosed cuff closure technique. CONCLUSION Vaginal evisceration after hysterectomy is a rare gynecological surgical complication. Sexual intercourse before the complete healing of the vaginal cuff is the main trigger event in young patients, while evisceration presents as a spontaneous event in elderly patients. Surgical repair can be performed either vaginally or laparoscopically with similar outcomes.

Fibrin sealant in laparoscopic adhesion prevention in the rabbit uterine horn model

OBJECTIVE To assess the effects of fibrin sealant on adhesions after laparoscopic surgery. DESIGN Standardized surgical trauma was induced in 60 female rabbits. The animals were randomized in three groups for different adhesion prevention treatment. SETTING University research laboratory. INTERVENTIONS After standardized trauma was induced, group 1 (n = 20) received no treatment, group 2 animals (n = 20) were injected in the abdominal cavity with 60 mL of Ringers lactate, and human fibrin sealant was applied on the surgical lesions under laparoscopic vision in group 3 (n = 20). MAIN OUTCOME MEASURES Five weeks after laparoscopy, a laparotomy was performed, and the adhesions were scored. RESULTS Fourteen of 20 rabbits in the control group (70%) presented postoperative adhesions, 11 of 20 (55%) in the Ringers group, and 5 of 20 (25%) in the fibrin sealant group. High-score adhesions were seen in 15% of cases in control and Ringers group and in 5% of cases in the fibrin sealant group. CONCLUSIONS When used during laparoscopic surgery, fibrin sealant has a preventive effect on de novo postsurgical adhesions. To assess the efficacy in reproductive surgery, a trial on recurrent postsurgical adhesions is required.

Hyperthermic intraperitoneal chemotherapy with cisplatin and paclitaxel in advanced ovarian cancer: a multicenter prospective observational study

Objective Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been recently reported with favorable oncological outcomes as treatment of advanced epithelial ovarian cancer (EOC). The aim of this study was to demonstrate the feasibility of CRS+HIPEC with cisplatin and paclitaxel for the treatment of advanced EOC. Methods This is a prospective observational study of 54 patients, from April 2007 to October 2013, with primary or recurrent peritoneal carcinomatosis due to EOC. The mean age was 54.51±9.34. Thirty patients (59%) had primary EOC, and 24 patients (41%) had recurrent disease. Results Mean peritoneal cancer index was 10.11 (range, 0 to 28), complete cytoreduction (CC0) was achieved for 47 patients (87%), CC1 for seven patients (13%). Patients with suboptimal cytoreduction (CC2 and CC3) were not included in the study. The mean stay in intensive care unit was 4.73±5.51 days and the mean hospitalization time was 24.0±10.03 days. We did not observe any intraoperative death. Seven patients (13%) required additional operations. Three patients (5.6%) died within 30 days from the procedure. Severe complications were seen in 19 patients (35.2%). During the follow-up period, disease recurred in 33 patients (61.1%); the median disease-free survival time was 12.46 months and the median overall survival time was 32.91 months. Conclusion CRS+HIPEC with cisplatin and paclitaxel for advanced EOC is feasible with acceptable morbidity and mortality. Additional follow-up and further studies are needed to determine the effects of HIPEC on long term survival.

BRCA-Associated Ovarian Cancer: From Molecular Genetics to Risk Management

Ovarian cancer (OC) mostly arises sporadically, but a fraction of cases are associated with mutations in BRCA1 and BRCA2 genes. The presence of a BRCA mutation in OC patients has been suggested as a prognostic and predictive factor. In addition, the identification of asymptomatic carriers of such mutations offers an unprecedented opportunity for OC prevention. This review is aimed at exploring the current knowledge on epidemiological and molecular aspects of BRCA-associated OC predisposition, on pathology and clinical behavior of OC occurring in BRCA mutation carriers, and on the available options for managing asymptomatic carriers.

Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: A retrospective MITO group study

OBJECTIVE To investigate the impact of morcellation on survival outcomes of patients affected by undiagnosed uterine sarcoma. METHODS This is a retrospective study performed in 8 referral centers of MITO group. Data of women undergoing morcellation for apparent benign uterine myomas who were ultimately diagnosed with stage I uterine sarcoma on final pathology were compared with data of women who did not undergo morcellation. Uterine sarcoma included: leiomyosarcomas (LMS), smooth muscle tumors of uncertain malignant potential (STUMP), low-grade endometrial stromal sarcomas (LG-ESS) and undifferentiated uterine sarcomas (UUS). Two-year survival outcomes were evaluated using Kaplan-Meir and Cox models. RESULTS Overall 125 patients were identified: 31(24.8%), 21(16.8%) and 73(58.4%) patients had power morcellation during laparoscopy, non power morcellation during open surgery and non morcellation during open procedures, respectively. Considering patients affected by LMS, morcellation did not correlated with disease-free survival. However, patients undergoing either morcellation or power morcellation experienced a 3-fold increase risk of death in comparison to patients who had not morcellation (p=0.02). A trend towards an increase of recurrence was observed for patients undergoing morcellation for STUMP (HR 7.7, p=0.09); while no differences in survival outcomes were observed for patients with LG-ESS and UUS. CONCLUSIONS Our data suggest that morcellation increase the risk of death in patients affected by undiagnosed LMS. Further prospective studies are warranted in order to assess the risk to benefit ratio of power morcellator utilization in patients with apparent benign uterine myomas.

Morbidity after pelvic exenteration for gynecological malignancies : A retrospective multicentric study of 230 patients

Objective Our study purpose was to evaluate morbidity and postoperative mortality in patients who underwent pelvic exenteration (PE) for primary or recurrent gynecological malignancies. Methods We identified 230 patients who underwent PE, referred to the gynecological oncology units of 4 institutions: Charitè University in Berlin, Friedrich-Schiller University in Jena, S. Orsola-Malpighi University in Bologna, and Catholic University in Rome and in Campobasso. Results The median age was 55 years. The tumor site was the cervix in 177 patients, the endometrium in 28 patients, the vulva in 16 patients, and the vagina in 9 patients. Sixty-eight anterior, 31 posterior, and 131 total PEs were performed in 116 women together with hysterectomy. A total of 82.6% of the patients required blood transfusion. The mean operative time was 446 (95–970) minutes, and the median hospitalization was 24 (7–210) days. We noted a major complication rate of 21.3% (n = 49). We registered 7 perioperative deaths (3%) calculated within 30 days. The operation was performed within clear margins in 166 patients (72.2%). The overall mortality rate depending on tumor site at the end of the study was 75% for vulvar cancer, 57.6% for cervical cancer, 55.6% for vaginal cancer, and 53.6% for endometrial cancer. Conclusions Although an important effort for surgeons and for patients, PE remains a therapeutic option with an acceptable complication rate and postoperative mortality. A strict selection of patients is mandatory to reach adequate surgical and oncologic outcomes.

Mitochondrial DNA Mutation in Serous Ovarian Cancer: Implications for Mitochondria-Coded Genes in Chemoresistance

