Journal of Pathology and Translational Medicine

Original Articles

The prognostic significance of p16 expression pattern in diffuse gliomas: Jin Woo Park, Jeongwan Kang, Ka Young Lim, Hyunhee Kim, Seong-Ik Kim, Jae Kyung Won, Chul-Kee Park, Sung-Hye Park; J Pathol Transl Med. 2021;55(2):102-111. Published online December 23, 2020; DOI: https://doi.org/10.4132/jptm.2020.10.22

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Background
CDKN2A is a tumor suppressor gene that encodes the cell cycle inhibitor protein p16. Homozygous deletion of the CDKN2A gene has been associated with shortened survival in isocitrate dehydrogenase (IDH)–mutant gliomas. This study aimed to analyze the prognostic value of p16 and to evaluate whether p16 immunohistochemical staining could be used as a prognostic marker to replace CDKN2A genotyping in diffuse gliomas.
Methods
p16 immunohistochemistry was performed on tissue microarrays of 326 diffuse gliomas with diagnoses that reflected IDH-mutations and 1p/19q codeletion status. The results were divided into three groups (negative, focal expression, overexpression) according to the presence and degree of p16 expression. Survival analysis was performed to assess the prognostic value of p16 expression.
Results
A loss of p16 expression predicted a significantly worse outcome in all glioma patients (n=326, p<.001), in the IDH-mutant glioma patients (n=103, p=.010), and in the IDH-mutant astrocytoma patients (n=73, p=.032). However, loss of p16 expression did not predict the outcome in the IDH-wildtype glioma patients (n=223, p=.121) or in the oligodendroglial tumor patients with the IDH-mutation and 1p/19q codeletion (n=30, p=.457). Multivariate analysis showed the association was still significant in the IDH-mutant glioma patients (p=.008; hazard ratio [HR], 2.637; 95% confidence interval [CI], 1.295 to 5.372) and in the IDH-mutant astrocytoma patients (p=.001; HR, 3.586; 95% CI, 1.649 to 7.801). Interestingly, patients who presented with tumors with p16 overexpression also had shorter survival times than did patients with tumors with p16 focal expression in the whole glioma (p< .001) and in IDH-mutant glioma groups. (p=.046).
Conclusions
This study suggests that detection of p16 expression by immunohistochemistry can be used as a useful surrogate test to predict prognosis, especially in IDH-mutant astrocytoma patients.

