Is the HSIL Subclassification Cytologically Real and Clinically Justified?

The aim of the study was to evaluate the justification of Croatian modification of Bethesda classification after thirteen years of its application, answering the question if the subclassification of high-grade squamous intraepithelial lesion (HSIL) into cervical intraepithelial lesion (CIN) grade 2 (CIN2) and grade 3 (CIN3) is cytologically real and clinically justified. The retrospective study included 3110 women to whom cervical intraepithelial lesion of different grade was diagnosed by cytological examination of vaginal-cervical-endocervical (VCE) smear at Department of Clinical Cytology, Clinical hospital Osijek in period from 1993 to 2005. 57.1% of women were monitored cytologically and colposcopically, while 42.9% of them had also pathohistological examination. The spontaneous regression of cytological finding was noted in 66.3% of the cases. Moderate dysplasia regressed more often (50.98%) than severe dysplasia (31.3%) and more rarely than mild dysplasia (70.1%), which was statistically significant (p0.05) in their biological behaviour and histological finding. In fact, 50.9% of moderate dysplasia spontaneously regressed, 14.4% persisted during follow-up, and 59.7% had a histological finding milder than CIN3. Therefore, in almost 65% of moderate dysplasia lesions it is not justified to apply the same diagnostic therapeutic procedures as for severe lesions, which means that cytological subclassification of HSIL into moderate dysplasia and severe dysplasia lesions is clinically justified. Positive predictive value of differential cytological diagnoses mild, moderate and severe dysplasia calculated in relation to histological CIN3+ statistically significantly increases for every single diagnosis, which also confirms that moderate dysplasia can be individual diagnostic category, thus the subclassification of HSIL is cytologically possible

Pap Test – With or Without Vaginal Smear?

The aim of this study was to evaluate medical and economic justification of vaginal smears as a part of primary screening for cervical carcinoma and its precursors. Study included 245.048 participants whose VCE (vaginal, cervical, endocervical) smears were examined at Department of clinical cytology of University Hospital Center Osijek from 2003 till 2008. There were 12.639 (5.2%) abnormal findings, and they were divided into three groups: abnormal cells found only in vaginal smear (V), abnormal cells found in vaginal and in at least one other smear (V+) and abnormal cells not found in vaginal smear (C/E). These three groups were analysed in respect to cytological differential diagnosis and age of participants. It was estimated how many women could be additionally included in the screening, if vaginal smear would be included in the Pap test only after 50 years of age. In 6.9% of cytologically diagnosed lesions abnormal cells were found exclusively in vaginal smears (0.35% of all findings). As for squamous cell lesions, 91.2% were mild lesions (ASC and LSIL). Invasive squamous cell carcinoma was not diagnosed exclusively by vaginal smear in either woman under 50 years of age, while in women over 50 years of age it was diagnosed in 2.3% of cases. Exclusively by vaginal smear was diagnosed 3.9% of all AGC and 6.3% of adenocarcinoma, while in 85.0% of glandular epithelium lesions abnormal cells were not found in vaginal smears. Two thirds of adenocarcinoma diagnosed exclusively by vaginal smears were endometrial adenocarcinoma, but that is only 10.3% of all endometrial carcinoma diagnosed by Pap test. Obtained results show that taking of vaginal smears along with cervical and endocervical smears as a part of primary screening for cervical carcinoma and its precursors in women under 50 years of age is not justifiable, since vaginal smear only has a role in detection of endometrial carcinoma that are extremely rare in younger age groups. If vaginal smear would be taken only in women over 50 years of age, additional 37.7% of women under 50, or 25.1% women over 50 years of age could be included in the screening

Assessment of HPV DNA Test Value in Management Women with Cytological Findings of ASC-US, CIN1 and CIN2

