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Objective: This study aims to analyze the role of artificial neural networks (ANNs) in cytopathology. More specifically, it aims to highlight the importance of employing ANNs in existing and future applications and in identifying unexplored or poorly explored research topics., Study Design: A systematic search was conducted in scientific databases for articles related to cytopathology and ANNs with respect to anatomical places of the human body where cytopathology is performed. For each anatomic system/organ, the major outcomes described in the scientific literature are presented and the most important aspects are highlighted., Results: The vast majority of ANN applications are related to cervical cytopathology, specifically for the ANN-based, semiautomated commercial diagnostic system PAPNET. For cervical cytopathology, there is a plethora of studies relevant to the diagnostic accuracy; in addition, there are also efforts evaluating cost-effectiveness and applications on primary, secondary, or hybrid screening. For the rest of the anatomical sites, such as the gastrointestinal system, thyroid gland, urinary tract, and breast, there are significantly less efforts relevant to the application of ANNs. Additionally, there are still anatomical systems for which ANNs have never been applied on their cytological material., Conclusions: Cytopathology is an ideal discipline to apply ANNs. In general, diagnosis is performed by experts via the light microscope. However, this approach introduces subjectivity, because this is not a universal and objective measurement process. This has resulted in the existence of a gray zone between normal and pathological cases. From the analysis of related articles, it is obvious that there is a need to perform more thorough analyses, using extensive number of cases and particularly for the nonexplored organs. Efforts to apply such systems within the laboratory test environment are required for their future uptake.

Fine-needle aspiration (FNA) cytology is an important diagnostic tool in patients with thyroid lesions. Several systems have been proposed for the cyropathologic diagnosis of the thyroid nodules. However cases with indeterminate cytological findings still remain a matter of debate. In this review we analyze all literature regarding Thyroid Cytopathology Reporting systems trying to identify the most suitable methodology to use in clinical practice for the preoperative diagnosis of thyroid nodules. A review of the English literature was conducted, and data were analyzed and summarized and integrated from the authors' perspective. The main purpose of thyroid FNA is to identify patients with higher risk for malignancy, and to prevent unnecessary surgeries for benign conditions. The Bethesda System for Reporting Thyroid Cytopathology is the most widely used system for the diagnosis of thyroid FNA specimens. This system also contains guidelines for the diagnosis and treatment of indeterminate or suspicious for malignancy cases. In conclusion, patients who require repeated FNAs for indeterminate diagnoses will be resolved by repeat FNA in a percentage of 72%-80%.

Unlabelled: Prolactinomas constitute the largest subsection of all secretory pituitary adenomas. Most are microprolactinomas and are satisfactorily treated by medical management alone. Giant prolactinomas, measuring more than 4 cm in diameter, are rare and usually occur more commonly in men. Macroprolatinomas tend to present with symptoms of mass effect rather than those of hyperprolactinaemia. Dopamine agonists (DA) are the treatment of choice for all prolactinomas. Surgery is usually reserved for DA resistance or if vision is threatened by the mass effects of the tumour. We describe the case of a 52 year-old woman with a giant invasive prolactinoma who required multiple surgical procedures as well as medical management with DA. One of the surgical interventions required a posterior approach via the trans cranial sub occipital transtentorial approach, a surgical technique that has not been previously described in the medical literature for this indication. The giant prolactinoma was reduced significantly with the above approach and patient symptoms from the compressing effects of the tumour were resolved. This case highlights the importance of a multidisciplinary approach to the management of such patients who present with florid neurological sequelae secondary to pressure effects. Although this presentation is uncommon, surgery via a sub occipital transtentorial approach may be considered the treatment of choice in suitable patients with giant invasive prolactinomas compressing the brainstem., Learning Points: Giant prolactinomas present with symptoms of mass effect or those of hyperprolactinaemia.Interpretation of the pituitary profile is crucial to guide further investigations and management.Treatment of giant invasive prolactinomas may involve a combination of medical management and multiple surgical interventions.Treatment with DA may cause pituitary haemorrhage or infarction in patients with these tumours.A sub occipital transtetorial approach may be considered the treatment of choice in invasive prolactinomas compressing the brainstem.Multidisciplinary approach of such patients is fundamental for a better outcome.

