Tumour markers and their utility in imaging of abdominal and pelvic malignancies.

The utility of tumour biomarkers has increased considerably in the era of personalised medicine and individualised therapy in oncology. Biomarkers may be prognostic or predictive, and only a handful of markers are currently US Food and Drug Administration (FDA)-approved for clinical use. Tumour markers have a wide array of uses such as screening, establishing a differential diagnosis, assessing risk, prognosis, and treatment response, as well as monitoring disease status. Major overlap exists between biomarkers and their associated pathologies; therefore, despite suggestive imaging features, establishing a differential diagnosis may be challenging for the radiologist. We review common biomarkers that are of interest to radiologists such as carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), prostate-specific antigen (PSA), beta human chorionic gonadotropin (ß-hCG), carbohydrate antigen 19-9 (CA 19-9), alpha fetoprotein (AFP), and carbohydrate or cancer antigen 125 (CA 125), as well as their associated malignant and non-malignant pathologies. We also present relevant case examples from our practice.

Exploratory Analysis of CA125-MGL and -STn Glycoforms in the Differential Diagnostics of Pelvic Masses.

BACKGROUND: The cancer antigen 125 (CA125) immunoassay (IA) does not distinguish epithelial ovarian cancer (EOC) from benign disease with the sensitivity needed in clinical practice. In recent studies, glycoforms of CA125 have shown potential as biomarkers in EOC. Here, we assessed the diagnostic abilities of two recently developed CA125 glycoform assays for patients with a pelvic mass. Detailed analysis was further conducted for postmenopausal patients with marginally elevated conventionally measured CA125 levels, as this subgroup presents a diagnostic challenge in the clinical setting. METHODS: Our study population contained 549 patients diagnosed with EOC, benign ovarian tumors, and endometriosis. Of these, 288 patients were postmenopausal, and 98 of them presented with marginally elevated serum levels of conventionally measured CA125 at diagnosis. Preoperative serum levels of conventionally measured CA125 and its glycoforms (CA125-MGL and CA125-STn) were determined. RESULTS: The CA125-STn assay identified EOC significantly better than the conventional CA125-IA in postmenopausal patients (85% vs. 74% sensitivity at a fixed specificity of 90%, P = 0.0009). Further, both glycoform assays had superior AUCs compared to the conventional CA125-IA in postmenopausal patients with marginally elevated CA125. Importantly, the glycoform assays reduced the false positive rate of the conventional CA125-IA. CONCLUSIONS: The results indicate that the CA125 glycoform assays markedly improve the performance of the conventional CA125-IA in the differential diagnosis of pelvic masses. This result is especially valuable when CA125 is marginally elevated.

Extended duration chemoprophylaxis for venous thromboembolism following abdominopelvic oncologic surgery.

Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is the most common cause of 30-day morbidity in oncology patients following surgery due to their hypercoagulable state. To combat this, VTE prophylaxis with anticoagulation extending beyond hospital discharge, termed extended duration chemoprophylaxis (EDCP), has been proposed, with the most recent guidelines recommending 28 post-operative days of EDCP. However, the literature has demonstrated poor compliance to these recommendations. We extended the duration of EDCP to 28 days post hospital discharge, effectively creating a standard discharge prescription for all surgical oncology patients. Our aim is to assess our EDCP protocol on patient compliance and VTE rate following major oncologic resection. We performed a retrospective, single institution, cohort study that involved chart review and telephone survey on patients who underwent major open abdominopelvic oncologic resection. A total of 130 patients were included; 60 received EDCP and 68 did not. VTE rate for the EDCP cohort was 0% and 7.4% for the non-EDCP cohort (p = 0.04). 85% of patients were fully compliant with EDCP. No bleeding related complications with EDCP were identified. Our data is consistent with prior literature in demonstrating a lower VTE rate with EDCP without an increase in bleeding related complications and we have demonstrated that it is possible to achieve a high rate of patient compliance with EDCP.

A multicenter clinical trial validating the performance of HE4, CA125, risk of ovarian malignancy algorithm and risk of malignancy index.

