Journal of Pathology and Translational Medicine

Original Articles

Evaluation of the characteristics of multiple human papillomavirus (HPV) infections identified using the BD Onclarity HPV assay and comparison with those of single HPV infection: Jinhee Kim, Moonsik Kim, Ji Young Park; J Pathol Transl Med. 2022;56(5):289-293. Published online September 13, 2022; DOI: https://doi.org/10.4132/jptm.2022.08.02

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Background
Human papillomavirus (HPV) infection is a major cause of cervical cancer and associated precursor lesions. Multiple HPV genotype infections have been reported. However, their clinicopathological characteristics still remain elusive.
Methods
For this study, 814 consecutive patients who had undergone colposcopy and HPV genotyping test using BD Onclarity HPV assay were retrospectively selected. Clinicopathological parameters of multiple HPV infections were compared with those of single HPV infection.
Results
Multiple HPV infections were found in 110 out of 814 cases (13.5%). Multiple HPV infections were associated with a significantly higher incidence of high-grade intraepithelial lesions (HSILs) compared with single HPV infection. Other high-risk HPV genotypes, in addition to HPV 16, were found more frequently in the multiple HPV infections group; these included HPV 51, 52, 33/58, 56/59/66, and 35/39/68. No specific coinfection pattern was not identified. Additionally, the number of HPV genotypes in multiple HPV infections was not associated with the progression to HSIL or squamous cell carcinoma.
Conclusions
Multiple HPV infections have distinct clinicopathological characteristics (compared with single HPV infection). As their biological behavior is uncertain, close and frequent follow-up is warranted.

Citations

Citations to this article as recorded by

The cervical cancer related distribution, coinfection and risk of 15 HPV types in Baoan, Shenzhen, in 2017–2023
Rukai Li, Weiwei Meng, Yunhai Zuo, Yanli Xu, Shaonan Wu
Virology Journal.2024;[Epub] CrossRef
Molecular findings and virological assessment of bladder papillomavirus infection in cattle
Francesca De Falco, Anna Cutarelli, Francesca Luisa Fedele, Cornel Catoi, Sante Roperto
Veterinary Quarterly.2024; 44(1): 1. CrossRef
Patterns of single and multiple HPV infections in female: A systematic review and meta-analysis
Dan Zhou, Jing Xue, Yaqiong Sun, Liling Zhu, Ming Zhao, Meimei Cui, Min Zhang, Jingjing Jia, Limei Luo
Heliyon.2024; 10(17): e35736. CrossRef
Age distribution of patients with multiple High-Risk Human Papilloma Virus (HR-HPV) genotypes and HPV vaccine recommendations by age
Gülçin Çetin Uysal, Nil Tekin
Family Practice and Palliative Care.2024; 9(3): 80. CrossRef
Relative distribution of HPV genotypes in histological cervical samples and associated grade lesion in a women population over the last 16 years in Burgundy, France
Christelle Auvray, Serge Douvier, Odile Caritey, Jean-Baptiste Bour, Catherine Manoha
Frontiers in Medicine.2023;[Epub] CrossRef
Epidemiologic characteristics of high-risk HPV and the correlation between multiple infections and cervical lesions
Qinli Luo, Xianghua Zeng, Hanyi Luo, Ling Pan, Ying Huang, Haiyan Zhang, Na Han
BMC Infectious Diseases.2023;[Epub] CrossRef

Clinical Significance of an HPV DNA Chip Test with Emphasis on HPV-16 and/or HPV-18 Detection in Korean Gynecological Patients: Min-Kyung Yeo, Ahwon Lee, Soo Young Hur, Jong Sup Park; J Pathol Transl Med. 2016;50(4):294-299. Published online June 26, 2016; DOI: https://doi.org/10.4132/jptm.2016.05.09

