Publications by authors named "Ivana Kholová"

74 Publications

The Role of Cell Blocks and Immunohistochemistry in Thyroid Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Bethesda Category.

Acta Cytol 2021 Mar 31:1-7. Epub 2021 Mar 31.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Introduction: Thyroid cytology is a widely accepted tool in the clinical triaging of nodular lesions. Cell blocks (CBs) can help in the diagnosis of atypical lesions, namely, thyroid Bethesda category of Atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS).

Methods: In a series of 224 AUS/FLUS thyroid samples with CB, we studied CB cellularity and feasibility of 3 immunohistochemical markers (cytokeratin 19 [CK19], HBME-1, and galectin-3) apart and in combination.

Results: The CBs were non-diagnostic in 34 cases. Twenty-four CBs contained <10 cells, 45 CBs 10-50 cells, and 121 CBs >50 cells. Notably, more cellularity was found in CBs performed by plasma-thrombin and in-house techniques (p < 0.001). The diagnostic accuracy to detect malignancy was 65.1% for CK19, 72.1% for HBME-1, and 70.3% for galectin-3.

Conclusion: In conclusion, CB cellularity is essential for successful immunohistochemistry application and further diagnostic workup of AUS/FLUS cases.
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http://dx.doi.org/10.1159/000514906DOI Listing
March 2021

The role of Pap smear in the diagnostics of endocervical adenocarcinoma.

APMIS 2021 Apr 2;129(4):195-203. Epub 2021 Feb 2.

Pathology, Fimlab Laboratories, Tampere, Finland.

In the high-income countries, the amount of cervical adenocarcinomas is on the rise. The pap smear sampling has a low sensitivity and a low specificity for endocervical malignancies, and there are only a few cytomorphological features, that are specifically associated with glandular atypia. In this study, 298 pap smears of 60 patients with endocervical adenocarcinoma or adenocarcinoma in situ (AIS) and 30 patients with high-grade intraepithelial lesion (HSIL) in histology were reviewed. The pap smear type (screening/clinical), the HPV status and the time from sampling to the histological confirmation of diagnosis were recorded for each case. Despite that no cytomorphological features could be associated with adenocarcinoma statistically, 70% of the pap smears were initially correctly diagnosed as an endocervical glandular lesion. Palisading cell borders, nuclear pleomorphism and the lack of single atypical cells present simultaneously were found to be associated with adenocarcinoma and AIS with the corresponding ORs of 5.89 (95% CI 1.96-17.70), 3.71 (95% CI 1.14-12.02) and 10.76 (95% CI 1.20-59.50). This combination of features was seen in smears taken up to 5 years before the histological diagnosis. Of all our screening samples, 10.9% were HPV-positive. There were no HPV-negative samples among patients with adenocarcinoma.
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http://dx.doi.org/10.1111/apm.13115DOI Listing
April 2021

Ascending aortic estrogen receptor positivity and aortic valve stenosis.

Anatol J Cardiol 2020 11;24(5):300-302

Department of Pathology, Fimlab Laboratories and Tampere University; Tampere-Finland.

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http://dx.doi.org/10.14744/AnatolJCardiol.2020.37665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724392PMC
November 2020

Autopsy examination in sudden cardiac death: a current perspective on behalf of the Association for European Cardiovascular Pathology.

Virchows Arch 2021 Apr 28;478(4):687-693. Epub 2020 Oct 28.

Medical Education, Bristol Medical School, Bristol, UK.

In sudden cardiac death, an autopsy is an essential step in establishing a diagnosis of inherited cardiac disease and identifying families that require cardiac screening. To evaluate aspects of post-mortem practice in Europe, a questionnaire was designed and circulated to both clinical and forensic pathologists. There was a 48% response rate and information was obtained from 17 countries. The results showed a wide variety in the management of sudden cardiac death, with a general tendency towards a lack of thorough investigation. In up to 40% of cases, autopsies were not performed in subjects less than 50 years who may have died from cardiac disease. Reasons for this were lack of finance and lack of interest from police, legal authorities, and doctors. Only 50% of pathologists seem to follow a standard protocol for autopsy examination, apparently due to lack of expertise and/or training. When autopsies were performed, histology and toxicology were almost always taken, genetic studies were generally available and retention of the heart for specialist study was usually permitted. Our results suggest that although the standard of practice is appropriate in many centres, many more cases should have autopsies, especially in sudden deaths in subjects less than 50 years.
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http://dx.doi.org/10.1007/s00428-020-02949-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990811PMC
April 2021

Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries.

Cancer Cytopathol 2020 Dec 27;128(12):885-894. Epub 2020 Oct 27.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported.

Methods: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach.

Results: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%).

Conclusions: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted.
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http://dx.doi.org/10.1002/cncy.22373DOI Listing
December 2020

Primary HPV screening for cervical cancer: Results after two screening rounds in a regional screening program in Finland.

Acta Obstet Gynecol Scand 2021 03 30;100(3):403-409. Epub 2020 Oct 30.

Faculty of Medicine and Health Technology, Tampere University, and Cancer Center, Tampere University Hospital, Tampere, Finland.