OBJECTIVE: To validate, in a multicenter clinical trial, the performance of biomarkers and algorithms for differential diagnosis in a population of women diagnosed with an unknown ovarian cyst or pelvic tumor. METHODS: Six hospitals in Western Sweden consecutively enrolled 638 women from September 2013 to February 2016. Serum, transvaginal ultrasound data, and basic patient characteristics were collected preoperatively. Biomarker levels, risk of malignancy algorithm (ROMA), and risk of malignancy index (RMI) were calculated and compared with the final pathology report. RESULTS: Our sample of 638 patients had 445 benign, 31 borderline, and 162 malignant tumors recorded, and the overall incidence of epithelial ovarian cancer was 21%. In postmenopausal women, RMI (>200), ROMA (≥29.9), CA125 (>35 U/mL), and HE4 (>140 pmol/L) showed sensitivity at 89%, 91%, 92%, and 72%, respectively, and specificity at 80%, 77%, 80%, and 92%. In premenopausal women, sensitivity of RMI, ROMA (≥11.6), CA125, and HE4 (>70 pmol/L) was 87%, 87%, 96%, and 83%, respectively, and specificity was 90%, 81%, 60%, 91%. Diagnostic accuracy (ROC AUC) of RMI and ROMA in postmenopausal women was 0.85 and 0.84, and in premenopausal women, 0.90 and 0.81. CONCLUSION: Our results suggest that CA125 is superior to HE4 as a biomarker to identify women with ovarian cancer. HE4 more correctly identifies benign lesions, which may help in differential diagnoses to guide the level of care and decrease overtreatment. This study confirms prior results from single-center studies and suggests the implementation of HE4 measurement in daily practice.

Discriminative value of CA-125, HE4, Risk of Malignancy Index II (RMI-II) and Risk of Malignancy Algorithm (ROMA) in the differential diagnosis of pelvic masses: conclusions from a referral Centre in Portugal.

The major purpose of this article was to compare the discriminative value of different algorithms and serum biomarkers in the differential diagnosis of adnexal masses. We performed a retrospective study with 247 women with adnexal neoplasia, submitted to surgical treatment and with a histological diagnosis. The evaluation of the area under the curve (AUC) for isolated CA-125 and HE4, and for ROMA and RMI-II, showed a better specificity of HE4 and RMI-II in premenopausal women. In the postmenopausal group, ROMA and RMI-II were the algorithms with a better performance. Impact Statement What is already known on this subject? CA-125 remains the most commonly used biomarker used to predict the behaviour of an adnexal mass, but it has a low sensitivity for stage I tumours. Other isolated serum markers have emerged more recently, such as HE4, as well as more complex algorithms, such as RMI or ROMA. It remains unclear which is the best marker/algorithm to predict the behaviour of an adnexal mass. What do the results of this study add? Our findings showed that ROMA is a suitable marker for postmenopausal women, with no advantage found in the premenopausal women when compared with an isolated HE4. What are the implications of these findings for clinical practice and/or further research? The different algorithms of the preoperative discrimination of ovarian neoplasia appear to have different AUC, SN and SP in the pre- or the postmenopausal patients. For the premenopausal women, the use of ROMA does not seem to have any advantage over the isolated use of HE4, which does not lose specificity even when the borderline tumours are considered for discrimination. In the postmenopausal women, ROMA is a valid algorithm with a good sensitivity. The RMI-II showed a good performance in both groups, although it depends on the ultrasound findings and has an important interobserver variability. This information allows a more targeted selection of markers and algorithms to be requested prior to surgery of ovarian neoplasms regarding the menopausal status of each patient.

Contemporary Incidence and Outcomes of Prostate Cancer Lymph Node Metastases.