The aim of this retrospective study was to answer the following questions: 1) is HPV DNA test for high-risk types able to predict lesion behaviour in women with cytological abnormalities lower than CIN3 (ASC-US, CIN1 and CIN2); 2) how to predict the histological diagnosis CIN3, and 3) is its use in diagnostic management in these patients justified or not? The study included 345 women (11 ASC-US, 312 CIN1 and 22 CIN2) that underwent conventional diagnostic management (repeat cytology and colposcopy with or without histology) and HPV testing for high-risk HPV types by PCR method. The value of HPV DNA test in predicting lesion regression/persistence was assessed in 275 subjects without histology. In 70 subjects, diagnostic accuracy (sensitivity, specificity, and positive and negative predictive value) of repeat cytology and HPV DNA test in predicting severe intraepithelial lesion (CIN3) was determined on the basis of colposcopy guided biopsy. The prevalence of persistent lesions was significantly higher in the group of HPV positive than in the group of HPV negative subjects (37.7% vs. 16.4%; p<0.001). Positive HPV test was associated with a 3.1-fold risk of lesion persistence [OR (95% CI) =3.095 (1.65–5.82)]. However, on screening to predict the outcome of cytologically diagnosed cervical lesion with sensitivity of 39.7% and positive predictive value of 37.7% showed that a positive test could not be considered a reliable indicator of lesion persistence. In contrast, the specificity of 82.5% and negative predictive value of 83.6% suggested that a negative test result could be taken as a good indicator of lesion regression. In comparison with repeat cytology, HPV test showed higher sensitivity (69.2% vs. 61.5%) but significantly lower specificity (63.2% vs. 93.0%) and positive predictive value (30.0% vs. 66.7%), and comparable negative predictive value (90.0% vs. 91.4%) in predicting histologically verified CIN3. In one patient with a histological diagnosis of squamous cell carcinoma with minimal invasion, repeat cytology indicated CIN3, whereas HPV test was negative. Due to authors experience in women with cytological abnormalities lower than CIN3, HPV testing is not a method to reliably predict lesion behaviour (regression, persistence) or presence of CIN3. HPV testing is of limited value in daily routine and should not be widely used until it is definitely demonstrated to be superior to conventional methods in improving the sensitivity, specificity and positive predictive value of CIN3 and invasive carcinoma detection

Current Organisation of Clinical Cytology in Croatia

Current cytological service in Croatia is organised in 46 cytological organisational units in 23 towns with total of 350 employees: 101 specialists of clinical cytology, 20 residents in clinical cytology, 141 cytotechnologists (cytoscreeners), 45 health technicians, and 25 administrators and 18 auxiliary personnel. In spite of employment of significant number of cytotechnologists in the last ten years, there is still an unacceptable ratio of number of cytologists and cytotechnologists (1:1.4) which is the result of unresolved education of cytotechnologists which should be permanent, complete and acknowledged. Education and scientific promotion of cytologists is continuous and today our profession has 31 masters of science and 9 doctors of science, one of which is the assistant professor, and four of them are associate or full professors at medical schools in Zagreb and Osijek. Croatian cytology, in average, is in its »best years«, i.e. an average cytologist is 46 years old and cytotechnologist is averagely 43 years old, but »suffers« from personnel deficit. With regard to the type of activity, the most numerous are units dealing the entire diagnostic cytology (72%), 13% general cytology without gynaecological cytology, while 15% are engaged in one diagnostic field (gynaecological, pulmological or thyroid cytology). According to accessible data, total of 770996 cytological examinations were done in Croatia in 2008. The increasing application of additional methods (cytochemical, immunocytochemical, molecular, cytogenetics and computer-assisted image analysis) has become a trend in numerous cytological units. Exclusively morphological analysis of standard stained samples is performed in 37% of units, morphological and cytochemical staining methods are used in 17% of units, and additional immunocytochemical methods in 30% of units. According to the long tradition of cytology in Croatia, that has progressed thanks to the enthusiasm and great effort of our teachers, we believe that the following generations of cytologists will continue working on its improvement and will be able to concord the basic cytomorphology and sophisticated diagnostic procedures with other diagnostics, to stay the field of optimal results in the shortest time with the reasonable price

Interobserver Variability in Cytologic Subclassification of Squamous Intraepithelial Lesions – The Bethesda System vs. World Health Organization Classification

The aim of the study was to compare interobserver variability for The Bethesda System (TBS) and World Health Organization (WHO) classification of cervical squamous intraepithelial lesions. A total of 1,000 conventional Papanicolaou smears (156 positive and 884 negative) were examined »blindly« by three cytologists and one cytotechnician. The degree of observer agreement was expressed by kappa statistics using a program for the calculation of interobserver variation and association »Agree« (Svanholm and Jergensen, 1989). Kappa (x) was determined for each cytologic diagnosis within a particular classification and total for either classification. The association with and separation from other diagnoses was determined for each cytologic diagnosis in the form of conditional probability (Pj). In WHO classification, the diagnoses of dysplasia media and dysplasia gravis showed poor reproducibility (x=0.114 and x= 0.259, respectively), the diagnosis of dysplasia levis good reproducibility (x=0.639), and the diagnosis of carcinoma in situ excellent reproducibility (x=0.762). WHO classification yielded pool x of 0.741. In TBS classification, the diagnosis of LSIL showed good, and HSIL excellent reproducibility (x=0.542 and x=0.763, respectively). TBS classification yielded pool x of 0.699. Dysplasia media (Pj=0.121) and dysplasia gravis (Pj=0.274) were found to be morphologically poorly defined, and carcinoma in situ (Pj=0.777) and dysplasia levis (Pj=0.651) well defined diagnoses. LSIL was morphologically moderately defined (Pj=0.587) and HSIL well defined (Pj=0.789) diagnosis. Accordingly, TBS does not substantially improve diagnostic reproducibility of the cytologic diagnoses of squamous intraepithelial lesions, while providing considerably less information to the clinician than the four-grade dysplasia/CIS terminology, thus eliminating the opportunity of choosing a different procedure for the diagnosis of dysplasia media, which is of utmost importance in the population of young nulliparae

Papa test - Sa ili bez vaginalnog razmaza?