Case Report A69-year-oldwomansufferingdyspneaandwidespreadabdominal pain was admitted. Preliminary tests detected mild anemia, leukocytosis, and high levels of CA125 (2,200 U/mL). Abdominal-pelvic ultrasound scan, toraco-abdominal computer tomography (CT) and positron emission tomography (PET) indicated a gastric expansive mass together with two adherent pelvic solid masses, vascularized, strictly contiguous to bowel, omental cake, peritoneal carcinomatosis marks and ascites (Figs 1A and 1C; Figs 1E and 1G, arrows). Esophageal-gastric duodenoscopy was normal. CT-guided biopsy of the pelvic masses led to diagnose a poorly differentiated ovarian carcinoma in July 2010. A six-cycle carboplatin-paclitaxel chemotherapy was administered from August 2010 to December 2010. Radiological CT and PET at the end of the chemotherapyshowednearlycomplete response(Figs1Band1D;1Fand 1H). Diagnostic laparoscopy confirmed the absence of peritoneal carcinomatosis and suggested that surgery had become feasible. In March 2011, the patient was submitted to hysterectomy with bilateral annessiectomy, pelvic and lomboartic lymphadenectomy, omentectomy and peritoneal biopsies with complete macroscopical removal of disease. The histologicalreportshowedpersistenceofmicroscopicfociofdisease inthe ovaries (G3serouspapillaryadenocarcinoma),with lymphnodes,omentum and peritoneum free from disease. No adjuvant chemotherapy was administered because the patient had received six full courses of preoperativechemotherapyandnomacroscopicdiseasewaspresentaftersurgery. The patient was enrolled in the Mitochondria in Progression of Endometrial and Ovarian Cancer (MiPEO) study approved by the local ethical committee at S. Orsola Hospital, Bologna. Signed informed consent was obtained. She was subjected to regular follow-ups every 4 months with CT, pelvic ultrasound, and test of CA125. With the aim to characterize the residual chemoresistant ovarian cancer, hematoxylin/eosin staining showed a clear-cut oncocytic component, undetected in the prechemotherapy biopsy. Therefore, the acquisition of oncocytic change was observed exclusively in the ovarian cancer tissueresidualafterchemotherapy(Fig2).Wehavepreviouslyshownthat mitochondrial DNA (mtDNA) mutations in respiratory complex I (CI) genes are markers of oncocytic transformation, which cause CI derangement and, consequently, impairment of mitochondrial respiration. In order to understand whether mtDNA mutations and CI disassembly underlay the oncocytic phenotype, whole mtDNA sequencing was performed. Sequence analysis revealed the presence of m.10875T C missense mutation of a conserved residue (p.39Leu Pro) in the MTND4 gene encoding a CI subunit (Figs 3 and 4 [boxed in red in Fig 4]). The mutation was nearly homoplasmic, although a minor contamination withadjacentnontumortissuecouldnotbecompletelyruledout.Predictor of amino acid change pathogenic potential PolyPhen2 revealed the mutation to be probably damaging. Proof of pathogenicity was obtained through negative immunohistochemistry (IHC) staining of nuclearencoded CI subunit NDUFB8, which does not integrate within the complex when ND4 is lacking (Fig 2). In order to ascertain that the mtDNA disruptive mutation had accumulated postchemotherapy, normal and prechemotherapy tissues were screened for the same mutation, which was shown to be absent (Fig 3). In order to exclude the presence of a possible low-level heteroplasmy, a sensitive locked nucleic acid–based technique with a detection limit of 0.1% was implemented. Green squares represent standard curve samples (slope: 3.364; r 0.995; PCR efficiency: 97%). Wild-type control is circled in black and prechemotherapy sample in red. Absence of the mutation in prechemotherapy and in nontumor tissue was confirmed (Fig 5), indicating that the homoplasmic m.10875T Cwasapostchemotherapy-specificevent,consistentwiththe NDUFB8-positive staining of prechemotherapy tissue (Fig 2). Concordantly with the previously determined correlation between the occurrence of mtDNA mutations and low proliferation of oncocytic tumors, Ki67 of the postchemotherapy mass was nearly zero (Fig 6). Next, we sought to determine whether the residual mass had retained the original pro-oncogenic lesions, in order to ascertain a modifier role for the MTND4 mutation in keeping the chemoresistant clone under alow-proliferativeconstraint.Screeningofoncogenesfrequentlyinvolved in ovarian carcinogenesis, namely KRAS, BRAF, CTNNB1, PIK3CA, ERBB2 and AKT1 did not reveal mutations. Screening of tumor suppressor genes TP53 and PTEN identified a TP53 pathogenic heterozygous p.220Y C mutation both in preand postchemotherapic tissue, but not in the nontumor lymph node (Fig 7). Moreover, the homozygous TP53 p.72P R variant detected in all three samples (Fig 7) was previously reported to render TP53 a sensitive target for oncogenic protein E6 of human papilloma virus strain 16 (HPV16), occasionally associated with ovarian carcinoma. HPV16 was indeed detected both in tumor and in thenontumorlymphnodeofthepatientas it isevidentfromalignmentof detected amino acidic viral sequence (Fig 8). These data suggested cell transformation was due to the viral oncogenic properties in combination with the TP53 mutations.