PURPOSE: The incidence of localized prostate cancer has decreased with shifts in prostate cancer screening. While recent population based studies demonstrated a stable incidence of locoregional prostate cancer, they categorized organ confined, extraprostatic and lymph node positive disease together. However, to our knowledge the contemporary incidence of prostate cancer with pelvic lymph node metastases remains unknown. MATERIALS AND METHODS: We used SEER (Surveillance, Epidemiology and End Results) data from 2004 to 2014 to identify men diagnosed with prostate cancer. We analyzed trends in the age standardized prostate cancer incidence by stage. The impact of disease extent on mortality was assessed by adjusted Cox proportional hazard analysis. RESULTS: During the study period the annual incidence of nonmetastatic prostate cancer decreased from 5,119.1 to 2,931.9 per million men (IR 0.57, 95% CI 0.56-0.58, p <0.01) while the incidence of pelvic lymph node metastases increased from 54.1 to 79.5 per million men (IR 1.47, 95% CI 1.33-1.62, p <0.01). The incidence of distant metastases in men 75 years old or older reached a nadir in 2011 compared to 2004 (IR 0.81, 95% CI 0.74-0.90, p <0.01) and it increased in 2012 compared to 2011 (IR 1.13, 95% CI 1.02-1.24, p <0.05). The risk of cancer specific mortality significantly increased in men diagnosed with pelvic lymph node metastases (HR 4.5, 95% CI 4.2-4.9, p <0.01) and distant metastases (HR 21.9, 95% CI 21.2-22.7, p <0.01) compared to men with nonmetastatic disease. CONCLUSIONS: The incidence of pelvic lymph node metastases is increasing coincident with a decline in the detection of localized disease. Whether this portends an increase in the burden of advanced disease or simply reflects decreased lead time remains unclear. However, this should be monitored closely as the increase in N1 disease reflects an increase in incurable prostate cancer at diagnosis.

[Clinical validation of multiple biomarkers suspension array technology for ovarian cancer].

Objective: To investigates the diagnostic value of combined detection serum CCL18, CXCL1 antigen, C1D, TM4SF1, FXR1, TIZ IgG autoantibody by suspension array for ovarian cancer. Methods: Suspension array was used to detect CCL18, CXCL1 antigen, C1D, TM4SF1, FXR1, TIZ IgG autoantibody in 120 cases of healthy women, 204 cases of patients with benign pelvic tumors, 119 cases of pelvic malignant tumor patients, and 40 cases with breast cancer, lung cancer oroliver cancer, respectively. Constructed diagnosis model of combined detection six biomarkers for diagnosis of ovarian malignant tumor. Constructed diagnosis model of combined detection autoantibodies to diagnose epithelial ovarian cancer. Analysed the value of detecting six biomarkers for diagnosis of ovarian malignant tumor and detecting autoantibodies for diagnosis of epithelial ovarian cancer. Analysed diagnostic value of detecting six biomarkers to diagnose stage Ⅰ and Ⅱepithelial ovarian cancer. Compared diagnostic value of detecting six biomarkers in diagnosis of tissue types and pathologic grading with that of CA(125). Results: Model of combined detecting six biomarkers to diagnose ovarian malignant tumor was logit (P) =-11.151+0.008×C1D+0.011×TM4SF1+0.011×TIZ-0.008×FXR1+0.021×CCL18+0.200×CXCL1. Model of combined detection autoantibodies to diagnose epithelial ovarian cancer was logit (P) =-5.137+0.013×C1D+0.014×TM4SF1+0.060×TIZ-0.060×FXR1. Sensitivity and specificity of detecting six biomarker to diagnose ovarian malignant tumor was 90.6% and 98.7%. Sensitivity and specificity of detecting autoantibodies to diagnose epithelial ovarian cancer was 75.8% and 96.7%. Combined detection for six biomarkers to diagnose serous and mucinous ovarian cancer was statistically no better than those of CA(125) (P=0.196 and P=0.602, respectively); there was significantly difference in diagnosis of ovarian cancer (P=0.023), and there was no significantly difference in diagnosis of different pathological grading (P=0.089 and P=0.169, respectively). Conclusions: Constructing diagnosis model of combined detection six biomarker to diagnose ovarian malignant tumor and constructed diagnosis model of combined detectionautoantibodies to diagnose epithelial ovarian cancer. Combined detection six biomarkers to diagnose serous and mucinous ovarian tumors is better than that of CA(125).