Introduction: Since 2012, cervical cancer screening has been conducted with a primary high-risk human papillomavirus (hrHPV) test and conventional cytology triage in the city of Tampere, Finland. The women who were screened with the hrHPV test in 2012 were invited to participate in the second screening round in 2017. The aim of the present report was to compare the number of colposcopy referrals and the number of histological high-grade squamous intraepithelial lesion (HSIL)+ (cervical intraepithelial neoplasia [CIN2+]) lesions between the first and second screening rounds of women of a specific age group who were screened twice with the hrHPV test.

Material And Methods: The primary hrHPV test used was the RealTime hrHPV PCR assay by Abbott. Women with a positive hrHPV test and cytology triage equal to or worse than low-grade squamous intraepithelial lesion or atypical glandular cells, favor neoplasia, were directly referred to colposcopy, whereas hrHPV-positive women with a negative or equivocal cytology triage were re-screened after approximately 12-16 months. hrHPV-negative women were scheduled for re-screening after 5 years. The present report focuses on the cohort of women who were screened twice with the hrHPV test, who were 35-55 years old in 2012, and 40-60 years old in 2017.

Results: In all, 8076 women were invited for HPV screening in 2012 and 8331 women were invited for the second round 5 years later, with attendance rates of 70% and 71%, respectively. Of the women who were screened in 2012, 4571 (69%) belonged to the 35- to 55-year age cohort. In 2017, 4807 (73%) of the women aged 40-60 years participated in the screening. In this cohort, 185 (4.0%) colposcopies were performed in the first screening round, compared with 139 (2.9%) in the second round, and the colposcopy rate was 29% smaller in the second round (P = .002). The number of histological HSIL+ cases was 38 (0.8%) during the first screening round and 29 (0.6%) during the second round (P = .220).

Conclusions: In the setting of routine organized cervical cancer screening, the initially high colposcopy rate associated with primary HPV screening seems to level off at the second screening round in women who were screened twice with an hrHPV test.
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http://dx.doi.org/10.1111/aogs.14021DOI Listing
March 2021

FNA diagnostics of secondary malignancies in the salivary gland: Bi-institutional experience of 36 cases.

Diagn Cytopathol 2021 Feb 5;49(2):241-251. Epub 2020 Oct 5.

Pathology, Fimlab Laboratories, Tampere, Finland.

Objective: Fine-needle aspiration (FNA) is a key diagnostic method in the evaluation of salivary gland lesions. Secondary tumors of salivary glands represent only 5% of all malignancies of major salivary glands. The goal of our study was to examine the cytological and clinical features of secondary tumors sampled by FNA.

Materials And Methods: A series of 36 secondary tumors from the pathology departments of two university hospitals are presented. Clinical referrals to FNA, cytological features, immunohistochemical results, and histopathological diagnoses were reviewed in all cases.

Results: The study population consisted of 36 cases (19 males and 17 females) with mean age 70.9 ± 13.0 years (range 41-96 years). The most common site of the metastasis was parotid gland (n = 26). The primary malignancy was known in 17 cases at the time of FNA diagnosis. The most common primary site was skin of head and neck area (11 cases) followed by lungs (n = 5) and tonsils (n = 5), kidney (n = 2) and breast (n = 2) and thyroid gland, gastrointestinal tract and soft tissue, 1 case of each. In 8 cases, the primary site remained unknown. The diagnostic or confirmatory immunocytochemistry was performed on cell blocks in 21 cases.

Conclusions: FNA is a reliable technique in the diagnosis of salivary gland secondary malignancies. The knowledge of the personal history of malignancy is essential for the successful immunocytochemical targeted diagnosis without any delay.
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http://dx.doi.org/10.1002/dc.24629DOI Listing
February 2021

Assessing the diagnostic accuracy for pleomorphic adenoma and Warthin tumor by employing the Milan System for Reporting Salivary Gland Cytopathology: An international, multi-institutional study.

Cancer Cytopathol 2021 Jan 7;129(1):43-52. Epub 2020 Aug 7.

Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has established distinct diagnostic categories for reporting cytopathological findings, and each is associated with a defined risk of malignancy (ROM). However, the ROM is applied at the overall category level and is not specific for particular morphological entities within a category. Here, the diagnostic performance of the MSRSGC for pleomorphic adenoma (PA) and Warthin tumor (WT) is reported.

Methods: The pathology archives of 11 institutions from 4 countries were retrospectively searched to identify all salivary gland fine-needle aspiration (FNA) biopsies with a differential or definitive diagnosis of PA or WT and all resection specimens with a diagnosis of PA or WT; only paired cases were included. All FNA diagnoses were retrospectively classified according to the MSRSGC.

Results: A total of 1250 cases met the inclusion criteria, and they included 898 PA cases and 352 WT cases. The ROM in the benign neoplasm category was 3.0% and 1.3% for cases with a differential or definitive diagnosis of PA and WT, respectively. The ROM in the salivary gland neoplasm with uncertain malignant potential (SUMP) category was 2.7% and 18.8% for PA and WT, respectively (P = .0277). The diagnostic accuracy for PA and WT was 95.1% and 96.1%, respectively.

Conclusions: The diagnostic accuracy for PA and WT on FNA is high. Furthermore, these findings highlight the difference in the ROMs associated with 2 specific differential diagnoses in the SUMP category: basaloid neoplasms and oncocytoid neoplasms.
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http://dx.doi.org/10.1002/cncy.22339DOI Listing
January 2021

Reply to letter to the editor "The role of fine-needle aspiration biopsy (FNAB) in the diagnostic management of parotid gland masses with emphasis on potential pitfalls".