Endometrial cancer is the most common malignancy of the female genital tract while aberrant DNA methylation seems to play a critical role in endometrial carcinogenesis. Galanin's expression has been involved in many cancers. We developed a new pyrosequencing assay that quantifies DNA methylation of galanin's receptor-1 (GALR1). In this study, the preliminary results indicate that pyrosequencing methylation analysis of GALR1 promoter can be a useful ancillary marker to cytology as the histological status can successfully predict. This marker has the potential to lead towards better management of women with endometrial lesions and eventually reduce unnecessary interventions. In addition it can provide early warning for women with negative cytological result.

Objective: To investigate the potential of a computerized system for the discrimination of benign from malignant endometrial nuclei and lesions., Study Design: A total of 228 histologically confirmed liquid-based cytological smears were collected: 117 within normal limits cases, 66 malignant cases, 37 hyperplasias without atypia, and 8 cases of hyperplasia with atypia. From each case we extracted nuclear morphometric features from about 100 nuclei using a custom image analysis system. Initially we performed feature selection, and subsequently we applied a logistic regression model that classified each nucleus as benign or malignant. Based on the results of the nucleus classification process, we constructed an algorithm to discriminate endometrium cases as benign or malignant., Results: The proposed system had an overall accuracy for the classification of endometrial nuclei equal to 83.02%, specificity of 85.09%, and sensitivity of 77.01%. For the case classification the overall accuracy was 92.98%, specificity was 92.86%, and sensitivity was 93.24%., Conclusion: The proposed computerized system can be applied for the classification of endometrial nuclei and lesions as it outperformed the standard cytological diagnosis. This study highlights interesting diagnostic features of endometrial nuclear morphology, and the proposed method can be a useful tool in the everyday practice of the cytological laboratory.

Occurrence of malignancy in a thyroglossal duct cyst (TDC) in children and adolescents is very rare, preoperative diagnosis is a challenge, and appropriate management is still debated. We report a 19-year-old male patient referred for a midline neck mass diagnosed as an atypical TDC after initial and subsequent investigations. Ultrasound-guided fine-needle aspiration (FNA) of the mass was diagnostic for papillary thyroid carcinoma. Sistrunk procedure and total thyroidectomy were performed. Histologic analysis confirmed the presence of papillary thyroid carcinoma within TDC, infiltrating surrounding soft tissues. Postoperatively, radioiodine ablation treatment was administered, followed by TSH suppression therapy.

'The objective of this study is to investigate the potential of classification and regression trees (CARTs) in discriminating benign from malignant endometrial nuclei and lesions. The study was performed on 222 histologically confirmed liquid based cytological smears, specifically: 117 benign cases, 62 malignant cases and 43 hyperplasias with or without atypia. About 100 nuclei were measured from each case using an image analysis system; in total, we collected 22783 nuclei. The nuclei from 50% of the cases (the training set) were used to construct a CART model that was used for knowledge extraction. The nuclei from the remaining 50% of cases (test set) were used to evaluate the stability and performance of the CART on unknown data. Based on the results of the CART for nuclei classification, we propose two classification methods to discriminate benign from malignant cases. The CART model had an overall accuracy for the classification of endometrial nuclei equal to 85%, specificity 90.68%, and sensitivity 72.05%. Both methods for case classification had similar performance: overall accuracy in the range 94-95%, specificity 95%, and sensitivity 91-94%. The results of the proposed system outperform the standard cytological diagnosis of endometrial lesions. This study highlights interesting diagnostic features of endometrial nuclear morphology and provides a new classification approach for endometrial nuclei and cases. The proposed method can be a useful tool for the everyday practice of the cytological laboratory., (© 2013 Wiley Periodicals, Inc.)

Unlabelled: A 56-year-old man was brought to the Emergency Department after being found collapsed at his office with a reduced level of consciousness. From clinical examination and initial investigations, he was diagnosed as having bacterial meningitis and was promptly commenced on empirical i.v. antibiotics. Computed tomography of the brain revealed a parenchymal mass at the base of the skull and subsequent magnetic resonance imaging of the head 4 days later confirmed a large soft tissue mass, which extended through to the cavernous sinus. Examination of the cerebrospinal fluid (CSF) following lumbar puncture confirmed pneumococcal meningitis and antibiotics were continued for 2 weeks in total. During the admission, hormone profiling revealed a grossly elevated prolactin. When coupled with the initial results of the brain imaging, this result helped to confirm a macroprolactinoma that was invading the postnasal space. A final diagnosis of pneumococcal meningitis secondary to invading prolactinoma was made. The patient was started on cabergoline and was followed up in the outpatient clinic upon discharge. He made a full recovery from the meningitis. Over the next few months, prolactin levels returned to be normal and the prolactinoma shrank significantly in size. The patient remains on cabergoline that will most likely be continued indefinitely., Learning Points: Bacterial meningitis is a rare first presentation of pituitary macroprolactinoma.Patients with invasive macroprolactinoma do not always present with CSF leakage.Prompt treatment with antibiotics and a dopamine agonist is of great importance for a favourable outcome.Close monitoring of the patient for signs of raised intracranial pressure is essential in the management of macroprolactinoma.Note the risk of CSF leakage after initiation of dopamine agonist therapy irrespective of concomitant meningitis in macroprolactinoma.