Atypical presentation of sacrococcygeal yolk sac tumor in infant: beware of the injuries of the gluteal region.

Malignant sacrococcygeal yolk sac tumor is a rare extra-gonadal germ cell tumor of infancy and childhood. We report the case of a 14-month-old white female infant with a rapidly growing supra-gluteal mass at first misdiagnosed as hemangioma after a clinical assessment. The lesion was then classified as extra-gonadal yolk sac tumor due to alarming ultrasound features, later confirmed at MRI and pathology. This report remarks the need of a rigorous methodology in the ultrasound exploration of the gluteal region.

Urology pertinent neuroendocrine tumors: focusing on renal pelvis, bladder, prostate located sympathetic functional paragangliomas.

Urology pertinent neuroendocrine neoplasias are more and more driving to research attractive contributions mainly as regards the urinary tract paragangliomas, besides the prostate cancer neuroendocrine differentiation. About such visceral sympathetic paragangliomas, a considerable attention is aroused by those concerning the renal pelvis, urinary bladder and, particularly, the prostate gland. Essential catecholamine/adrenergic signal-mediated pathophysiological implications and outlined diagnostic approaches are here taken into consideration. Particularly, to reach an accurate functional diagnostic assessment, both plasma and urine catecholamine level tests are required together with ¹²³I or ¹³¹I-meta-iodobenzylguanidine (MIBG) scan while ¹³¹I-, instead of ¹²³I-, labeled MIBG, proving to be also useful to targeted radionuclide therapy of sympathetic paragangliomas. Nevertheless, a thorough diagnostic confirmation should be obtained by a proper histologic/ immunohistochemical study, so that it respectively highlighting the typical "zellballen" cell setting and neuroendocrine tumor cell specific biomarkers such as chromogranin-A, synaptophysin, neuron-specific enolase. Open/laparoscopic/robot-assisted surgical procedures are performed under α1 (doxazosin, prazosin) - and ß(propranolol)-adrenergic blockade to avoid the risk of an intraoperative adrenergic signal-triggered hypertensive crisis, what moreover may occur also during cystoscopy and biopsy in case of bladder or prostate paraganglioma. Given a conceivable likeness, about some adrenergic-mediated pathophysiological implications, between prostate paraganglioma and prostate cancer neuroendocrine transdifferentiation - although as regards two obviously different diseases - a reliable pathogenetic matter concerning prostate paraganglioma is requiring novel research approaches.

Tissue CA125 and HE4 Gene Expression Levels Offer Superior Accuracy in Discriminating Benign from Malignant Pelvic Masses.

BACKGROUND: Ovarian cancer remains a major worldwide health care issue due to the lack of satisfactory diagnostic methods for early detection of the disease. Prior studies on the role of serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in detecting ovarian cancer presented conflicting results. New tools to improve the accuracy of identifying malignancy are urgently needed. We here aimed to evaluate the diagnostic utility of tissue CA125 and HE4 gene expression in comparison to serum CA125 and HE4 in discriminating benign from malignant pelvic masses. MATERIALS AND METHODS: One-hundred Egyptian women were enrolled in this study, including 60 epithelial ovarian cancer (EOC) patients and 20 benign ovarian tumor patients, as well as 20 apparently healthy women. Preoperative serum levels of CA125 and HE4 were measured by immunoassays. Tissue expression levels of genes encoding CA125 and HE4 were determined by quantitative real time polymerase chain reaction (qRT-PCR). The diagnostic performance of CA125 and HE4, measured either as mRNA or protein levels, was evaluated by receiver operating characteristic (ROC) curves. RESULTS: The serum CA125+HE4 combination and serum HE4, with area under the curve (AUC) values of 0.935 and 0.932, respectively, performed significantly better than serum CA125 (AUC=0.592; P<0.001). Tissue CA125 and HE4 (AUC=1) performed significantly better than serum CA125 (P<0.001), serum HE4 (P=0.016) and the serum CA125+HE4 combination (P=0.018). CONCLUSIONS: Measurement of tissue CA125 and HE4 gene expression not only improves discriminatory performance, but also broadens the range of differential diagnostic possibilities in distinguishing EOC from benign ovarian tumors.