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Abstract PDF

Background
Human papillomavirus (HPV) is a major risk factor for cervical cancer.
Methods
We evaluated the clinical significance of the HPV DNA chip genotyping assay (MyHPV chip, Mygene Co.) compared with the Hybrid Capture 2 (HC2) chemiluminescent nucleic acid hybridization kit (Digene Corp.) in 867 patients.
Results
The concordance rate between the MyHPV chip and HC2 was 79.4% (kappa coefficient, κ = 0.55). The sensitivity and specificity of both HPV tests were very similar (approximately 85% and 50%, respectively). The addition of HPV result (either MyHPV chip or HC2) to cytology improved the sensitivity (95%, each) but reduced the specificity (approximately 30%, each) compared with the HPV test or cytology alone. Based on the MyHPV chip results, the odds ratio (OR) for ≥ high-grade squamous intraepithelial lesions (HSILs) was 9.9 in the HPV-16/18 (+) group and 3.7 in the non-16/18 high-risk (HR)-HPV (+) group. Based on the HC2 results, the OR for ≥ HSILs was 5.9 in the HR-HPV (+) group. When considering only patients with cytological diagnoses of “negative for intraepithelial lesion or malignancy” and “atypical squamous cell or atypical glandular cell,” based on the MyHPV chip results, the ORs for ≥ HSILs were 6.8 and 11.7, respectively, in the HPV-16/18 (+) group.
Conclusions
The sensitivity and specificity of the MyHPV chip test are similar to the HC2. Detecting HPV-16/18 with an HPV DNA chip test, which is commonly used in many Asian countries, is useful in assessing the risk of high-grade cervical lesions.

Citations

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Human papilloma virus identification in ocular surface squamous neoplasia by p16 immunohistochemistry and DNA chip test
Tina Shrestha, Won Choi, Ga Eon Kim, Jee Myung Yang, Kyung Chul Yoon
Medicine.2019; 98(2): e13944. CrossRef
Comparison of the PANArray HPV Genotyping Chip Test with the Cobas 4800 HPV and Hybrid Capture 2 Tests for Detection of HPV in ASCUS Women
Eun Young Ki, Yoon Kyung Lee, Ahwon Lee, Jong Sup Park
Yonsei Medical Journal.2018; 59(5): 662. CrossRef

Difference of Genome-Wide Copy Number Alterations between High-Grade Squamous Intraepithelial Lesions and Squamous Cell Carcinomas of the Uterine Cervix: Bum Hee Lee, Sangyoung Roh, Yu Im Kim, Ahwon Lee, Su Young Kim; Korean J Pathol. 2012;46(2):123-130. Published online April 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.2.123

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Abstract PDF

Background

About 10% of high-grade squamous intraepithelial lesions (HSILs) progress to invasive carcinomas within 2-10 years. By delineating the events that occur in the early stage of the invasion, the pathogenesis of cervical cancer could be better understood. This will also propose the possible methods for inhibiting the tumor invasion and improving the survival of patients.

Methods

We compared the genomic profiles between the HSIL and the invasive squamous cell carcinoma (SCC) using an array comparative genomic hybridization. Using recurrently altered genes, we performed a principal component analysis to see variation of samples in both groups. To find possibly affected pathways by altered genes, we analyzed genomic profiles with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and GOEAST software.

Results

We found 11q12.3 and 2p24.1 regions have recurrent copy number gains in both groups. 16p12-13 and 20q11-13 regions showed an increased copy number only in cases of HSIL. 1q25.3 and 3q23-29 regions showed copy number gains only in cases of SCC. Altered genes in the SCC group were related to the mitogen-activated protein kinase signaling pathway and the RNA transport. Altered genes in the HSIL group were related to the ubiquitin mediated proteolysis and cell adhesion molecules.

Conclusions

Our results showed not only that gains in 11q12.3 and 2p24.1 were early events occurring in the premalignant lesions and then maintained in cases of SCC but also that gains in 1q25.3 and 3q23-29 were late events occurring after invasion in those of SCC.