Nowadays, there are molecular biology techniques providing information related to cervical cancer and its cause: the human Papillomavirus (HPV), including DNA microarrays identifying HPV subtypes, mRNA techniques such as nucleic acid based amplification or flow cytometry identifying E6/E7 oncogenes, and immunocytochemistry techniques such as overexpression of p16. Each one of these techniques has its own performance, limitations and advantages, thus a combinatorial approach via computational intelligence methods could exploit the benefits of each method and produce more accurate results. In this article we propose a clinical decision support system (CDSS), composed by artificial neural networks, intelligently combining the results of classic and ancillary techniques for diagnostic accuracy improvement. We evaluated this method on 740 cases with complete series of cytological assessment, molecular tests, and colposcopy examination. The CDSS demonstrated high sensitivity (89.4%), high specificity (97.1%), high positive predictive value (89.4%), and high negative predictive value (97.1%), for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In comparison to the tests involved in this study and their combinations, the CDSS produced the most balanced results in terms of sensitivity, specificity, PPV, and NPV. The proposed system may reduce the referral rate for colposcopy and guide personalised management and therapeutic interventions.

Unlabelled: The present review aims at providing an assessment of the clinical significance of Biphosphonates (BPs) in the treatment of patients with cancer., Materials and Methods: A systematic literature review was performed based on database search in PubMed/Medline and included articles up to August 2013., Results: BPs can reduce, delay, and prevent complications related to bone metastases. They improve mobility, functionality, pain, and quality of life. They limit survival of any inactive cancer cells in the microenvironment of the bone marrow, contributing to their death from anti-neoplastic treatments. Moreover, they limit and delay bone morbidity due to osteoporosis related to hormonotherapy in breast and prostate cancer. Finally, benefits can be derived from the combination of BPs with radiotherapy in bone density, recalcification, opioid use, and patient's quality of life and performance status., Conclusion: The contribution of BPs in the course of certain neoplasms is preventive and synergistic to other treatments.

Purpose: The aim of the current study was to compare the immunocytochemical expression of ki-67, HER-2 and p53 on ThinPrep (TP)-processed smears, obtained by preoperative fine-needle aspiration (FNA) biopsies from primary breast carcinoma with the immunohistochemical results obtained on the corresponding surgical samples., Methods: FNA biopsies were collected from 119 female patients during a 31-month period. Subsequently, these patients underwent surgical resection of the tumors., Results: The overall accuracy (OA) of the TP cytology for ki-67, p53 and HER-2 expression was 96, 99 and 97%, respectively. There was a strong positive correlation between immunohistochemistry and immunocytochemistry results for ki-67 (Spearman's test 0.875) for p53 (Cramer's phi test 0.965) and HER-2 (Kendall's tau test 0.891)., Conclusion: This pilot study demonstrates that it is possible to monitor multiple molecular markers by using the TP cytology. Sample collection and storage is simple and permits the assortment of the FNA sample for both morphologic diagnosis and ancillary studies. The accuracy of TP technique in the evaluation of ki-67, p53 and HER-2 expression is comparable to those of the histological evaluation, and could be of paramount importance for the preoperative planning of treatment.