The Role of Matrix Metalloproteinase-9 (MMP-9) as a Prognostic Factor in Epithelial and Lymphatic Neoplasia.

Matrix metalloproteinase 9 is a zinc-dependent extracellular matrix remodeling endopeptidase directly involved in the local invasion mechanisms and in metastasis. The current review aims to evaluate the expression of MMP-9 and its prognostic value in the most common epithelial and lymphatic neoplasia of the pelvic-abdominal region. We included 19 studies published between January 1st, 1995 and July 31st 2015, involving a total of 1523 patients. The analysis indicate that MMP-9 is valid marker of poor survival in epithelial and lymphatic neoplasia.

Development of a multimarker assay for differential diagnosis of benign and malignant pelvic masses.

BACKGROUND: HE4, a novel tumor marker for detecting ovarian cancer, has been recently applied to clinical practice. However, the comprehensive evaluation of HE4 combined with other markers is still missing. We evaluated an optimal mode of HE4 employment for differential diagnosis of benign and malignant pelvic masses. METHODS: Serum HE4, CA125, CA153, CA199, CA211 and CA724 were measured from 232 patients with pelvic messes (100 malignant masses, 132 benign diseases), and the risk of ovarian malignancy algorithm (ROMA) was also calculated. Receiver operating characteristic curves (ROC), the area under the curve (AUC), sensitivity and specificity were estimated. RESULTS: The combination of HE4 and CA125 (AUC of 0.963, sensitivity of 96.6%, specificity of 65.7%) provided the best differential power in diagnosing ovarian cancer. ROMA performed better in the diagnosis of pelvic masses (AUC of 0.917, sensitivity of 82.0%, specificity of 78.8%) and uterine cancer (AUC of 0.838, sensitivity of 82.0%, specificity of 60.0%) compared with applying HE4 and CA125 individually. CONCLUSION: The optimal cut-off values (CA125: 93.2U/ml, HE4: 87.6 pmol/l, ROMA: 18.1% for pre- and 31.5% for postmenopausal women), simultaneous use of CA125 and HE4 complemented by ROMA showed better performance than the traditional detection modes for differential diagnosis of ovarian cancer. We also observed that ROMA added more accuracy for differentiating the benign and malignant pelvic masses and auxiliary diagnosis of uterine cancer.

IgG4-related systemic disease mimicking renal pelvic cancer: a rare case.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity. Characteristic features of IgG4-RD are elevated serum IgG4 levels, infiltration of IgG4-positive cells, mass-forming lesions with fibrosis and good response to corticosteroids. The variable imaging features of IgG4-RD and the overlap with other differential diagnoses often pose a diagnostic challenge, as they frequently mimic malignant tumors or other inflammatory diseases in the abdomen. CASE PRESENTATION: A 54-year-old woman visited our hospital with left flank discomfort and palpebral edema. Computed tomography, magnetic resonance imaging, retrograde pyelography and positron emission tomography/computed tomography indicated renal pelvic cancer. However, after a left-sided nephroureteral cystectomy was performed, the mass was pathologically confirmed as an IgG4-related lesion. Her elevated serum IgG4 level and a past history of sicca complex supported the diagnosis of IgG4-RD. CONCLUSIONS: It is critical to recognize the importance of laboratory examinations such as serum IgG4 level if a patient has a past history of rheumatic disease.

Evaluation of serum CA 125 level and its relation to surgical, histopathologic and ultrasonographic findings in patients with pelvic mass.

