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

Klinička praksa hrvatskih urologa i usklađenost sa smjernicama u liječenju simptoma donjeg mokraćnog trakta u muškaraca

The aim of this study was to assess the Croatian urologists’ management of non-neurogenic male lower urinary tract symptoms (LUTS) and their compliance with the European Association of Urology (EAU) guidelines. A cross-sectional survey included 51/179 Croatian urologists. We developed a questionnaire with questions addressing compliance with EAU guidelines. The rate of performing recommended evaluations on the initial assessment of patients with benign prostate hyperplasia (BPH)/LUTS varied from 8.0% (serum creatinine and voiding diary) to 100.0% (physical examination, prostate specific antigen and ultrasound). The international prostate symptom score was performed by 31%, analysis of urine sediment by 83%, urine culture by 53%, and serum creatinine by 8% of surveyed urologists. Only 8% of urologists regularly used bladder diary in patients with symptoms of nocturia. Our results indicated that 97% of urologists preferred alpha blockers as the first choice of treatment; 5-alpha reductase inhibitors (5ARI) were mostly prescribed (84%) in combination with an alpha-blocker, preferably as a continuous treatment, whilst 29% of urologists used to discontinue 5ARI after 1-2 years. Half of the Croatian urologists used antimuscarinics in the treatment of BPH/LUTS and recommended phytotherapeutic drugs in their practice. In conclusion, Croatian urologists do not completely comply with the guidelines available.Cilj ovoga istraživanja bio je uvrditi kliničku praksu hrvatskih urologa u pristupu bolesnicima sa simptomima donjeg mokraćnog trakta (LUTS) i njihovo pridržavanje Smjernica Europskoga urološkog društva (EAU). Provedeno je presječno istraživanje među 51/179 (28%) hrvatskih urologa. Izradili smo upitnik koji sadrži pitanja glede poštivanja smjernica EAU. Primjena preporučenih pretraga u početnoj procjeni bolesnika s benignom hiperplazijom prostate (BPH)/LUTS varirala je od 8,0% (kreatinin i dnevnik mokrenja) do 100,0% (fizikalni pregled, antigen specifičan za prostatu (PSA) i ultrazvuk). U početnoj procjeni bolesnika s BPH/LUTS uz anamnezu i digitorektalni pregled hrvatski urolozi primjenjuju još PSA i ultrazvuk (100%). Međunarodni zbroj prostatičnih simptoma (IPSS) primjenjuje 31%, analizu sedimenta mokraće 83%, kulturu mokraće 53%, a serumski kreatinin 8% ispitanih urologa. Samo 8% urologa redovito koristi dnevnik mokrenja kod bolesnika sa simptomima nokturije. Rezultati su pokazali kako 62% hrvatskih urologa smatra da provodi dijagnostičku obradu koja je u skladu sa smjernicama EAU. U terapijskom pogledu rezultati pokazuju da 97% urologa smatra alfa blokatore lijekom prvog izbora. Inhibitori 5-alfa reduktaze (5ARI) uglavnom (84%) su propisani u kombinaciji s alfa-blokatorima, ponajprije kao kontinuirano liječenje, dok 29% prekida 5ARI nakon 1-2 godine. Polovica hrvatskih urologa rabi antimuskarinike u liječenju BPH/LUTS i preporučuje fitoterapiju u svojoj praksi. Praksa hrvatskih urologa nije u potpunosti usklađena sa smjernicama

Impact of positive surgical margins after radical prostatectomy on disease progression and adjuvant treatment in pathologically localized prostate cancer