Citations

Citations to this article as recorded by

Cytokeratin and protein expression patterns in squamous cell carcinoma of the oral cavity provide evidence for two distinct pathogenetic pathways
GESCHE FROHWITTER, HORST BUERGER, PAUL J. VAN DIEST, EBERHARD KORSCHING, JOHANNES KLEINHEINZ, THOMAS FILLIES
Oncology Letters.2016; 12(1): 107. CrossRef
'Drawing' a Molecular Portrait of CIN and Cervical Cancer: a Review of Genome-Wide Molecular Profiling Data
Olga V Kurmyshkina, Pavel I Kovchur, Tatyana O Volkova
Asian Pacific Journal of Cancer Prevention.2015; 16(11): 4477. CrossRef

The Usefulness of p16INK4a Immunocytochemical Staining in ASC-H Patients.: Kwang Il Yim, Yeo Ju Kang, Tae Eun Kim, Gyeongsin Park, Eun Sun Jung, Yeong Jin Choi, Kyo Young Lee, Chang Seok Kang, Ahwon Lee; Korean J Pathol. 2011;45(3):290-295.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.3.290

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Abstract PDF

BACKGROUND
The grey zone of cervical cytology, and in particular atypical squamous cells, cannot exclude HSIL (ASC-H) causes diagnostic difficulties and increases medical expenses. We analyzed p16INK4a expression in ASC-H liquid-based cytology specimens (LBCS) to develop more effective methods for the management of ASC-H patients.
METHODS
We carried out p16INK4a immunostaining with 57 LBCS of ASC-H diagnostic categories, all of which were histologically cofirmed and 43 cases of which were compared with the results of a human papillomavirus (HPV) chip test.
RESULTS
p16INK4a immunostaining with ASC-H LBCS was positive in 20% (3/15) of cervicitis, 25.0% (3/12) of tissue-low-grade squamous intraepithelial lesion, 75.0% (18/24) of tissue-high grade squamous intraepithelial lesion (HSIL), and 100% (6/6) of invasive cancer cases. The positivity of p16INK4a in LBCS was correlated with higher grade of histologic diagnosis (r=0.578, p=0.000). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of p16INK4a immunostaining for the prediction of tissue-HSIL+ were 80.0%, 77.8%, 80.0%, and 77.8%, respectively. The sensitivity, specificity, PPV, and NPV of p16INK4a immunostaining plus HPV chip test for predicting tissue-HSIL+ were 71.2%, 86.4%, 84.2%, and 79.2%.
CONCLUSIONS
p16INK4a immunostaining as well as HPV chip testing with remaining LBCS with ASC-H are useful objective markers for the prediction of tissue-HSIL+.

Citations

Citations to this article as recorded by

Usefulness of p16INK4a Immunocytochemical staining for the Differentiation between Atrophy and ASCUS in Diagnosis of Uterine Cervical Cancer
Hye Ryoung Shin, Taekil Eom, Wan-Su Choi
Biomedical Science Letters.2023; 29(3): 144. CrossRef

Evaluation of Low-Grade Squamous Intraepithelial Lesions, Cannot Exclude High-Grade Squamous Intraepithelial Lesions on Cervical Smear.: Sung Ran Hong, Bock Man Kim, Hye Sun Kim, Yi Kyeong Chun, Hy Sook Kim; Korean J Pathol. 2010;44(5):528-535.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.5.528

