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Biochimica Clinica: VOL.37 N.3

Il laboratorio nel cancro dell’ovaio: e pur si muove!
Laboratory and ovarian cancer: and yet it moves!
Biochimica Clinica 2013; 37(3) 176-178
Editoriale - Editorial
Serum human epididymis protein 4 vs. carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review

Human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of ovarian cancer (OC). This study sought to critically revise the available literature on the comparison between the diagnostic accuracy of HE4 and carbohydrate antigen 125 (CA-125) to provide evidence of HE4 additional clinical value. Literature search was undertaken on electronic databases and references from retrieved articles, and articles analyzed according to predefined criteria. Meta-analyses for HE4 and CA-125 biomarkers with odds ratio (OR), diagnostic sensitivity, specificity, positive (LR+) and negative (LR–) likelihood ratios as effect sizes were performed. Sixteen articles were originally included in meta-analyses, but two for HE4 and one for CA-125 were eliminated as outliers. Furthermore, for HE4 a publication bias was detected. ORs for both HE4 (37.2, 95% CI: 19.0-72.7, adjusted for publication bias) and CA-125 (15.4, 95% CI: 10.4-22.8) were significant, although in a heterogeneous set of studies (P <0.0001). By combining sensitivity and specificity, the overall LR+ and LR– were 13.0 (95% CI: 8.2-20.7) and 0.23 (95% CI: 0.19-0.28) for HE4 and 4.2 (95% CI: 3.1-5.6) and 0.27 (95% CI: 0.23-0.31) for CA-125, respectively. HE4 measurement seems to be superior to CA-125 in terms of diagnostic performance for identification of OC in women with suspected gynecological disease. Due to the high prevalence of OC in post-menopausal women and the need of data focused on early tumor stages, more studies tailored on these specific subsets are needed.

Biochimica Clinica 2013; 37(3) 179-189
Rassegne - Reviews
Antigene carboidratico 125 (CA-125) vs. proteina 4 dell’epididimo umano (HE4) in una popolazione di donne con massa pelvica
Carbohydrate antigen 125 (CA-125) vs. human epididymis protein 4 (HE4) in a population of women with pelvic mass

Aim of this study was to compare the diagnostic performance of CA-125 and HE4 for epithelial ovarian carcinoma (OC) in 505 consecutive women referred to our hospital for an adnexal mass. The population consisted of 18 (3.6%) patients with OC (13 in post-menopausal status, 72.2%) and 487 patients with a benign mass (171 in postmenopausal status, 35.1%). Employed diagnostic thresholds were 35 kU/L for CA-125 and 70 or 140 pmol/L for HE4 in pre-menopause and post-menopause, respectively. CA-125 and HE4 concentrations were significantly lower in patients with benign mass in comparison to women with OC. Overall sensitivity and specificity were higher for HE4 than for CA-125: 94.4% vs. 61.1% (P=0.04) and 91.0% vs. 82.8% (P=0.0002). False positive results for CA-125 and HE4 were found in 16.8% and 6.6% of women in pre-menopause and in 18.1% and 13.5% of women in postmenopause, respectively. Our results confirmed a higher specificity for HE4 vs. CA-125. Thus, the additional evaluation of HE4 would enable a more accurate referral of patients at risk for OC to the gynecological oncology services.

Biochimica Clinica 2013; 37(3) 190-194
Contributi Scientifici - Scientific Papers
La proteina 4 dell’epididimo umano (HE4) come marcatore di recidiva di carcinoma dell’ovaio
Human epididymis protein 4 (HE4) as a marker of ovarian cancer relapse