The aim of our study was to evaluate the impact of margin positivity in clinically and pathologically localized prostate cancer (pT2) after radical prostatectomy on biochemical recurrence and time to adjuvant treatment. We analyzed data from 371 patients who underwent radical prostatectomy. At the mean follow up of 36 (25-54) months, impact of margin positivity in pT2 patients on prostate specific antigen (PSA) recurrence and time to introduction of adjuvant treatment was noted. Out of 371 radical prostatectomies there were 277 (74.6%) pT2 and 94 (25.4%) pT3 (locally advanced) prostate cancers. Mean age was 67.6 years, mean Gleason score 6.78, mean preoperative PSA 11.45 ng/mL. Out of 277 pT2 pts., 233 (84%) had negative (SM-) and 44 (16%) positive surgical margins (SM+). Only 3% of SM- pts. had biochemical relapse (BCR). Among pT2 patients with SM+, 18 (41%) had BCR while 26 were free of recurrence at 3 years follow up. Positive surgical margins had an adverse impact on biochemical progression free survival (3% SM- vs. 41% SM+; p<0,001). No difference was found in age, preoperative PSA, Gleason score or follow up between BCR-SM+ and BCR+SM+ patients. Mean time to PSA recurrence in surgical margin positive pT2 patients was 15.7 months. Surgical margin status pT2 disease has an impact on biochemical progression but only 41% of margine positive patients show biochemical recurrence at 3 yr follow up. Not all SM+ patients need to receive treatment after radical prostatectomy. Longer follow up should be awaited to see the impact on overall survival in this group of patients

Potential Value and Disadvantages of Fine Needle Aspiration Cytology in Diagnosis of Ameloblastoma

Ameloblastoma is a benign, slow growing but locally aggressive tumor that is clinically manifested as swelling in a jaws1. Prone to relapse (30%)2 even 30 years after inadequate primary operation3. The most important cytological features of this tumor are small bazaloid cells in clusters, and single spindle and stellate shaped cells. We report on a case of 79-year-old patient, who was hospitalized due to tumor formation in the buccal region. FNA was performed and liquid material that contained only fagocites was collected. The conclusion was – cyst, while biopsy finding – adenoma baseocellulare, pointed to the salivary gland tumor. Patient refused the proposed surgical treatment. Four years later, the patient was urgently hospitalized due heavy bleeding from the tumor in the same region. It affected the crest portion of the upper jaw and a section of hard palate, and was bleeding on palpation.In second FNA we found phagocytes and a few small clusters of basaloid cells with palisade arrangement at the edges. Because of uniform and benign cytomorphological features it was concluded that it was a cystic tumor. On biopsy pattern the diagnose of ameloblastoma was determinated. The patient underwent surgery, however due to postoperative complications he died. Preoperative diagnosis is usually set on the basis of clinical and often nonspecific radiological findings. As it is very important to get the correct diagnose before planning an adequate surgical procedure, we would like to point out the potential value and disadvantages of FNA cytology in the diagnosis of ameloblastoma

Impact of positive surgical margins after radical prostatectomy on disease progression and adjuvant treatment in pathologically localized prostate cancer

The aim of our study was to evaluate the impact of margin positivity in clinically and pathologically localized prostate cancer (pT2) after radical prostatectomy on biochemical recurrence and time to adjuvant treatment. We analyzed data from 371 patients who underwent radical prostatectomy. At the mean follow up of 36 (25-54) months, impact of margin positivity in pT2 patients on prostate specific antigen (PSA) recurrence and time to introduction of adjuvant treatment was noted. Out of 371 radical prostatectomies there were 277 (74.6%) pT2 and 94 (25.4%) pT3 (locally advanced) prostate cancers. Mean age was 67.6 years, mean Gleason score 6.78, mean preoperative PSA 11.45 ng/mL. Out of 277 pT2 pts., 233 (84%) had negative (SM-) and 44 (16%) positive surgical margins (SM+). Only 3% of SM- pts. had biochemical relapse (BCR). Among pT2 patients with SM+, 18 (41%) had BCR while 26 were free of recurrence at 3 years follow up. Positive surgical margins had an adverse impact on biochemical progression free survival (3% SM- vs. 41% SM+; p<0,001). No difference was found in age, preoperative PSA, Gleason score or follow up between BCR-SM+ and BCR+SM+ patients. Mean time to PSA recurrence in surgical margin positive pT2 patients was 15.7 months. Surgical margin status pT2 disease has an impact on biochemical progression but only 41% of margine positive patients show biochemical recurrence at 3 yr follow up. Not all SM+ patients need to receive treatment after radical prostatectomy. Longer follow up should be awaited to see the impact on overall survival in this group of patients

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

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

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

Does cytological laboratory hold the responsibility for the low sensitivity of the Pap test in detecting endometrial cancer?