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Abstract PDF

BACKGROUND
We examined cervicovaginal smears that contained definite low-grade squamous intraepithelial lesion (LSIL) cells and rare atypical cells suggestive of high-grade SIL (HSIL) (ASC-H) or contained borderline dysplastic cells between LSIL and HSIL. Such lesions were classified as LSIL-H. This study aimed to investigate the cytologic and histologic characteristics of LSIL-H category and we evaluated the associated clinical risk.
METHODS
The histologic outcomes of LSIL-H were compared with those of LSIL and ASC-H. Both the cytologic and histologic findings of LSIL-H that were confirmed as cervical intraepithelial neoplasia 2 (CIN2) or greater (CIN2+) were investigated.
RESULTS
LSIL-H accounted for 0.09% of the Pap tests. On the follow-up histology, the most frequent outcome was CIN2, and the risk of CIN2+ was higher than that for ASC-H. In the cases of LSIL-H that was histologically confirmed as CIN2+, most of the atypical cells suggestive of HSIL were cytologically similar to those of CIN2, and the corresponding cervical tissues were characterized by small CIN2+ lesions in a large background of flat condyloma/CIN1. The LSIL-H cases not confirmed on initial colposcopically-directed biopsy required further follow-up.
CONCLUSIONS
LSIL-H may be a valid diagnostic category with distinctive features that are different from LSIL or ASC-H. LSIL-H needs further follow-up for the proper management.

Citations

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The Clinical Significance of “Squamous Intraepithelial Lesion of Indeterminate Grade” as a Distinct Cytologic Category
Dorothy Wong, Crystal Teschendorf, Grace Y. Lin, Farnaz Hasteh
American Journal of Clinical Pathology.2012; 137(5): 753. CrossRef

Expression Patterns of Bcl-2 and PCNA in Cervical Intraepithelial Neoplasia.: Mee Sook Roh, Gi Yeung Huh, Sook Hee Hong; Korean J Pathol. 1995;29(6):703-713.

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Abstract PDF: Immunohistochemical stains for bcl-2 oncoprotein and PCNA and examination of the mitosis level were perfon-ned in 76 cases of cervical intraepithelial neoplasia (CIN). We studied the expression pattern of bcl-2 protein according to histologic grades and the function of bcl-2 oncogene associated with cellular proliferation by comparing with PCNA expression and the mitosis level. The results were as follows: 1) Of 76 cervical intraepithelial neoplasias, 23 (30.3%) were CIN I, 23 (30.3%) were CIN II, and 30 (39.4%) were CIN III. 2) Of 23 CIN I cases, grade 0 and 1 mitosis level were seen in 20 (87.0%), PCNA in 16 (69.6%), and bcl-2 in 19 (82.6%) cases, respectively, which indicates that CIN I lesions have a low cellular proliferative activity. 3) Of 30 CIN III cases, grade 2 and 3 mitosis level were noted in 28 (93.3%), PCNA in 25 (83.3%) and bcl-2 in 19 (63.3%) cases, respectively, which indicates that CIN III lesions have a high cellular proliferative activity. The results suggest that progressive increase of dysfunctional proliferative activity and abnormal decrease of cell death result in increased number of neoplastic cells according to CIN grade. Also the expression rate of bcl-2, PCNA and mitosis level were significantly different between CIN I and 111, which suggest that they might be good parameters for classifying CIN into low and high grade and for prediction of the biologic behavior of the CIN lesion.

Expression of Apoptosis, bcl-2, and PCNA in Uterine Cervical Intraepithelial Neoplasia and Invasive Carcinoma.: Myoung Ja Chung, Kyu Yun Jang, Myoung Jae Kang, Dong Geen Lee, Byung Chan Oh; Korean J Pathol. 1997;31(11):1180-1189.

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Abstract: This study was undertaken to know the extent of apoptosis, expression of bcl-2 and proliferating cell nuclear antigen (PCNA) in uterine cervical intraepithelial neoplasia (CIN; 15 cases) and invasive carcinoma (27 cases) and to evaluate them as a prognostic marker. Apoptosis was analysed by using the in situ apoptosis detection kit and bcl-2 and PCNA were detected by the immunohistochemical method. The results were as follows: Apoptotic indices (AI) in the invasive carcinoma (mean: 4.3) were 10-times higher than that in the CIN (mean: 0.43). Bcl-2 was expressed 60% of the cases in the dysplastic cells of the CIN II and CIN III, 33.3% of cases in the invasive carcinoma and not expressed in the CIN I except basal cells. The expression of the PCNA was increased by the grades of CIN and was strong in invasive carcinoma. The mean survival time of the patient with invasive carcinoma was significantly decreased in the higher AI index (above 4.3) than in the lower AI index (below 4.3). There was no significant correlation between the extent of apoptosis and the expression of bcl-2. According to the above results, AI are able to be used as an independent prognostic marker in the invasive cervical carcinoma, and bcl-2 and PCNA have an important role in the tumorigenesis of uterine cervical carcinoma.