Eur Arch Otorhinolaryngol 2020 10 7;277(10):2941. Epub 2020 Aug 7.

Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine, University Hospital Motol, Charles University, V Uvalu 84, 150 06, Prague, Czech Republic.

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http://dx.doi.org/10.1007/s00405-020-06269-0DOI Listing
October 2020

Multifunctional Roles of miR-34a in Cancer: A Review with the Emphasis on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer with Clinical Implications.

Diagnostics (Basel) 2020 Aug 5;10(8). Epub 2020 Aug 5.

Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, deregulation of miR-34a was shown to play important roles in tumorigenesis and processes associated with cancer progression, such as tumor-associated epithelial-mesenchymal transition, invasion, and metastasis. Moreover, further understanding of miR-34a molecular mechanisms in cancer are indispensable for the development of effective diagnosis and treatments. In this review, we summarized the current knowledge on miR-34a functions in human disease with an emphasis on its regulation and dysregulation, its role in human cancer, specifically head and neck squamous carcinoma and thyroid cancer, and emerging role as a disease diagnostic and prognostic biomarker and the novel therapeutic target in oncology.
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http://dx.doi.org/10.3390/diagnostics10080563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459507PMC
August 2020

IgG4-positive plasma cells in Hashimoto thyroiditis: IgG4-related disease or inflammation-related IgG4-positivity?

APMIS 2020 Sep 6;128(9):531-538. Epub 2020 Jul 6.

Pathology, Fimlab Laboratories, Tampere, Finland.

Despite the interest of researchers in IgG4-related disease (IgG4-RD), many questions still remain unanswered regarding the thyroid gland. We aimed to clarify the relationship between IgG4-positive plasma cells and the histopathological pattern in the Hashimoto thyroiditis (HT) in a Finnish series. HT specimens (n = 280) were retrieved from the Department of Pathology, Fimlab Laboratories. After re-evaluation, 82 (29%) cases (72 females and 10 males, 52 ± 17 years) with significant fibrosis were selected. CD38, IgG and IgG4 positivity in plasma cells was evaluated by immunohistochemistry. Adjusted IgG4-positive plasma cells per HPF > 20 and IgG4- to IgG-positive plasma cell ratio > 30% were adopted as threshold criteria and related to other morphological features. IgG4-positive HT group included 13 cases (15% from fibrotic HT, 4.6% from all HT, 50 ± 15 years, 11 females) with adjusted HPF count 30 ± 5 (23-40) IgG4-positive cells. IgG4-positivity significantly correlated with the presence of lobulation, oncocytic metaplasia and certain type of fibrosis, fibrosis spread outside the gland, lymphocytes/plasma cells epithelial penetration, the predominance of microfollicles and follicular atrophy in the present study. Despite the persisting uncertainty whether HT is IgG4-RD, HT with IgG4-positive plasma cells is histopathologically distinct entity with some geographic variability.
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http://dx.doi.org/10.1111/apm.13067DOI Listing
September 2020

Insulinoma-associated protein 1 (INSM-1) expression in medullary thyroid carcinoma FNA: a multi-institutional study.

J Am Soc Cytopathol 2020 May - Jun;9(3):185-190. Epub 2020 Feb 21.

Department of Pathology, Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland; Department of Pathology, Fimlab Laboratories, Tampere, Finland.

Introduction: Insulinoma-associated protein 1 (INSM-1) is expressed in both normal tissues and neoplasms with neuroendocrine differentiation such as small cell lung carcinoma and pancreatic neuroendocrine tumors. The aim of this study was to evaluate the INSM-1 expression in medullary thyroid carcinoma (MTC) in the aspirated material and its preoperative diagnostic value.

Materials And Methods: MTC cases with available cytological material from 5 institutions were retrospectively identified. INSM-1 expression was analyzed in 48 cell blocks prepared from fine-needle aspiration samples from histologically confirmed cases of MTC. Twenty-nine samples were aspirates from primary thyroid lesions and 19 from secondary lesions lymph node or liver lesions. INSM-1 immunostain was done using the Ventana Automatic System (Ventana Medical Systems, Tucson, AZ). The control group consisted of 20 samples from histologically confirmed cases of papillary, follicular, and anaplastic thyroid carcinomas and secondary thyroid malignancies (squamous cell carcinoma, malignant melanoma).

Results: The male to female (M:F) ratio in MTC group was 1:1.5 and the average age was 55.6 years (range: 24-84 years). INSM-1 nuclear staining in at least 5% of cells was considered positive. Forty-five (93.75%) MTC samples were positive including all primary tumor aspirates. All control samples were negative.

Conclusions: INSM-1 nuclear positivity is a reliable marker of MTC neuroendocrine differentiation on cytology material from both primary tumor and metastases. INSM-1 can also discriminate MTC from other primary and secondary thyroid carcinomas when there are cytomorphologic overlaps.
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http://dx.doi.org/10.1016/j.jasc.2020.01.005DOI Listing
February 2020

The role of fine-needle aspiration biopsy (FNAB) in the diagnostic management of parotid gland masses with emphasis on potential pitfalls.

Eur Arch Otorhinolaryngol 2020 Jun 27;277(6):1763-1769. Epub 2020 Feb 27.

Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine, University Hospital Motol, Charles University, V Uvalu 84, 150 06, Prague, Czech Republic.