Objective: This study evaluated the accuracy and reproducibility of telecytological diagnoses proffered on the basis of digitized images from cervical smears prepared by means of liquid-based cytology., Materials and Methods: Representative digital cytological images from a total of 404 cervical smears (benign, 135; atypical squamous cells of undetermined significance, 92; low-grade squamous intraepithelial lesion, 62; high-grade squamous intraepithelial lesion, 87; squamous cell carcinoma, 26; and adenocarcinoma, 2) were uploaded to the CytoTrainer e-learning telecytology platform (developed in the Department of Cytopathology, "ATTIKON" University General Hospital, Athens, Greece) with specific password-protected accounts and were reviewed remotely by four independent board-certified cytopathologists (checking round). Their reports were recorded and classified. After 12 and 24 months, the same representative digital images were transferred in random order to the same cytopathologists and were reviewed again (first and second review rounds, respectively). The cytopathologists' first and second round diagnoses were recorded and compared with their initial ones., Results: Statistical evaluation of cytological diagnoses detected no significant difference in diagnostic accuracy among checking and review diagnoses. The overall interobserver agreement was almost perfect with κ values of 0.79-0.97, whereas intraobserver agreement ranged from almost perfect to perfect with κ values of 0.76-1 in all diagnostic rounds., Conclusions: Digital images of cervical smears can be used for rapid and accurate diagnosis, by diminishing turnaround times and improving small cytology departments' quality indices. Diagnoses made by using static telecytological systems can be as reliable as those made by using conventional microscopy, under the conditions that representative images are taken and that standard cytological diagnostic criteria are applied. Telecytology can be used as an alternative method for the cytologic diagnosis of cervical smears, particularly in quality assurance programs.

Objective: To investigate capability of combination of learning vector quantizer (LVQ) neural networks (NNs) in discrimination of benign from malignant thyroid lesions., Study Design: The study included 335 liquid-based cytology, fine needle aspiration (FNA), Papanicolaou-stained specimens. All cases were compared to the histologic diagnosis. Features describing size, shape, and texture of -100 nuclei per case were extracted from cytologic images using a custom image analysis system. These features were used to classify each nucleus by LVQ type NNs. The nucleus classification results were used to classify individual lesions with a second LVQ NN. Cases were distributed by histologic diagnosis. Data from -50% from each category were used for training LVQ classifiers. Remaining data were used to test classifier performance. The system was used to discriminate to individual cellular level and individual patient level between benign and malignant nuclei., Results: Application of the proposed algorithm combining two LVQ NNs allows discrimination between benign and malignant cell nuclei and lesions., Conclusion: Results indicate that use of NNs, combined with image morphometry, can provide information on thyroid lesion malignancy potential. The system could improve FNA diagnostic accuracy of the thyroid gland, especially in follicular neoplasms suspicious for malignancy and in Hürthle cell tumors.

Aim: To measure the dose distribution, related to the treatment planning calculations, in the contralateral mammary gland of breast cancer patients treated with accelerated hypofractionated 3-dimensional conformal radiotherapy., Methods: Thirty-four prospectively selected female patients with right breast cancer (pN0, negative surgical margins) were treated with breast-conserving surgery. A total dose of 42.5 Gy (2.66 Gy/fraction) was prescribed; it was requested that planning target volumes be covered by the 95% isodose line. The contralateral mammary gland was defined on CT simulation. The dose received was evaluated by dose volume histograms., Results: The measured contralateral breast doses were: (1) Dose maximum: 290-448 cGy [Equivalent (Eq) 337-522 cGy]; (2) Mean dose: 45-70 cGy (Eq 524-815 cGy); and (3) Median dose: 29-47 cGy (337-547 cGy) for total primary breast dose of 42.5 Gy in 16 equal fractions. The spearman rho correlation showed statistical significance between the contralateral breast volume and maximum dose (P = 0.0292), as well as mean dose (P = 0.0025) and median dose (P = 0.046) to the breast., Conclusion: Minimizing the dose to the contralateral breast has to be one of the priorities of the radiation oncologist when using short schedules because of the radiosensitivity of this organ at risk. Further study is necessary to assess the long-term clinical impact of this schedule.

Objective: To investigate the potential value of tree classifiers for the triage of high-grade squamous intraepithelial lesions., Study Design: The dataset comprised 808 histologically confirmed cases having a complete range of the cytologic sample assessments--liquid-based cytology, reflex human papillomavirus (HPV) DNA test, E6/E7 HPV mRNA test, and p16 immunocytochemical examinations. Data include 488 histologically negative (cervical intraepithelial neoplasia [CIN] 1 and below) or clinically negative cases and 320 with histologic diagnosis of CIN 2 or worse. Cytologic diagnosis was made according to the criteria of the Bethesda System. Cases were classified in two groups according to histology: those with CIN 2 or worse and those with CIN 1 and below. Fifty percent were randomly selected as a training set and the remaining were as a test set., Results: Application of tree classifier on the test set gave correct classification of 66.9% for CIN 2 and above cases and 97.3% for CIN 1 and below, producing overall accuracy of 91.5%, outperforming cytologic diagnosis alone., Conclusion: Application of tree classifiers, based on standard cytologic diagnosis and expression of studied biomarkers, produces improved classification results for cervical precancerous lesions and cancer diagnosis and