Citations

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p16 Expression in Laryngeal Squamous Cell Carcinoma: A Surrogate or Independent Prognostic Marker?
Roberto Gallus, Davide Rizzo, Giorgia Rossi, Luca Mureddu, Jacopo Galli, Alberto Artuso, Francesco Bussu
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CDKN2A/B deletion in IDH-mutant astrocytomas: An evaluation by Fluorescence in-situ hybridization
Manali Ranade, Sridhar Epari, Omshree Shetty, Sandeep Dhanavade, Sheetal Chavan, Ayushi Sahay, Arpita Sahu, Prakash Shetty, Aliasgar Moiyadi, Vikash Singh, Archya Dasgupta, Abhishek Chatterjee, Sadhana Kannan, Tejpal Gupta
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Molecular prognostication in grade 3 meningiomas and p16/MTAP immunohistochemistry for predicting CDKN2A/B status
Kira Tosefsky, Karina Chornenka Martin, Alexander D Rebchuk, Justin Z Wang, Farshad Nassiri, Amy Lum, Gelareh Zadeh, Serge Makarenko, Stephen Yip
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E. D. Namiot, G. M. Zembatov, P. P. Tregub
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CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1/2-Mutation in CNS WHO Grade 4 Gliomas
Sang Hyuk Lee, Tae Gyu Kim, Kyeong Hwa Ryu, Seok Hyun Kim, Young Zoon Kim
Biomedicines.2024; 12(10): 2256. CrossRef
p16 Immunohistochemical Expression as a Surrogate Assessment of CDKN2A Alteration in Gliomas Leading to Prognostic Significances
Lucas Geyer, Thibaut Wolf, Marie-Pierre Chenard, Helene Cebula, Roland Schott, Georges Noel, Eric Guerin, Erwan Pencreach, Damien Reita, Natacha Entz-Werlé, Benoît Lhermitte
Cancers.2023; 15(5): 1512. CrossRef
P16 immunohistochemistry is a sensitive and specific surrogate marker for CDKN2A homozygous deletion in gliomas
Meenakshi Vij, Benjamin B. Cho, Raquel T. Yokoda, Omid Rashidipour, Melissa Umphlett, Timothy E. Richardson, Nadejda M. Tsankova
Acta Neuropathologica Communications.2023;[Epub] CrossRef
CDKN2A mutations have equivalent prognostic significance to homozygous deletion in IDH-mutant astrocytoma
Raquel T Yokoda, William S Cobb, Raymund L Yong, John F Crary, Mariano S Viapiano, Jamie M Walker, Melissa Umphlett, Nadejda M Tsankova, Timothy E Richardson
Journal of Neuropathology & Experimental Neurology.2023; 82(10): 845. CrossRef
Efficient diagnosis of IDH-mutant gliomas: 1p/19qNET assesses 1p/19q codeletion status using weakly-supervised learning
Gi Jeong Kim, Tonghyun Lee, Sangjeong Ahn, Youngjung Uh, Se Hoon Kim
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Chun Wang, Cuimin Chen, Wenting Hu, Lili Tao, Jiakang Chen
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Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors
Hyunhee Kim, Ka Young Lim, Jin Woo Park, Jeongwan Kang, Jae Kyung Won, Kwanghoon Lee, Yumi Shim, Chul-Kee Park, Seung-Ki Kim, Seung-Hong Choi, Tae Min Kim, Hongseok Yun, Sung-Hye Park
Laboratory Investigation.2022; 102(2): 160. CrossRef
Simple approach for the histomolecular diagnosis of central nervous system gliomas based on 2021 World Health Organization Classification
Maher Kurdi, Rana H Moshref, Yousef Katib, Eyad Faizo, Ahmed A Najjar, Basem Bahakeem, Ahmed K Bamaga
World Journal of Clinical Oncology.2022; 13(7): 567. CrossRef
P16INK4A—More Than a Senescence Marker
Hasan Safwan-Zaiter, Nicole Wagner, Kay-Dietrich Wagner
Life.2022; 12(9): 1332. CrossRef

Evaluation of human papillomavirus (HPV) prediction using the International Endocervical Adenocarcinoma Criteria and Classification system, compared to p16 immunohistochemistry and HPV RNA in-situ hybridization: Hezhen Ren, Jennifer Pors, Christine Chow, Monica Ta, Simona Stolnicu, Robert Soslow, David Huntsman, Lynn Hoang; J Pathol Transl Med. 2020;54(6):480-488. Published online August 31, 2020; DOI: https://doi.org/10.4132/jptm.2020.07.18

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Abstract PDF

Background
The International Endocervical Adenocarcinoma Criteria and Classification (IECC) separated endocervical adenocarcinomas into human papillomavirus (HPV) associated (HPVA) and non–HPV-associated (NHPVA) categories by morphology alone. Our primary objective was to assess the accuracy of HPV prediction by the IECC system compared to p16 immunohistochemistry and HPV RNA in-situ hybridization (RISH). Our secondary goal was to directly compare p16 and HPV RISH concordance.
Methods
Cases were classified by IECC and stained for p16 and HPV RISH on tissue microarray, with discordant p16/HPV RISH cases re-stained on whole tissue sections. Remaining discordant cases (p16/HPV, IECC/p16, IECC/HPV discordances) were re-reviewed by the original pathologists (n = 3) and external expert pathologists (n = 2) blinded to the p16 and HPV RISH results. Final IECC diagnosis was assigned upon independent agreement between all reviewers.
Results
One hundred and eleven endocervical adenocarcinomas were classified originally into 94 HPVA and 17 NHPVA cases. p16 and HPV RISH was concordant in 108/111 cases (97%) independent of the IECC. HPV RISH and p16 was concordant with IECC in 103/111 (93%) and 106/111 (95%), respectively. After expert review, concordance improved to 107/111 (96%) for HPV RISH. After review of the eight discordant cases, one remained as HPVA, four were reclassified to NHPVA from HPVA, two were unclassifiable, and one possibly represented a mixed usual and gastric-type adenocarcinoma.
Conclusions
p16 and HPV RISH have excellent concordance in endocervical adenocarcinomas, and IECC can predict HPV status in most cases. Focal apical mitoses and apoptotic debris on original review led to the misclassification of several NHPVA as HPVA.