OBJECTIVE: The aim of this study was to determine the relationship between the levels of tumour marker CA 125 antigen and pelvic tumour size, histopathological type, stage, bilateral status, ascites, type of surgery, and postoperative complications. MATERIALS AND METHODS: A retrospective cross-sectional descriptive study was conducted on 203 patients with a pelvic mass who were visited in the Shahid Sadoughi hospital in Yazd, Iran from 2007 to 2010. Data were analyzed by software SPSS v.14. RESULTS: Statistical analysis, based on Fisher's exact test, showed that patients with pelvic mass who presented with either of bilateral involvement/ascites (p = 0.000), higher stage (p = 0.001), inability for complete resection (p = 0.000), or postoperative complications (p = 0.001) had significantly higher serum concentrations of CA 125 antigen. There was no relationship between serum level of CA 125 and such variables as tumor size (p = 0.883) and abdominal ultrasound findings (p = 0.297). CONCLUSION: Using CA 125 as a diagnostic and prognostic tool in patients with newly-discovered pelvic mass can be helpful in some aspects, but cannot estimate size of the tumor and its solid/cystic status. It also cannot predict post-surgical complications of malignant pelvic masses.

High burden of metastases and poor outcome in pelvic PNET.

Data on prognostic factors in pelvic PNET are minimal. We analyzed patients with pelvic PNET treated between June 2003 and November 2011 for prognostic factors. Forty-eight (13%) of 374 patients with PNET were pelvic PNET with median age 14.5 years (range: 5-33); 31 (65%) had metastases. After median follow-up of 20.4 months (range: 1.3-64.9), 3-year EFS, OS, and local-control-rate were 13.5 ± 5.5%, 15.4 ± 9%, and 41.3 ± 14.9%, respectively. Hypoalbuminemia (≤3.4 g/dl) predicted inferior EFS and OS for both entire cohort and metastatic group. All patients with hypoalbuminemia (n = 10) had low BMI as compared to 23/38 without hypoalbuminemia (P = 0.02).

A pilot study examining circulating interleukin-6 and transforming growth factor-ß levels during pelvic radiation therapy.

OBJECTIVES: To determine if circulating levels of the inflammatory cytokines interleukin-6 (IL-6) and transforming growth factor-ß (TGF-ß levels) are elevated during pelvic radiotherapy (RT). METHODS: Patients receiving pelvic RT with a minimum dose of 45 Gy were eligible for this prospective observational study. Patients were assessed before RT, during week 3 of RT, and during the last week of RT. Assessment included determination of gastrointestinal toxicity and laboratory evaluation for serum IL-6 and plasma TGF-ß using quantitative 2-site enzyme immunoassays. Dose to the rectum, colon, and small bowel were analyzed using dose-volume histograms. A 2-sided 0.05-level Kruskal Wallis one-way analysis of variance test was used to test the equality of the means of IL-6 and TGF-ß levels at the different time points. RESULTS: Twenty patients were enrolled, of whom 18 were eligible. The mean (95% confidence interval) serum IL-6 levels at baseline, 3 weeks, and during the last week of RT were 5.1 (1.9-8.3) pg/mL, 4.1 (2.6-5.7) pg/mL, and 7.5 (4.9-10.1) pg/mL, respectively (P-value > 0.05). The mean (95% confidence interval) plasma TGF-ß levels at baseline, 3 weeks, and during the last week of RT were 8.7 (5.0-12.3) ng/mL, 5.5 (3.8-7.2) ng/mL, and 7.0 (4.5-9.5) ng/mL, respectively (P-value > 0.05). There was no correlation between cytokine levels and clinically evident RT enteritis or volume of bowel receiving RT. CONCLUSIONS: We did not observe significant changes in circulating levels of TGF-ß and IL-6 during pelvic RT.

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass.

OBJECTIVE: Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. METHODS: Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. RESULTS: 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). CONCLUSION: HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.

Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.