Nucleic acids of human papillomavirus (HPV) isolated by manual extraction method (AmpliLute) and automated MagNA pure system were compared and evaluated with cytohistological findings in 253 women. The concordance level between AmpliLute and MagNA was very good 93.3% (κ = 0.864, P < .0001). Overall HPVpositivity detected by AmpliLute was 57.3% (30.4% as single and 27% as multiple infections) in contrast to MagNA 54.5% (32% and 23%, resp.). Discrepant results observed in 25 cases: 11 MagNA(-)/AmpliLute(+), 10 of which had positive histology; 5 MagNA(+)/AmpliLute(-) with negative histology; 8 MagNA(+)/AmpliLute(+): in 7 of which AmpliLute detected extra HPV genotypes and 1 MagNA(invalid)/AmpliLute(+) with positive histology. Both methods performed well when compared against cytological (area under curve (AUC) of AmpliLute 0.712 versus 0.672 of MagNA) and histological diagnoses (AUC of AmpliLute 0.935 versus 0.877 of MagNA), with AmpliLute showing a slightly predominance over MagNA. However, higher sensitivities, specificities, and positive/negative predictive values were obtained by AmpliLute.

Background: Cervical cancer is the second most common cancer in women worldwide comprising a major concern of public health. Liquid-based cytology provides significantly more effective detection of low-grade intraepithelial neoplasia or more severe lesions, without loss of diagnostic specificity and reduces the number of cases classified as unsatisfactory. The objective of the study is the evaluation of flow cytometry as a rapid tool for quality control of the liquid specimen adequacy for the purpose of precise cytological diagnosis in detecting cervical abnormalities., Methods: A total of 1,854 women undergoing routine cervical cytology joined this cohort study. A monolayer smear was prepared and 1 ml aliquot was removed and prepared for flow cytometric analysis. Cells were fixed and run on a Partec CyFlow SL, with front scatter (FSS) and side scatter (SSC) set on logarithmic scale. The forward scatter versus side scatter dot-plot was used for the distinction of ectocervical, endocervical, and polymorphonuclear cells., Results: In the total of 1,854 cases, 15 specimens (0.8%) were characterized by the cytopathologist as unsatisfactory. Inadequacy was confirmed by flow cytometric analysis for four samples. Monolayer smears were reprepared for the remaining 11 samples. After the second microscopic observation, six out of the 11 cases (54.5%) were found to be satisfactory, whereas the remaining five were still designated as unsatisfactory by the cytopathologist., Conclusion: The parallel screening of adequacy by quantification of cell populations with flow cytometry can serve as an internal control for diagnosis and can overall decrease the number of unsatisfactory samples.

Background: The evolution of information technologies and telecommunications has made the World Wide Web a low cost and easily accessible tool for the dissemination of information and knowledge. Continuous Medical Education (CME) sites dedicated in cytopathology field are rather poor, they do not succeed in following the constant changes and lack the ability of providing cytopathologists with a dynamic learning environment, adaptable to the development of cytopathology. Learning methods including skills such as decision making, reasoning and problem solving are critical in the development of such a learning environment., Objectives: The objectives of this study are (1) to demonstrate on the basis of a web-based training system the successful application of traditional learning theories and methods and (2) to effectively evaluate users' perception towards the educational program, using a combination of observers, theories and methods., Implementation: Trainees are given the opportunity to browse through the educational material, collaborate in synchronous and asynchronous mode, practice their skills through problems and tasks and test their knowledge using the self-evaluation tool. On the other hand, the trainers are responsible for editing learning material, attending students' progress and organizing the problem-based and task-based scenarios. The implementation of the web-based training system is based on the three-tier architecture and uses an Apache Tomcat web server and a MySQL database server., Methods: By December 2008, CytoTrainer's learning environment contains two courses in cytopathology: Gynaecological Cytology and Thyroid Cytology offering about 2000 digital images and 20 case sessions. Our evaluation method is a combination of both qualitative and quantitative approaches to explore how the various parts of the system and students' attitudes work together., Results: Trainees approved of the course's content, methodology and learning activities. The triangulation of evaluation methods revealed that the training program is suitable for the continuous distance education in cytopathology and that it has improved the trainees' skills in diagnostic cytopathology., Conclusions: The web-based training system can be successfully involved in the continuous distance education in cytopathology. It provides the opportunity to access learning material from any place at any time and supports the acquisition of diagnostic knowledge.