The aim of this study was to evaluate medical and economic justification of vaginal smears as a part of primary screening for cervical carcinoma and its precursors. Study included 245.048 participants whose VCE (vaginal, cervical, endocervical) smears were examined at Department of clinical cytology of University Hospital Center Osijek from 2003 till 2008. There were 12.639 (5.2%) abnormal findings, and they were divided into three groups: abnormal cells found only in vaginal smear (V), abnormal cells found in vaginal and in at least one other smear (V+) and abnormal cells not found in vaginal smear (C/E). These three groups were analysed in respect to cytological differential diagnosis and age of participants. It was estimated how many women could be additionally included in the screening, if vaginal smear would be included in the Pap test only after 50 years of age. In 6.9% of cytologically diagnosed lesions abnormal cells were found exclusively in vaginal smears (0.35% of all findings). As for squamous cell lesions, 91.2% were mild lesions (ASC and LSIL). Invasive squamous cell carcinoma was not diagnosed exclusively by vaginal smear in either woman under 50 years of age, while in women over 50 years of age it was diagnosed in 2.3% of cases. Exclusively by vaginal smear was diagnosed 3.9% of all AGC and 6.3% of adenocarcinoma, while in 85.0% of glandular epithelium lesions abnormal cells were not found in vaginal smears. Two thirds of adenocarcinoma diagnosed exclusively by vaginal smears were endometrial adenocarcinoma, but that is only 10.3% of all endometrial carcinoma diagnosed by Pap test. Obtained results show that taking of vaginal smears along with cervical and endocervical smears as a part of primary screening for cervical carcinoma and its precursors in women under 50 years of age is not justifiable, since vaginal smear only has a role in detection of endometrial carcinoma that are extremely rare in younger age groups. If vaginal smear would be taken only in women over 50 years of age, additional 37.7% of women under 50, or 25.1% women over 50 years of age could be included in the screening.Cilj ove studije bio je procijeniti medicinsku i ekonomsku opravdanost uzimanja vaginalnog razmaza u sklopu primarnog probira cervikalnog karcinoma i njegovih prekursora. U studiju je uključeno 245.408 ispitanica čiji su VCE (vaginalni, cervikalni, endocervikalni) razmazi bili pregledani na Odjelu za kliničku citologiju Kliničkog bolničkog centra Osijek od 2003. do 2008. godine. Abnormalnih je nalaza bilo 12.639 (5,2%), a podijeljeni su u tri skupine: abnormalne stanice nađene samo u vaginalnom razmazu (V), abnormalne stanice nađene u vaginalnom i bar u još jednom razmazu (V+) i abnormalne stanice nisu nađene u vaginalnom razmazu (C/E). Te su tri skupine analizirane u odnosu na citološku diferencijalnu dijagnozu i životnu dob ispitanica. Procijenjeno je koliko bi se `ena moglo dodatno obuhvatiti probirom ukoliko bi se vaginalni razmaz uključio u PAPA test tek nakon pedesete godine života. U 6,9% citološki dijagnosticiranih lezija abnormalne su stanice nađene isključivo u vaginalnim razmazima (0,35% svih nalaza). Kod lezija pločastog epitela u 91,2% slučajeva radilo se o lakšim lezijama (ASC i LSIL). Invazivni pločasti karcinom isključivo vaginalnim razmazom nije dijagnosticiran niti u jedne žene mlađe od 50 godina, dok je u žena starijih od 50 godina dijagnosticiran u 2,3% slučajeva. Isključivo vaginalnim razmazom otkriveno je 3,9% svih AGC i 6,3% adenokarcinoma, dok kod 85,0% lezija žljezdanog epitela abnormalne stanice nisu nađene u vaginalnim razmazima. Dvije trećine adenokarcinoma dijagnosticiranih isključivo vaginalnim razmazom čini adenokarcinom endometrija, no to je samo 10,3% svih PAPA testom dijagnosticiranih endometralnih karcinoma. Iz navedenih se rezultata može zaključiti da čenama mlađim od pedeset godina nema opravdanja uz cervikalni i endocervikalni uzeti i vaginalni razmaz u sklopu primarnog probira cervikalnog karcinoma i njegovih prekursora, budući da vaginalni razmaz ima ulogu jedino u detekciji endometralnih karcinoma koji su u mlađim dobnim skupinama izuzetno rijetki. Ukoliko bi se vaginalni razmaz uzimao samo ženama starijim od 50 godina moglo bi se dodatno pregledati još 37,7% žena mlađih od 50 godina, ili 25,1% žena starijih od 50 godina