Carbohydrate antigen 125 (CA-125) is considered a good marker of ovarian cancer (OC) progression, although high CA-125 concentrations may be observed in several benign conditions, such as pelvic inflammatory disease and endometriosis. Recent studies sought to identify markers with improved specificity for OC detection and monitoring, highlighting interesting results only for HE4. The aim of this study was to evaluate HE4 as marker of OC relapse in 18 patients (50% in relapse) monitored after surgery and adjuvant chemotherapy. Serum HE4 and CA-125 concentrations were determined by ELISA and IRMA methods, respectively. Each patient contributed three serum samples drawn at 3-month intervals (between 1-3, 4-6 and 7-10 months from surgery). Concerning OC patients in remission, marker increase over the threshold level was observed only for CA-125 (n=3, 33%). Conversely, in patients with relapsed OC the increase of HE4 occurred in 22%, 78% and 89% of patients at 3, 6 and 10 months from treatment, respectively. The positivity for CA-125 was found later (7-10 months after surgery) and only in 44% of patients. According to the reference change value available only for CA-125 (69%), 11% of patients both in remission and in relapse showed a clinically significant CA-125 increase at 6 months. However, no further increase was later detectable in patients in remission. Conversely, 67% of patients with recurrent disease showed a further significant CA-125 increase in the following three months. In conclusion, although preliminarily, this study shows that HE4 is more specific and sensitive than CA-125 for the detection of OC relapse.

Biochimica Clinica 2013; 37(3) 195-199
Contributi Scientifici - Scientific Papers
Confronto tra due metodi per la misura nel siero della proteina 4 dell’epididimo umano (HE4) nella diagnosi di carcinoma ovarico
Comparison between two methods for the determination of serum human epididymis protein 4 (HE4) in the diagnosis of ovarian cancer

Analytical performance and diagnostic accuracy of two commercial immunoassays for the determination of HE4 in the diagnosis of ovarian cancer were evaluated. HE4 was determined on sera consecutively obtained from 205 women (163 with benign ovarian or adnexal disease and 42 with ovarian cancer) by using a manual EIA (Fujirebio Diagnostics, Inc.) and an automated chemiluminescent microparticle assay (CMIA) (Abbott Architect platform). The intra- and interassay imprecision for EIA and CMIA was satisfactory (CV <10%). The linearity test showed recovery values between 86% and 120%. Comparison analysis showed an acceptable agreement between the two methods (r=0.99), with an average bias of 1.2%. ROC curve analysis showed an area under the curve of 0.893 for EIA and 0.899 for CMIA, respectively. Setting the specificity of each assay at 95% (cutoff, 102,7 pmol/L for EIA and 101,8 pmol/L for CMIA), the sensitivity for both methods was 67%. Both EIA and CMIA appear reliable for clinical application.

Biochimica Clinica 2013; 37(3) 200-207
Contributi Scientifici - Scientific Papers
Biomarcatori nella diagnosi del carcinoma dell’ovaio: dialogo fra un patologo clinico e un ginecologo oncologo
Biomarkers in the diagnosis of ovarian cancer: a dialogue between a clinical pathologist and a gynecologic oncologist
M. Gion  |  T. Maggino  | 

 A general consensus exists on the effectiveness of CA125 in ovarian cancer management, where it is currently used as an aid in clinical decisions for the initial work-up, post-operative follow-up and for monitoring chemotherapy in advanced disease. It is, however, apparent that no effective marker is presently available for costeffective screening of asymptomatic population. The debate is still open on the role of markers in the differential diagnosis of adnexal masses and some agreement exists on the following issues: 1) the referral to a gynecologic oncologist improves outcome for ovarian cancer patients, including overall survival; 2) markers should not be intended as a cancer diagnostic test, but as one of the criteria for the selection of patients with adnexal mass at a higher cancer risk; 3) CA125 appears to have several shortcomings: low sensitivity for early stage disease and low specificity, especially in premenopausal women; 4) algorithms combining CA125, age and imaging to assess the risk of a mass being malignant improve diagnostic accuracy of CA125 used alone; 5) among novel markers, HE4 has emerged as the most effective, overperforming CA125 mainly in premenopausal women; 6) mixed data have been reported on the advantages of ROMA, a diagnostic algorithm integrating HE4, CA125 and menopausal status, vs. HE4 alone; 7) conflicting data suggest that properly designed and well performed studies are still needed to identify the most effective diagnostic approach to assess cancer risk in patients with adnexal mass.