Purpose: The treatment strategy of parotid gland tumours depends mainly on the histopathological type of the lesion. Fine-needle aspiration biopsy (FNAB) is recommended in preoperative diagnostics. The aim of the study was to evaluate the FNAB standing in the diagnostic algorithm of parotid gland lesions and to correlate FNAB results in relation to the definitive histopathological diagnosis.

Material And Methods: The retrospective analyses of 651 examined and consequently surgically treated parotid gland lesions at the Department of Otorhinolaryngology and Head and Neck Surgery, 1st Faculty of Medicine, Charles University in Prague between 2006 and 2016 were used. Preoperative cytological results were consequently evaluated in relation to the definitive histopathological diagnosis.

Results: The cohort consisted of 367 women and 284 men (average age 58 years). FNAB was diagnostic in 604 (92.8%) patients and non-diagnostic in 47 (7.2%) patients. The result of FNAB was positive (suspicious for malignant tumour) in 89 (14.7%) patients and negative (benign) in 515 (85.3%) patients. Sensitivity of the examination was 80.00%, specificity was 93.82%, PPV 62.92%, NPV 97.28%, and LR + and LR- were 12.95 and 0.21, respectively, with an accuracy of 92.22%.

Conclusion: Our results confirm the significant role of FNAB in the diagnostic algorithm of parotid gland lesions.
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http://dx.doi.org/10.1007/s00405-020-05868-1DOI Listing
June 2020

Clonal Evolution of MEK/MAPK Pathway Activating Mutations in a Metastatic Colorectal Cancer Case.

Anticancer Res 2019 Nov;39(11):5867-5877

Central Finland Central Hospital, Jyväskylä, Finland.

Background/aim: The aim of this study was to examine clonal heterogeneity, to test the utility of liquid biopsy in monitoring disease progression and to evaluate the usefulness of ex vivo drug screening in a BRAF L597Q-mutated colorectal cancer (CRC) patient developing metastases during adjuvant therapy.

Materials And Methods: Next generation sequencing (NGS) and droplet digital PCR (ddPCR) were performed in samples from tumor tissues and liquid biopsies. Live cancer cells from a metastatic lesion were used in ex vivo drug sensitivity assays.

Results: We found evidence of continued dependence of MEK/MAPK pathway activation, but different activating mutations in primary tumor and metastases. Liquid biopsy based BRAF L597Q ddPCR testing was a sensitive personalized biomarker predicting the rise of clinically aggressive metastatic disease. Ex vivo drug sensitivity assays with BRAF L597Q mutated cells showed response to MEK/MAPK targeted therapies.

Conclusion: The rare BRAF L597Q mutation may be associated with aggressive tumor behavior in CRC. Liquid biopsy can be used to capture clinically relevant tumor features.
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http://dx.doi.org/10.21873/anticanres.13791DOI Listing
November 2019

Thyroid Bethesda Category AUS/FLUS in Our Microscopes: Three-Year-Experience and Cyto-Histological Correlation.

Cancers (Basel) 2019 Oct 28;11(11). Epub 2019 Oct 28.

Department of Pathology, Fimlab Laboratories, 33520 Tampere, Finland.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) introduced a new category: Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) comprising of heterogenous lesions with a lesser degree of atypia. Its routine use is a bit controversial. The study cohort included AUS/FLUS thyroid cytopathological diagnoses signed out at Fimlab Laboratories from the period of 1 October 2013 to 31 December 2016. We analyzed all the AUS/FLUS cases, their cytology subclassification, and their cyto-histological correlation, when available. In total, there were 331 AUS/FLUS cases from 252 patients. The mean age was 59.8 years and there were 196 females and 56 males. Repeated AUS/FLUS was diagnosed in 75 (29.8%) cases. Out of 252 patients, 118 (46.8%) were operated on. Sixty-eight were operated on after the first AUS/FLUS diagnosis, 46 after 2 AUS/FLUS diagnoses, and 4 after 3 AUS/FLUS diagnoses. In total, there were 37 (14.7%) malignancies and 40 benign tumors. The risk of malignancy for AUS/FLUS (14.7%) is in agreement with the original TBSRTC risk of malignancy. The risk of neoplasia was 30.6% in our series.
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http://dx.doi.org/10.3390/cancers11111670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895794PMC
October 2019

Salivary Gland FNA Diagnostics in a Real-Life Setting: One-Year-Experiences of the Implementation of the Milan System in a Tertiary Care Center.

Cancers (Basel) 2019 Oct 18;11(10). Epub 2019 Oct 18.

Department of Pathology, Fimlab Laboratories, Tampere University Hospital, 335 20 Tampere, Finland.

The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was introduced in 2018 following other organ specific cytopathological reporting systems and it aimed at bringing a practical, evidence-based, user-friendly classification system with characterization and management algorithms. At the Department of Pathology, Fimlab Laboratories, Tampere, Finland all salivary fine needle aspirations (FNAs) have been given cytopathological diagnoses according to the MSRSGC since January 2018. Analyses of a one-year-period (January 2018-December 2018) consisted of 183 salivary FNA samples from 138 patients with correlation to histopathology in 90 cases with surgical follow-up. The MSRSGC performance in patient based analysis was as follows: accuracy was 90.9%, sensitivity was 61.5%, specificity was 100%, positive predictive value was 100%, and negative predictive value was 89.4%, respectively. Risks of malignancy (ROMs) in MSRSGC categories were: 0.0% (0/15) in non-diagnostic category, 100.0% (1/1) in non-neoplastic category biased by only one falsely-negative lymphoma case, 14.3% (1/7) in atypia of undetermined significance category, 0.0% (0/28) in benign neoplasm category, 27.3% (3/11) in neoplasm of uncertain malignant potential category, and 100% for both suspicious for malignancy (4/4) and malignancy (4/4) categories, respectively. The MSRSGC has been proven as a reliable classification system in salivary gland FNA routine diagnostics in a tertiary care center.
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http://dx.doi.org/10.3390/cancers11101589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826610PMC
October 2019

Diagnosis of myocardial infarction at autopsy: AECVP reappraisal in the light of the current clinical classification.