Interobserver varijabilnost u citološkoj subklasifikaciji skvamoznih intraepitelnih lezija

The aim of the study was to compare interobserver variability for The Bethesda System (TBS) and World Health Organization (WHO) classification of cervical squamous intraepithelial lesions. A total of 1,000 conventional Papanicolaou smears (156 positive and 884 negative) were examined »blindly« by three cytologists and one cytotechnician. The degree of observer agreement was expressed by kappa statistics using a program for the calculation of interobserver variation and association »Agree« (Svanholm and Jergensen, 1989). Kappa (x) was determined for each cytologic diagnosis within a particular classification and total for either classification. The association with and separation from other diagnoses was determined for each cytologic diagnosis in the form of conditional probability (Pj). In WHO classification, the diagnoses of dysplasia media and dysplasia gravis showed poor reproducibility (x=0.114 and x= 0.259, respectively), the diagnosis of dysplasia levis good reproducibility (x=0.639), and the diagnosis of carcinoma in situ excellent reproducibility (x=0.762). WHO classification yielded pool x of 0.741. In TBS classification, the diagnosis of LSIL showed good, and HSIL excellent reproducibility (x=0.542 and x=0.763, respectively). TBS classification yielded pool x of 0.699. Dysplasia media (Pj=0.121) and dysplasia gravis (Pj=0.274) were found to be morphologically poorly defined, and carcinoma in situ (Pj=0.777) and dysplasia levis (Pj=0.651) well defined diagnoses. LSIL was morphologically moderately defined (Pj=0.587) and HSIL well defined (Pj=0.789) diagnosis. Accordingly, TBS does not substantially improve diagnostic reproducibility of the cytologic diagnoses of squamous intraepithelial lesions, while providing considerably less information to the clinician than the four-grade dysplasia/CIS terminology, thus eliminating the opportunity of choosing a different procedure for the diagnosis of dysplasia media, which is of utmost importance in the population of young nulliparae.Cilj rada je bio usporediti interobserver varijabilnost za The Bethesda System (TBS) i World Health Organization (WHO) klasifikaciju skvamoznih intraepitelnih lezija cerviksa uterusa. Set od 1000 konvencionalnih Papa razmaza (156 pozitivnih i 884 negativnih) »na slijepo« su pregledala 3 citologa i jedan citotehničar. Stupanj slaganja je izražen kappa statistikom pomoću programa za računanje interobserver varijacija i asocijacija »Agree« (Svanholm i Jergensen, 1989.). Weighted je određen za svaku citološku dijagnozu unutar klasifikacije, kao i za klasifikacije u cijelosti. Za svaku citološku dijagnozu je određena povezanost, odnosno razgraničenost s drugim dijagnozama u obliku uvjetne vjerojatnosti (Pj). Kod WHO klasifikacije su slabo reproducibilne dijagnoze dysplasia media (=0,114) i dysplasia gravis (=0,259), prilično dobro je reproducibilna dijagnoza dysplasia levis (=0,639), a odlično je reproducibilna dijagnoza carcinoma in situ (=0,762). Za klasifikaciju u cijelosti je 0,741. Kod TBS klasifikacije LSIL je prilično dobro reproducibilna dijagnoza (=0,542), dok je HSIL odlično reproducibilna dijagnoza (=0,763). Za klasifikaciju u cijelosti je 0,699. Dysplasia media (P=0,121) i dysplasia gravis (Pj=0,274) su morfološki slabo definirane dijagnoze, carcinoma in situ (Pj=0,777) i dysplasia levis (Pj=0,651) su dobro definirane dijagnoze. LSIL (Pj=0,587) je morfološki srednje definirana dijagnoza, dok je HSIL (Pj=0,789) dobro definirana dijagnoza.TBS ne popravlja bitno dijagnostičku reproducibilnost citoloških dijagnoza za skvamozne intraepitelne lezije, a kliničaru daje znatno manje informacija nego četverodijelna dysplasia / CIS terminologija i time oduzima mogućnost različitog postupka za dijagnozu dysplasia media što je osobito važno za populaciju mladih nulipara i trudnica