More than 200,000 women undergo exploratory surgery for a pelvic mass in the United States each year and 13%-21% of pelvic lesions are found to be malignant. Individual reports and meta-analysis indicate better outcomes when cancer surgery is performed by gynecologic oncologists. Despite the advantages provided by more thorough staging and cytoreductive surgery, only 30%-50% of women with ovarian cancer are referred to surgeons with specialized training in the United States. Imaging, menopausal status and biomarkers can aid in distinguishing malignant from benign pelvic masses to inform decisions regarding appropriate referral. The risk of malignancy index (RMI) uses ultrasound, menopausal status and CA125 and has been utilized in the United Kingdom for two decades, providing sensitivity that has ranged from 71%-88% and specificity it from 97%-74% for identifying patients with malignant disease. Criteria have been established by the Society of Gynecology Oncology and American College of Obstetrics and Gynecology for referral to a gynecologic oncologist, but these have lower sensitivity and specificity than the RMI. Recently, two new algorithms have been developed to identify women at sufficiently high risk to prompt referral to a specialized surgeon. The OVA1 multivariate index incorporates imaging, menopausal status, CA125 and four other proteomic biomarkers. Use of OVA1 provides 85%-96% sensitivity at 28%-40% specificity depending upon menopausal status. The negative predictive value for women judged to be at low risk is 94%-96%. The risk of malignancy algorithm (ROMA) includes CA125, human epididymal protein 4 and menopausal status, but not imaging results. The ROMA has yielded 93%-94% sensitivity at 75% specificity with a negative predictive value of 93%-98%. In a direct comparison, ROMA has achieved greater sensitivity (94%) than the RMI (75%) at 75% specificity. OVA1 has not been compared directly to ROMA, but is likely to be as sensitive, but substantially less specific. Both algorithms have high negative predictive values 94%-98%. Although a difference in specificity should not affect patient outcomes, it could affect distribution of medical resources.

Circulating antinuclear antibodies in patients with pelvic masses are associated with malignancy and decreased survival.

BACKGROUND: Circulating autoantibodies occur more frequently in cancer patients than in patients without cancer. METHODS AND FINDINGS: We examined sera from patients referred for pelvic mass symptoms to a tertiary university clinic. A total of 127 were diagnosed with epithelial ovarian cancer while 386 had a benign condition. A screen for IgG anti-nuclear antibodies (ANA) by indirect immunofluorescence on HEp-2 cells confirmed a highly significant overrepresentation of ANA in the cancer group where 40% had detectable (i.e., a titer ≥160) ANA compared with less than 12% in the benign group. The overrepresentation of ANA in the cancer group persisted (p<0.0001) after matching the age-profile of the benign group with the ovarian cancer group. Only 19 out of 127 patients in the age-matched benign subgroup were positive for ANA corresponding to an 85% specificity at 40% sensitivity of ANA as the only marker for malignancy. No correlation of ANA positivity in either group with specific bands in immunoblots could be demonstrated even though immunoblot positivity was clearly increased in the malignant group (41% vs. 3%). The presence, strength, and type of ANA did not correlate with serum CA-125 values or with staging, and ANA outcome did not contribute with independent diagnostic information. However, survival was significantly shorter in ANA-positive compared with ANA-negative cancer patients and patients with CA-125 below the median CA-125 value in the cancer group had a significantly decreased survival when positive for ANA. ANA status made no difference in the group with CA-125 values above the median. Also, there was a significant correlation between speckled ANA-strength and histological tumor grade. CONCLUSIONS: Circulating antibodies are a promising source for new biomarkers in cancer. Characterization of epitope specificities and measurements of consecutive samples will be important for further elucidating the role of ANA in evaluating ovarian cancer patients.

Using a multivariate index assay to assess malignancy in a pelvic mass.

A multivariate index assay recently was developed to assist physicians in the assessment of the risk of ovarian cancer in women with pelvic masses undergoing operative intervention. Its aim is to improve the identification of patients with ovarian malignancy so that these patients can be appropriately referred to a subspecialist with ovarian cancer-management expertise, thereby affording the opportunity for improved outcome. This commentary questions the need to obtain a multivariate index assay test in all women with pelvic masses who are scheduled for operative intervention. Common-sense guidelines for more judicious use of this new triage test in the evaluation of these patients also are provided.