Three‐dimensional sonographic diagnosis of ovarian pregnancy

Among ectopic pregnancies, ovarian ones are extremely rare. Sonographic diagnosis is feasible although differential diagnosis from the more common tubal location is difficult. Furthermore, owing to their similar sonographic appearance, even distinction from an ipsilateral corpus luteum is not straightforward. We report a case of an ovarian pregnancy that was sonographically identified in a patient with a past ipsilateral salpingectomy because of a tubal pregnancy. The role of three-dimensional (3D) ultrasound in assisting standard sonographic diagnosis is highlighted. A 35-year-old para 1 woman was admitted to our unit because of acute pelvic pain associated with a 2-week delay in menstruation. Her left Fallopian tube had been laparoscopically removed a few months previously owing to an ectopic pregnancy. At laparoscopy a massive hemoperitoneum caused by left tubal rupture had been documented and gestational tissue had been retrieved from the salpinx at pathological examination. A positive urine pregnancy test had been obtained a few hours prior to admission for her current symptoms and she was assumed to be at 6 weeks’ gestation. Her past medical history included appendicectomy and a Cesarean section owing to fetal distress. Gynecological examination documented a mildly enlarged uterus without overt vaginal bleeding or adnexal masses. On external palpation, the abdomen was mildly contracted, with no frank sign of peritoneal irritation. A blood test revealed mild sideropenic anemia (hemoglobulin 9.9 g/dL, mean cell volume 82 fL, hematocrit 28%), and 1726 IU/L of serum beta-hCG. A transvaginal ultrasound examination was performed using a Voluson 730 Exp machine (General Electrics, Milwaukee, USA) equipped with a multifrequency volumetric probe. In the standard two-dimensional (2D) view a thick endometrial lining with no intrauterine gestational sac was demonstrated. The right ovary appeared normal with no suspicious mass within the ipsilateral tube. The left ovary was mildly enlarged owing to a 30-mm unilocular hypoechoic cyst and a 22-mm irregularly-shaped mass, whose sonographically mixed content was consistent with that of a corpus luteum. At the very medial pole of the left ovary, an 18-mm round hypoechoic mass with thick and hyperechoic borders was detected. Power Doppler imaging demonstrated peripheral blood flow distributed in a ring around this mass and the corpus luteum. Mild effusion in the pouch of Douglas was also observed. Volume acquisition and 3D rendering of the left ovary were carried out, revealing a small hypoechoic mass bulging from the cortex and surrounded by a thick hyperechoic ring that was consistent with the ‘bagel’ appearance (Figure 1). Because of these sonographic findings, a small ruptured left ovarian pregnancy co-existing with a corpus luteum and a unilocular cyst was suspected. On the same day an emergency laparoscopy documented a mild blood effusion from a small bulge on the left ovarian surface that was compatible with a gestational sac (Figure 2). An ovarian wedge containing the ectopic sac was resected and removed through the endobag. The patient was discharged home the following day in good condition. Sonographic and surgical findings were pathologically confirmed a few days later. The specimen was described as a juxtacortical ovarian pregnancy associated with normal ovarian stroma. As shown in a large study from a single center1, ovarian ectopic pregnancy does not exceed 3% of all ectopic pregnancies, with almost one case expected out of 3000–40 000 livebirths2. Among the risk factors for ovarian pregnancy, endometriosis or intrauterine device usage have been commonly described3. According to developmental stage and appearance, four types are commonly acknowledged, i.e. ovarian hematoma, clear ovum, embryonized ovum < 3 months and placenta with fetus aged > 3 months4. Four types of ovarian pregnancy have been histologically described, i.e. intrafollicular, juxtafollicular, juxtacortical and interstitial4. In comparison with tubal pregnancies, the clinical presentation is slightly unusual and, as observed in our case, acute pelvic pain is expected to arise prior to 7 completed gestational weeks. Thanks to dramatic improvements in ultrasound equipment, accurate sonographic diagnosis, as confirmed