Virchows Arch 2020 Feb 14;476(2):179-194. Epub 2019 Sep 14.

Amsterdam UMC, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

Ischemic heart disease is one of the leading causes of morbidity and death worldwide. Consequently, myocardial infarctions are often encountered in clinical and forensic autopsies, and diagnosis can be challenging, especially in the absence of an acute coronary occlusion. Precise histopathological identification and timing of myocardial infarction in humans often remains uncertain while it can be of crucial importance, especially in a forensic setting when third person involvement or medical responsibilities are in question. A proper post-mortem diagnosis requires not only up-to-date knowledge of the ischemic coronary and myocardial pathology, but also a correct interpretation of such findings in relation to the clinical scenario of the deceased. For these reasons, it is important for pathologists to be familiar with the different clinically defined types of myocardial infarction and to discriminate myocardial infarction from other forms of myocardial injury. This article reviews present knowledge and post-mortem diagnostic methods, including post-mortem imaging, to reveal the different types of myocardial injury and the clinical-pathological correlations with currently defined types of myocardial infarction.
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http://dx.doi.org/10.1007/s00428-019-02662-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028821PMC
February 2020

Pretreatment Serum Levels of Soluble Cytokeratin Fragments (Cyfra 21-1, TPS, MonoTotal) in Relation to Clinical and Pathobiological Aspects of Head and Neck Squamous Cell Carcinomas.

Anticancer Res 2019 Sep;39(9):5171-5177

Department of Biology, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.

Background/aim: The aim of this study was to analyze the pretreatment cytokeratin serum levels in head and neck squamous cell carcinoma (HNSCC) by three assays in relation to selected clinicopathological characteristics in an effort to find diagnostic/prognostic biomarkers for HNSCC and determine the best assay.

Patients And Methods: In total, 46 patients with HNSCC with different subsite (oropharyngeal-21 cases, hypopharyngeal-4 and laryngeal-21) were included in this prospective study. MonoTotal, Cyfra 21-1, and TPS radioimmunoassay kits were used to analyze cytokeratin fragments serum levels.

Results: Statistically significant differences in serum levels of TPS and Cyfra 21-1 were found between low (stage I-II)- and high-stage (stage III-IV) tumors (p=0.0057; p=0.0138 respectively). Cyfra21-1 assay showed significant differences between tumors of different sites with prominent elevation being found in oropharyngeal carcinomas and between patients with p16 positive and p16 negative HNSCC (p=0.0242), being elevated in p16 positive tumors.

Conclusion: The present study is the first to compare cytokeratin serum levels between various subgroups of HNSCC using three different assays. Cyfra 21-1 seems to be the most useful for clinical practice. The relation between elevated Cyfra 21-1 serum levels and p16 expression requires further investigation.
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http://dx.doi.org/10.21873/anticanres.13713DOI Listing
September 2019

New Cell Block Method to Enhance the Cellular Yield in Mucous and/or Bloody Samples.

Acta Cytol 2020 30;64(3):265-269. Epub 2019 Aug 30.

Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland,

Objective: Cell blocks (CBs) are used to complement cytological diagnosis and for ancillary testing. Dissatisfaction with the cellular yield of the CB is widely recognized. Various techniques have been developed to increase the diagnostic utility of CBs.

Study Design: We invented a new CB technique to increase cellular yield and diagnostic accuracy suitable especially for mucous and/or bloody cytological samples.

Results: The new CB technique is described in detail with illustrations and cases, where it increased the cellular yield and diagnostic accuracy. CBs prepared by this method are suitable also for ancillary techniques, namely immunocytochemistry.

Conclusions: The newly described method showed a better cellular yield in mucous and/or bloody cytological specimens.
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http://dx.doi.org/10.1159/000501817DOI Listing
May 2020

HIGH-RISK HPV testing as the primary screening method in an organized regional screening program for cervical cancer: the value of HPV16 and HPV18 genotyping?

APMIS 2019 Nov 11;127(11):710-716. Epub 2019 Sep 11.

Department of Pathology, Fimlab Laboratories Ltd, Tampere, Finland.