Tumor Angiogenesis and Vascular Endothelial Growth Factor Expression in Cervical Intraepithelial Neoplasia.: Hye Jean Park, Hye Jin Park, Hye Sung Moon, Woon Sup Han, Sun Hee Sung; Korean J Pathol. 2000;34(7):524-530.

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Abstract PDF: Angiogenesis is an essential requirement for development, progression, and metastasis of malignant tumors. Vascular endothelial growth factor (VEGF) is one of the important angiogenic factors. Recently the role of angiogenesis has been known in premalignant lesions. This study was performed to determine whether the angiogenesis and VEGF expression were increased in association with histological grade of cervical intraepithelial neoplasia (CIN) and to see the relationship between the angiogenesis and VEGF. Immunostainings for factor VIII and VEGF were performed on 52 cases of cervical neoplasia (12 cases of CIN I, 11 cases of CIN II, 15 cases of CIN III, 7 cases of microinvasive squamous cell carcinoma, and 7 cases of invasive carcinoma) and 5 cases of normal cervix. The results showed a significant increase of microvessel count from normal cervix through CIN grades to invasive squamous cell cacinoma. VEGF expression was increased in proportion to the CIN grades. There was no significant correlation between microvessel count and VEGF expression. In conclusion, the tumor angiogenesis is an early event in tumorigenesis of uterine cervix. In addition, no significant relationship between the microvessel count and VEGF expression in CIN suggests the possibility of other growth factors affecting mainly angiogenesis of premalignant lesion of uterine cervix.

Immunohistochemical Analysis of Midkine Expression in Preinvasive and Invasive Squamous Cell Neoplasia of the Uterine Cervix.: Suk Jin Choi, Eun Seop Song, Lucia Kim, In Suh Park, Jee Young Han, Joon Mee Kim, Young Chae Chu; Korean J Pathol. 2007;41(2):79-86.

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Abstract PDF: BACKGROUND
Midkine (MK) is a member of the heparin-binding growth factor family. Overexpression of MK is observed not only in cancerous tissue but also in precancerous lesions of the colon and the prostate. Using immunohistochemical methods, we investigated MK expression in preinvasive and invasive neoplasia of the uterine cervix.
METHODS
We performed immunohistochemical analysis of archived cone biopsy and hysterectomy specimens from 161 squamous cell lesions of the uterine cervix (29 cervical intraepithelial neoplasia 1 (CIN1), 35 CIN2, 49 CIN3, 30 microinvasive squamous cell carcinomas (MIC), and 18 invasive squamous cell carcinoma). In addition, we examined if there is a correlation between MK expression and status of human papilloma virus infection determined by a commercially available DNA chip.
RESULTS
None of the normal cervical mucosa showed MK immunostaining. The level of MK expression gradually increased according to the histologic grade. Moderate and strong expressions were most frequently observed in cervical tissue with CIN3 and MIC. MK immunostaining was more accentuated in the invasive border of MIC.
CONCLUSION
MK may play a functional role in the disease progression of cervical squamous cell neoplasia.

Morphometric Study on Cervical Intraepithelial Neoplasia.: Jae Dong Cho, Byung Tae Park, Jung Dal Lee; Korean J Pathol. 1990;24(3):267-274.