Biochimica Clinica 2013; 37(3) 208-213
Opinioni - Opinions
Indicazioni per un approccio multidisciplinare alla gestione del carcinoma ovarico
A multidisciplinary approach in the mangement of ovarian cancer

Ovarian cancer is one of the most lethal gynecologic malignancies mainly because of the advanced tumor stage at diagnosis. The outcome for women with ovarian cancer is generally poor, with an overall 5-year survival rate <35%. Disease stage is the most important factor affecting outcome. The woman's general health at the time of presentation is also important, because it affects the choice of treatment options. The contribution of imaging techniques in patient management is gaining acceptance for the staging of ovarian cancer, the selection of candidates suitable for cytoreductive surgery and the macroscopic documentation of residual tumor after primary surgery. Recent reports have demonstrated that, besides utilizing CA125 as a predictor of optimal cytoreduction and response to treatment, diagnostic accuracy may be improved utilizing a new biomarker, the human epidydimis protein 4, whose expression closely relates to the presence of epithelial ovarian cancer in women. Despite the relatively poor overall survival rate for ovarian cancer, there was a two-fold increase in survival over the last 30 years, which has coincided with the advent of effective chemotherapy, and, particularly, the introduction of platinum-based agents, as well as changes in surgical practice. More recently, there has been a significant shift towards greater specialization in the delivery of care, resulting from the implementation of the cancer service guidance improving outcomes in gynecologic cancers.

Biochimica Clinica 2013; 37(3) 214-219
Opinioni - Opinions
“The recognition and initial management of ovarian cancer”: un’analisi commentata del documento preparato dal National Institute for Health and Clinical Excellence (NICE)
The recognition and initial management of ovarian cancer: a commented analysis of the document prepared by the National Institute for Health and Clinical Excellence (NICE)

The document "Ovarian cancer: the recognition and initial management of ovarian cancer" is a guideline issued in April 2011 by NICE, which revises a number of clinical issues related to the diagnosis and initial management of ovarian cancer. For this purpose, several databases were used, carrying out the work between April 2009 and July 2010, and then updating the guideline with data from the literature published before July 16, 2010. NICE clinical guidelines are based on the best available evidence of clinical and cost effectiveness and are produced to help professionals and patients make informed choices about appropriate healthcare. In this document, we translated the most salient parts of the guideline, relating to the chapters entitled "Detection in primary care" and "Establishing the diagnosis in secondary care", integrated by some comments in order to contextualize and discuss the use of this guideline in daily clinical practice.

Biochimica Clinica 2013; 37(3) 220-228
Documenti - Documents
VEQ: sfide attuali e prospettive future
Proficiency Testing/External Quality Assessment: Current Challenges and Future Directions

Proficiency testing or EQA is intended to verify on a recurring basis that laboratory results conform to expectations for the quality required for patient care. Key factors for interpreting EQA results are knowledge of the commutability of the samples used and the process used for target value assignment. A commutable EQA sample demonstrates the same numeric relationship between different measurement procedures as that expected for patients' samples. Noncommutable EQA samples frequently have a matrix-related bias of unknown magnitude that limits interpretation of results. EQA results for commutable samples can be used to assess accuracy against a reference measurement procedure or a designated comparison method. In addition, the agreement of the results between different measurement procedures for commutable samples reflects that which would be seen for patients' samples. EQA results for noncommutable samples must be compared to a peer group mean/median of results from participants who use measurement procedures that are expected to have the same or very similar matrix-related bias. Peer group evaluation is used to asses whether a laboratory is using a measurement procedure in conformance to the manufactur er' s specifications and/or in conformanc e t o ot her labor atori es u sing the same technology. A noncommutable EQA sample does not give meaningful information about the relationship of results for patients' samples between different measurement procedures. EQA provides substantial value to the practice of laboratory medicine by assessing the performance of individual laboratories and, when commutable samples are used, the status of standardization or harmonization among different measurement procedures.