Endometrial cancer is the most common gynecological cancer but there is no economically justified screening method. Although we can detect endometrial cells in the sample using PAP test, many studies show low sensitivity and positive predictive value of PAP test for the diagnosis of endometrial cancer. The goal of this research was to determine significance of PAP test for the diagnostics of endometrial carcinoma. Sensitivity and specificity were analyzed with statistical parameters. VCE (vaginal, cervical, endocervical) smears of patients with histologically proven endometrial carcinoma were re-examined in order to determine the proportion of false negative results for endometrial cancer cells in the VCE samples. Study group consisted of all consecutive patients with PAP test performed at the Department of Clinical Cytology of the University Hospital Osijek from 2002. until the end of 2014. There was one inclusion criteria: subsequent hysterectomy or curettage within the six month after the PAP test, regardless of histological finding. From a total of 263 patients with previous PAP test and histologically proven endometrial cancer, endometrial cancer was cytologicaly diagnosed in 24.7% (including suspicious and positive findings), while 66.2% patients had normal cytological findings. The diagnostic value of PAP test in detection of endometrial cancer was statistically revealed with 25% sensitivity and 99% specificity. To determine false negative rate VCE samples were reviewed for patients with histologically proven endometrial cancer and negative VCE findings. There were a total of five negative results. In one case revision did not changed the original negative diagnosis, but benign endometrial cells, a lot of blood and inadequate cytohormonal status were found. In three out of four reviewed samples there were missed cells of endometrial adenocarcinoma. Review of remaining VCE sample upgraded the diagnosis from negative to suspicious for endometrial cancer. Proportion of error in the detection of endometrial cancer using cytological findings was 3.4% (true false negatives). Negative rate of the cytological findings in the detection of endometrial cancer was 66.2%. PAP test is not a suitable method for detection of endometrial carcinoma due to low sensitivity (25%). The main cause of negative findings in PAP test was lack of diagnostic cells in the sample

Does cytological laboratory hold the responsibility for the low sensitivity of the Pap test in detecting endometrial cancer?

Endometrial cancer is the most common gynecological cancer but there is no economically justified screening method. Although we can detect endometrial cells in the sample using PAP test, many studies show low sensitivity and positive predictive value of PAP test for the diagnosis of endometrial cancer. The goal of this research was to determine significance of PAP test for the diagnostics of endometrial carcinoma. Sensitivity and specificity were analyzed with statistical parameters. VCE (vaginal, cervical, endocervical) smears of patients with histologically proven endometrial carcinoma were re-examined in order to determine the proportion of false negative results for endometrial cancer cells in the VCE samples. Study group consisted of all consecutive patients with PAP test performed at the Department of Clinical Cytology of the University Hospital Osijek from 2002. until the end of 2014. There was one inclusion criteria: subsequent hysterectomy or curettage within the six month after the PAP test, regardless of histological finding. From a total of 263 patients with previous PAP test and histologically proven endometrial cancer, endometrial cancer was cytologicaly diagnosed in 24.7% (including suspicious and positive findings), while 66.2% patients had normal cytological findings. The diagnostic value of PAP test in detection of endometrial cancer was statistically revealed with 25% sensitivity and 99% specificity. To determine false negative rate VCE samples were reviewed for patients with histologically proven endometrial cancer and negative VCE findings. There were a total of five negative results. In one case revision did not changed the original negative diagnosis, but benign endometrial cells, a lot of blood and inadequate cytohormonal status were found. In three out of four reviewed samples there were missed cells of endometrial adenocarcinoma. Review of remaining VCE sample upgraded the diagnosis from negative to suspicious for endometrial cancer. Proportion of error in the detection of endometrial cancer using cytological findings was 3.4% (true false negatives). Negative rate of the cytological findings in the detection of endometrial cancer was 66.2%. PAP test is not a suitable method for detection of endometrial carcinoma due to low sensitivity (25%). The main cause of negative findings in PAP test was lack of diagnostic cells in the sample