Since 2012, testing high-risk (HR)HPV has been used as the primary screening test for women ≥35 years attending the organized cervical cancer screening program in the city of Tampere. We evaluated the contribution of HPV16/18 genotyping. Data from 2012 and 2013, and the follow-up samples in 2013 and 2014, respectively, were analyzed. Abbott RealTime High-Risk HPV test detecting 14 HRHPV genotypes combined with concurrent genotyping for HPV16 and HPV18 was used. HPV was positive in 794 samples out of 11 346 HPV tested women (7%). HPV16/18 was represented in 22% of HPV-positive cases. Negative cervical cytology (NILM) was reported in 51% of HPV-positive samples. HPV16/18 genotype was accompanied with 50% of HSIL/ASC-H cases. The predominance of HPV16/18 in higher grade lesions was even more evident in cervical biopsies as 57% of CIN3 cases were associated with HPV16/18, and only 20% of carcinomas were associated with nonspecified high-risk (NSHR) genotypes. In agreement with previous studies HPV16/18 genotypes caused higher grade cytological and histological changes/pathologies than NSHR genotypes in primary screening. Nevertheless, the majority of HRHPV genotypes detected in the screened population were nonHPV16/18, and especially within persistent infections, precancerous lesions were found also among women with NSHR genotypes.
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http://dx.doi.org/10.1111/apm.12990DOI Listing
November 2019

Mucoepidermoid carcinoma, acinic cell carcinoma, and adenoid cystic carcinoma on fine-needle aspiration biopsy and The Milan System: an international multi-institutional study.

J Am Soc Cytopathol 2019 Sep - Oct;8(5):270-277. Epub 2019 Apr 9.

Division of Cytopathology, Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland. Electronic address:

Background: We evaluated the diagnostic accuracy (DA), risk of neoplasm (RON), and risk of malignancy (ROM) for the commonly encountered malignant salivary gland tumors mucoepidermoid carcinoma (MECa), acinic cell carcinoma (ACCa), and adenoid cystic carcinoma (ADCa) applying The Milan System for Reporting Salivary Gland Cytology (MSRSGC).

Materials And Methods: The cytology archives from 2007 to 2017 of 9 academic institutions were searched for salivary gland FNAs for the following key words mentioned either in the principal and/or differential diagnosis: MEC, ACCa, and ADCa. The original cytology diagnosis was retrospectively classified according to the MSRSGC. Patient demographics, biopsy site, and available surgical follow-up were recorded. The final analysis included only cases with surgical follow-up.

Results: A total of 212 salivary gland FNAs were included. Based on retrospective reclassification according to MSRSGC, 97 of 212 (46%) FNA cases carried a diagnosis of malignancy specific for either MECa, ACCa, or ADCa. In the remaining 115 cases, 24 of 212 (11%) were reclassified as suspicious for malignancy (SM) and 91 of 212 (43%) as salivary gland neoplasm of uncertain malignant potential (SUMP). The DA for MECa, ACCa, and ADCa was 78.7%, 75% and 89%, respectively. The RON was 100% for all 3 tumors and the ROM was 93.6% for MECa, 96.8% for ACCa, and 94.4% for ADCa.

Conclusions: The DA of 78.7% for MECa, 75% for ACCa, and 89% for ADCa is reasonable in FNA specimens. Although the management of definitive cases of malignancy remains unchanged, the MSRSGC provides a ROM for SM and SUMP categories, which can improve patient management.
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http://dx.doi.org/10.1016/j.jasc.2019.04.001DOI Listing
July 2020

Application of the Milan System for Reporting Submandibular Gland Cytopathology: An international, multi-institutional study.

Cancer Cytopathol 2019 05 3;127(5):306-315. Epub 2019 May 3.

Department of Pathology, McGill University, Montreal, Quebec, Canada.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs.

Methods: Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category.

Results: The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%.

Conclusions: This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA.
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http://dx.doi.org/10.1002/cncy.22135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404554PMC
May 2019

Cytopathological features of secretory carcinoma of salivary glands and ancillary techniques in its diagnostics: impact of new Milan system for reporting salivary gland cytopathology.

APMIS 2019 Jul 24;127(7):491-502. Epub 2019 May 24.

Department of Pathology, Fimlab Laboratories, Tampere, Finland.

Secretory carcinoma (SC) of salivary glands is a newly described low-grade malignancy characterized by the presence of ETV6 rearrangement. Only a few cases and very small series with cytomorphology were reported so far. Six cases of fine-needle aspirations (FNAs) from afterward histologically, immunohistochemically and genetically confirmed SCs were retrieved from the archives of the authors. Ancillary immunocytochemistry (ICC) and translocation detection were performed on cell blocks (CBs). All aspirates were sufficiently cellular and cells were arranged in more or less cohesive groups with only mild nuclear polymorphism. The cytoplasm was eosinophilic, granulated and vacuolated, especially in CBs. Secretory material within the microcystic spaces was periodic acid-Schiff (PAS) positive. Triple positivity of immunomarkers S-100 protein, mammaglobin and vimentin was present. The proliferation index was low. Ancillary techniques suggested the possibility of SC in a few cytology cases; nevertheless, the final diagnosis was based on histomorphology, immunohistochemistry and genetics. The SC of salivary glands is detectable pre-operatively using ICC and genetics. The presence of the diagnostic ETV6 rearrangement increases the accuracy of FNA to the maximum. According to the Milan system, cases genetically not confirmed should be categorized as Suspicious for Malignancy or Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP), both requiring surgery.
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http://dx.doi.org/10.1111/apm.12950DOI Listing
July 2019

Implementation of HPV-based cervical cancer screening in an organised regional screening programme: 3 years of experience.

Cytopathology 2019 03 6;30(2):150-156. Epub 2018 Dec 6.

Department of Gynaecology and Obstetrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Objective: The aim of this study was to evaluate the performance of human papillomavirus (HPV)-based screening in the framework of an organised cervical cancer screening programme.