Citations

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Joint detection of multiple HPV-testing technologies and evaluation of clinicopathological characteristics discriminate between HPV-independent and low-copy HPV-associated cervical squamous cell carcinoma (CSCC) -an analysis of 3869 cases
Linghui Lu, Tianqi Liu, Shunni Wang, Jing Li, Feiran Zhang, Yan Ning, Yiqin Wang
Gynecologic Oncology.2023; 170: 59. CrossRef
Incidence and Clinicopathologic Characteristics of Human Papillomavirus–independent Invasive Squamous Cell Carcinomas of the Cervix
Simona Stolnicu, Douglas Allison, Aaron M. Praiss, Basile Tessier-Cloutier, Amir Momeni Boroujeni, Jessica Flynn, Alexia Iasonos, Rene Serrette, Lien Hoang, Andrei Patrichi, Cristina Terinte, Anna Pesci, Claudia Mateoiu, Ricardo R. Lastra, Takako Kiyokawa
American Journal of Surgical Pathology.2023; 47(12): 1376. CrossRef
Testing Algorithms for the Diagnosis of Malignant Glandular Tumors of the Uterine Cervix Histotyped per the International Endocervical Adenocarcinoma Criteria and Classification (IECC) System
Máire A. Duggan, Qiuli Duan, Ruth M. Pfeiffer, Mary Anne Brett, Sandra Lee, Mustapha Abubakar, Martin Köbel, Monica Rodriguez, Aylin Sar
Applied Immunohistochemistry & Molecular Morphology.2022; 30(2): 91. CrossRef
Local and Metastatic Relapses in a Young Woman with Papillary Squamous Cell Carcinoma of the Uterine Cervix
Ha Young Woo, Hyun-Soo Kim
Diagnostics.2022; 12(3): 599. CrossRef
Clinical correlation of lymphovascular invasion and Silva pattern of invasion in early-stage endocervical adenocarcinoma: proposed binary Silva classification system
Simona Stolnicu, Lien Hoang, Noorah Almadani, Louise De Brot, Glauco Baiocchi, Graziele Bovolim, Maria Jose Brito, Georgia Karpathiou, Antonio Ieni, Esther Guerra, Takako Kiyokawa, Pavel Dundr, Carlos Parra-Herran, Sofia Lérias, Ana Felix, Andres Roma, An
Pathology.2022; 54(5): 548. CrossRef
Reproducibility of Morphologic Parameters of the International Endocervical Adenocarcinoma Criteria and Classification System and Correlation With Clinicopathologic Parameters: A Multi-Institutional Study
Pinar Bulutay, Nihan Haberal, Özlem Özen, Özlem Erdem, Emine H. Zeren, İbrahim Kulac, Çagatay Taskiran, Dogan Vatansever, Ali Ayhan, Nilgün Kapucuoğlu
International Journal of Gynecological Pathology.2022; 41(5): 447. CrossRef
HPV-Negative Cervical Cancer: A Narrative Review
Francesca Arezzo, Gennaro Cormio, Vera Loizzi, Gerardo Cazzato, Viviana Cataldo, Claudio Lombardi, Giuseppe Ingravallo, Leonardo Resta, Ettore Cicinelli
Diagnostics.2021; 11(6): 952. CrossRef
International Endocervical Adenocarcinoma Criteria and Classification (IECC): An Independent Cohort With Clinical and Molecular Findings
Hezhen Ren, Noorah Almadani, Jennifer Pors, Samuel Leung, Julie Ho, Christine Chow, Monica Ta, Kay J. Park, Simona Stolnicu, Robert Soslow, David Huntsman, Blake C. Gilks, Lynn Hoang
International Journal of Gynecological Pathology.2021; 40(6): 533. CrossRef