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Abstract PDF: Cervical intraepithelial neoplasia in human consist of dysplasia of various developmental stages and squamous cell carcinoma in situ of various types. These lesions can be diagnosed cytologically on cervico-vaginal smears, although the diagnostic reproducibility is limited. To obtain the objects morphologic distinction between normal squamous epithelial cell in different maturation, different stages of dysplastic cells and varieties of in situ carcinoma cells, Kontron IBAS-1 imaging analyzer was applied for the measurement of nuclear and cytoplasmic areas of each categorised cells. The followings are results obtained: 1) Nuclear and cytoplasmic areas of superfical (36.9 micrometer2, 2319.9 micrometer2) intermedicate (45.7 micrometer2, 2989.7 micrometer2) and parabasal cells (50.8 micrometer2, 432.7 micrometer2) of normal squamous epithelium origin are mostly distinctive between cell types. However, cytoplasmic areas of both superficial and intermediate cells and nuclear areas of both intermediate and parabasal cells are not significantly different. 2) Normal squamous cells and various dysplastic cells show obvious difference in their nuclear and cytoplasmic areas, while difference between cytoplasmic areas of both parabasal (432.7 micrometer2) and severe dysplastic cells (409.7 micrometer2) are not statistically significant. 3) No statistical difference is observed in between nuclear areas of both moderate dysplastic (112.3 micrometer2) and severe dysplastic cell (117.6 micrometer2). 4) Varieties of carcinoma in situ cells and severe dysplastic cells are in difference in their nuclear and cytoplastic areas, whereas nuclear areas from both in situ carcinoma cells (95.3 micrometer2) of large cell type and severe dysplasia (117.6 micrometer2) are not distinctive. The results lead the author to consider that the morphometric analysis for various parameters of cell constituents are of value in making objective distinction between cells from cervical intraepithelial neoplasia in human.

Human Papillomavirus Infection and Its Relationship to Cervical Intraepithelial Neoplasia: An immunohistochemical, histopathological and Cytological Study.: Mi Jin Kim, Won Hee Choi, Tae Sook Lee; Korean J Pathol. 1989;23(2):240-253.

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Abstract PDF: It has suggested that a significant proportion of intraepithelial lesion of the cervix may be related to the influence of human papillomaviurs (HPV). Its etiological relation with cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma has recently been proposed. The 131 cases of CIN and 6 condyloma acuminata were stained by immunoperoxidase technique for HPV anigen. The results are as follows: The 18 cases (13.1%) exhibited positive staining, localized in nuclei of koilocytotic cells confined to superficial and intermediate layer of epithelium. HPV antigen was found in 1 case (16.7) of 6 condyloma acuminata, 4 cases (12.5%) of 32 mild dysplasia, 3 cases (13.6%) of 22 moderate dysplasia, 2 cases (14.3%) of 14 severe dysplasia and 8 cases (12.7%) of 63 carcinoma in situ. In the positive cases of mild and moderate dysplasia, HPV antigen was localized directly within the lesion, while those cases of severe dysplaia and carcinoma in situ contained positive cells in areas of mild or moderate dysplasia adjacent to the lesion. Of three distinct morphologic patterns, flat type was most common and papillary type was least. Histologically condylomatous lesions were present in 67 cases (51.1%) out of 131 cases of CIN. The histological and cytological feature encountered most frequently was koilocytotic arypia. Other main histological features are bi- or multinucleation, exocytosis of inflammatory cells, acanthosis, mitotic figures, dyskeratosis and epithelial pearl. On the cervical smear, the evidence of condyloma was proved in 50.0%. Cytologically in the condyloma with high degree of CIN, the nuclear atypia was so prominent that the differentiation from dysplasia or carcinoma in situ was very difficult, although the chromatin appeared somewhat smudged. The mean age of 18 cases was 42.4 years which is older than previous study. The results of this study provide common association with HPV and CIN and add great weight to the suggestion that the infection with HPV plays an important part in genesis of cervical cancer.

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