Methods: A total of 46 708 women aged 35-60 years invited to the regional cervical cancer screening programme from 1 January 2012, to 31 December 2014, were enrolled. Overall, 17 770 women were screened by the Abbot RealTime hrHPV test with cytology triage and 15 605 were screened by conventional (Papanicolaou, Pap) cytology. In both groups, women with at least low-grade squamous intraepithelial lesions were referred directly for colposcopy, whereas HPV-positive women with borderline or normal cytology were invited to intensified screening in the following year. In the Pap group, the indication for intensified follow-up was borderline cytology.

Results: The attendance rate was similar in the HPV and Pap groups (72% and 71%, respectively). Overall, 6.0% of women in the HPV group vs 6.4% in the Pap group were referred to intensified follow-up (relative risk 0.94, 95% confidence interval [CI]: 0.87-1.03). At the index screening years, the relative sensitivity of the HPV test with cytology triage vs conventional screening was 1.64 (95% CI: 1.05-2.55) for CIN2+ and 2.06 (95% CI: 1.17-3.41) for CIN3+. The specificity of the hrHPV test with cytology triage for CIN2+ and CIN3+ was equal to that of the Pap screening (99.2% vs 99.2% for CIN2+ and 99.1% vs 99.1% for CIN3+).

Conclusions: Due to its high sensitivity and specificity, primary hrHPV testing with cytology triage seems to be acceptable for cervical cancer screening in an organised setting.
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http://dx.doi.org/10.1111/cyt.12652DOI Listing
March 2019

Neovascularization with chronic inflammation characterizes ascending aortic dissection.

Anatol J Cardiol 2018 Nov;20(5):289-295

Departments of Pathology, Fimlab Laboratories, *Heart Center, Cardiac Research, Tampere University Hospital and Tampere University Medical School; Tampere-Finland.

Objective: Neovascularization of the aortic wall may be associated with aortic dissection (AD). Aortic wall endothelial CD31 deposition together with chronic inflammation indicates angiogenesis that may lead to tissue disruption. We studied the presence of neovascularization of the ascending aortic wall by characterizing CD31 positive endothelial cells.

Methods: Aortic wall routine histology and immunohistochemistry for CD31, T- and B-lymphocytes, plasma cells, macrophages, endothelial cells, smooth muscle cells, and cell proliferation were performed on 35 selected patients who underwent surgery for the ascending aorta, and the samples were grouped according to the presence of AD.

Results: Three subjects with Marfan syndrome were excluded from the study. A total of 14 out of 32 patients had AD. A total of 18 patients were operated on due to dilatation only. Chronic inflammation of the adventitia (p=0.003), media (p=0.001), and intima (p=0.005) was increased in AD. Neovascularization was predominant in the outer third medial layer in AD (p=0.037), corresponding to the site of aortic wall disruption. A receiver operating characteristic curve analysis showed that neovascularization was associated with AD (AUC 0.750; SE 0.092; p=0.022; 95% CI 0.570-0.930).

Conclusion: Endothelial immunohistochemistry confirms neovascularization of the outer third medial layer during AD. Aortic wall remodeling including neovascularization characterizes AD. Chronic inflammation and neovascularization of the dilated ascending aorta suggest susceptibility for AD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280283PMC
http://dx.doi.org/10.14744/AnatolJCardiol.2018.42223DOI Listing
November 2018

Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis - Tampere Vascular Study.

Sci Rep 2018 10 10;8(1):15078. Epub 2018 Oct 10.

Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

α-melanocyte-stimulating hormone (α-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. α-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and α-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. α-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating α-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque α-MSH levels. Second, immunohistochemical analyses revealed the presence of α-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of α-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, α-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of α-MSH might protect against atherosclerosis.
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http://dx.doi.org/10.1038/s41598-018-33523-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180013PMC
October 2018

Cell Block in Cytological Diagnostics: Review of Preparatory Techniques.

Acta Cytol 2018 15;62(4):237-243. Epub 2018 Jun 15.

Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.

Objective: The cell block (CB) technique refers to the processing of sediments, blood clots, or grossly visible tissue fragments from cytological specimens into paraffin blocks that can be cut and stained by the same methods used for histopathology. The technique brings additional tissue architectural information. CB can be used for ancillary techniques such as immunocytochemistry and molecular techniques.

Study Design: We reviewed the literature on the various preparatory techniques of CBs.

Results: There is a wide range of preparatory techniques for CBs and no golden standard for CBs exists: tens of methods are used in various institutions. The majority of the methods are modified in house techniques with a few commercially available kits. The techniques most commonly used are the plasma/thrombin method, the agar method, and commercially available Histogel- and Cellient CB-methods. Dissatisfaction with the cellular yield of the CBs is common.

Conclusions: In the CBs, the cytological material is preserved for future use, which is a tremendous advantage in the era of targeted therapy and biobanking. The CB is thus central to the future of cytology: more can be done with less material and with less invasiveness to the patient.
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http://dx.doi.org/10.1159/000489769DOI Listing
August 2018

Vascular Proliferation of the Thyroid: Potential Histopathological Pitfalls as a Consequence of Fine Needle Aspiration.

Acta Cytol 2017 18;61(3):179-186. Epub 2017 May 18.

Department of Pathology, Fimlab Laboratories, Tampere University Hospital, and Department of Pathology, School of Medicine, Tampere University, Tampere, Finland.