Biochimica Clinica 2013; 37(3) 229-240
Il meglio di Clinical Chemistry - Clinical Chemistry highlights
Un raro caso di mesotelioma multicistico del peritoneo associato ad aumento di CA 125 e CA 19.9 nel siero
A rare case of benign multicystic mesothelioma of the peritoneum associated to CA 125 and CA 19.9 elevations in serum
S. Ferraro  |  R. Mozzi  |  C. Villa  |  M. Crespi  |  M. Panteghini  | 

Markedly increased CA 125 and CA 19.9 concentrations in serum are considered specific enough to reliably identify malignant cancers (ovarian and gastrointestinal tumours, respectively), although a consistent body of literature has reported marker elevations in several benign conditions. Here we report the case of a woman in post-menopausal status, with a previous history of hysterectomy, presenting with a 12-cm pelvic mass at sonography and serum CA 125 and CA 19.9 concentrations >400 kU/L. One month after initial presentation, she underwent surgical evaluation for laparoscopy, repeating marker determinations. Concentrations of CA 125 and CA 19.9 were still elevated, but decreased if compared with the previous data (~200 kU/L). Magnetic resonance imaging characterized a multicystic mass in the mesentery, allowing to hypothesize a benign multicystic mesothelioma of the peritoneum (BMMP). The laparoscopy revealed multiple cysts, some of them resulting in colliquation, associated to ascites. Histological examination of biopsy specimens confirmed BMMP as composed of multiple, thin-walled, irregularly spaced cysts lined by flattened and cuboidal mesothelial cells. The cystic colliquation was though as the main cause for decrease in marker concentrations. To our knowledge, this is the first case of BMMP associated with significantly increased concentrations of CA 125 and CA 19.9 and their decrease before any surgical treatment.

Biochimica Clinica 2013; 37(3) 241-245
Casi Clinici - Case Report
Troponin elevation reflects myocardial injury in carbon monoxide poisoning

We describe the case of a 48-year-old white man, who was admitted to the emergency department with neurologic deficits and high suspicion of carbon monoxide (CO) poisoning. Blood carboxyhemoglobin (COHb) level was found substantially increased (i.e., 18%). Clinical symptoms of myocardial infarction were lacking and the medical history was negative for major risk factors of coronary heart disease. However, electrocardiogram and troponin value were both suggestive for an acute coronary syndrome (i.e., a highly-sensitive troponin T value of 0.12 μg/L), while the echocardiogram showed hypokinesia of left ventricular apical lateral wall. The coronary angiogram performed one week after admission did not reveal the presence of coronary obstructions. It is hence assumed that high levels of COHb in blood, such as after CO exposure, may trigger myocardial injury by severe generalized tissue hypoxia (i.e., impaired oxygen delivery) and a direct toxic effect on myocardium. Contributing factors that also decrease myocardial oxygenation include inadequate myocardial perfusion and prothrombotic state. This case report suggests that increased troponin values, especially when measured with highly-sensitive immunoassays, may be observed in patients with CO poisoning, and mirror the presence of myocardial injury. Therefore, although the measurement of cardiac biomarkers may be advisable in the presence of CO toxicity to identify cardiac involvement, caution should be used when troubleshooting the underlying source of troponin elevations in order to preven t overdiagnosis or misdiagnosis of acute coronary syndrome.

Biochimica Clinica 2013; 37(3) 246-249
Casi Clinici - Case Report
Per favore, non dimentichiamo le crioglobuline
Please, do not forget cryoglobulins
R. Cesati  |  S. Besana  |  P. Tramacere  | 
Biochimica Clinica 2013; 37(3) 250-251
Lettere all'Editore - Letters to the Editor
Un aggiornamento sulle attività del Comitato “Reference systems for enzymes” (C-RSE) dell’IFCC
An update on the activities of IFCC Committee of “Reference systems for enzymes” (C-RSE)
F. Ceriotti  | 
Biochimica Clinica 2013; 37(3) 252
Notizie SIBioC - SIBioC News