Objective: Fine needle aspiration biopsy (FNAB) can cause reactive histopathological changes, commonly including haemorrhage and granulation tissue. The literature describing vascular proliferation after FNAB is sparse. We aimed to describe neovascularisation in thyroid gland specimens as a consequence of FNAB.

Study Design: We analysed all thyroid histopathological specimens from the Fimlab Laboratories collected between 2010 and 2013 for neovascularisation and distortions in the accompanying tissue. We evaluated HE-stained slides and CD31-, podoplanin-, and Ki-67-immunostained slides.

Results: We observed vascular proliferation in 64 out of 787 specimens (8.1%). In these patients, the mean age was 62 years, 43 were female and 21 were male. Previous FNAB data were available in 49 cases (76.6%). In 51 cases (79.7%), the neovascularisation occupied less than 5% of the thyroid gland area. The vessel dilatation was moderate in 28 cases (43.8%) and low in 20 cases (31.3%). In tumours, neovessels were detected within the tumour and in the surrounding tissue.

Conclusions: Post-FNAB tissue samples include dilated newly formed vessels, which pathologists should differentiate from rare thyroid vascular tumours. The proposed mechanism is a traumatically induced haemorrhage followed by haematoma and thrombosis that resolves by recanalisation. A knowledge of tissue alteration is needed to avoid misdiagnoses.
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http://dx.doi.org/10.1159/000476024DOI Listing
July 2017

Talin and vinculin are downregulated in atherosclerotic plaque; Tampere Vascular Study.

Atherosclerosis 2016 12 15;255:43-53. Epub 2016 Oct 15.

BioMediTech, University of Tampere and Fimlab Laboratories, Tampere, Finland. Electronic address:

Background And Aims: Focal adhesions (FA) play an important role in the tissue remodeling and in the maintenance of tissue integrity and homeostasis. Talin and vinculin proteins are among the major constituents of FAs contributing to cellular well-being and intercellular communication.

Methods: Microarray analysis (MA) and qRT-PCR low-density array were implemented to analyze talin-1, talin-2, meta-vinculin and vinculin gene expression in circulating blood and arterial plaque.

Results: All analyzed genes were significantly and consistently downregulated in plaques (carotid, abdominal aortic and femoral regions) compared to left internal thoracic artery (LITA) control. The use of LITA samples as controls for arterial plaque samples was validated using immunohistochemistry by comparing LITA samples with healthy arterial samples from a cadaver. Even though the differences in expression levels between stable and unstable plaques were not statistically significant, we observed further negative tendency in the expression in unstable atherosclerotic plaques. The confocal tissue imaging revealed gradient of talin-1 expression in plaque with reduction close to the vessel lumen. Similar gradient was observed for talin-2 expression in LITA controls but was not detected in plaques. This suggests that impaired tissue mechanostability affects the tissue remodeling and healing capabilities leading to development of unstable plaques.

Conclusions: The central role of talin and vinculin in cell adhesions suggests that the disintegration of the tissue in atherosclerosis could be partially driven by downregulation of these genes, leading to loosening of cell-ECM interactions and remodeling of the tissue.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.10.031DOI Listing
December 2016

Human papillomavirus test with cytology triage in organized screening for cervical cancer.

Acta Obstet Gynecol Scand 2016 Nov;95(11):1220-1227

Department of Obstetrics and Gynecology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.

Introduction: In randomized studies, testing for high-risk (HR) human papillomavirus (hrHPV) has been more sensitive than conventional cytology in detecting cervical intraepithelial neoplasia (CIN). The aim of this study was to evaluate the performance of HPV testing in the setting of an organized routine screening program.

Material And Methods: Since 2012, 35- to 60-year-old women living in the city of Tampere have been screened with the Abbott RealTime hrHPV test. HPV-negative women are referred to the next screening round in five years. HPV-positive women are triaged with conventional cytology, and women with at least low-grade squamous intraepithelial lesion (LSIL ) are referred to colposcopy. The remaining HPV-positive women are referred for re-testing after 12 months, and then all HPV-positive women are referred to colposcopy. The data from the last cohort with cytological screening (screened in 2011) is presented for comparison.

Results: A total 5637 (70%) women attended the first round of HPV screening, and 369 were HPV-positive. Of them, 54 women LSIL were referred to colposcopy, resulting in 16 CIN2 lesions found. Of the remaining HPV-positive women, 66% were still positive one year later, and were referred to colposcopy, with 18 additional CIN2 lesions found. The attendance rate to the last round of cytological screening was 71% (5814 women). Sixty-four women with LSIL cytology were referred to colposcopy, and 11 CIN2 lesions were found. Of the 777 women with borderline cytology and scheduled for reflex screening in the following year, 109 (19%) had ASC-US , and 57 underwent colposcopy, resulting in six additional CIN2 lesions found. The total detection rate of CIN2 was significantly higher in the HPV-screened cohort (6.0/1000 vs. 2.9/1000, p = 0.015). However, the total colposcopy rate was 4% vs. 2%, respectively (p < 0.001).

Conclusion: Human papillomavirus testing also seems to be more sensitive than cytology in detecting CIN2 lesions in the setting of a routine organized screening program, besides in the context of randomized trials. The problem of an increased colposcopy rate needs to be addressed in the future.
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http://dx.doi.org/10.1111/aogs.13013DOI Listing
November 2016