Distribution of Human Papillomavirus 52 and 58 Genotypes, and Their Expression of p16 and p53 in Cervical Neoplasia: Tae Eun Kim, Hwal Woong Kim, Kyung Eun Lee; Korean J Pathol. 2014;48(1):24-29. Published online February 25, 2014; DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.1.24

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Abstract PDF

Background

This study investigates the prevalence of human papillomavirus (HPV) 52 and 58 genotypes among women residing in Busan, and the expression of p16 and p53 proteins in cervical neoplasia with HPV 52 and 58 infections.

Methods

A total of three hundred fifteen cases were analyzed using the HPV DNA chip test for HPV genotypes, and of these, we retrospectively examined p16 and p53 expression in 62 cases of cervical tissues infected with HPV 52 and 58 using immunohistochemistry.

Results

HPV 52 and 58 genotypes were identified in 62 (54.9%) out of 113 high-risk, HPV-infected cases. Of the cases examined, there were 19 single HPV 52 infections (16.8%), 23 single HPV 58 infections (20.4%), 4 multiple HPV 52 infections (3.5%), and 16 multiple HPV-58 infections (14.2%). Immunoreactivity of p16 and p53 was observed in 41 (66.1%) and 23 (37.1%) of the 62 cases of cervical neoplasia infected with HPV 52 and 58 genotypes, respectively.

Conclusions

This study demonstrates a high prevalence of HPV 52 and 58 genotypes, in addition to HPV 16, among high-risk strains of cervical neoplasia in Korea. These findings suggest that development of more vaccines would be beneficial for the prevention of the various HPV genotypes.

Citations

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Screening for High-Risk Human Papillomavirus Reveals HPV52 and HPV58 among Pediatric and Adult Patient Saliva Samples
Hunter Hinton, Lorena Herrera, Sofia Valenzuela, Katherine M. Howard, Karl Kingsley
Dentistry Journal.2024; 12(3): 56. CrossRef
Usefulness Analysis of Urine Samples for Early Screening of Human Papilloma Virus Infection
Yoon Sung Choi, Hyunwoo Jin, Kyung Eun Lee
Journal of Cancer Prevention.2019; 24(4): 240. CrossRef
Relationship between Expression of P16 and Ki-67 and Persistent Infection of HPV in Cervical Carcinoma Patients
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Advances in Clinical Medicine.2018; 08(08): 776. CrossRef
Analysis of Sequence Variation and Risk Association of Human Papillomavirus 52 Variants Circulating in Korea
Youn Jin Choi, Eun Young Ki, Chuqing Zhang, Wendy C. S. Ho, Sung-Jong Lee, Min Jin Jeong, Paul K. S. Chan, Jong Sup Park, Xuefeng Liu
PLOS ONE.2016; 11(12): e0168178. CrossRef

Primary Squamous Cell Carcinoma of the Upper Genital Tract: Utility of p16^INK4a Expression and HPV DNA Status in its Differential Diagnosis from Extended Cervical Squamous Cell Carcinoma: Su Hyun Yoo, Eun-Mi Son, Chang Okh Sung, Kyu-Rae Kim; Korean J Pathol. 2013;47(6):549-556. Published online December 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.6.549

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Abstract PDF

Background

Primary squamous cell carcinoma (SCC) of the upper genital tract, including the endometrium, fallopian tubes, and ovaries, is extremely rare. It must be distinguished from the mucosal extension of primary cervical SCC because determination of the primary tumor site is important for tumor staging. However, patients with SCC of the fallopian tubes or ovarian surface have often undergone prior hysterectomy with inadequate examination of the cervix, making it difficult to determine the primary site.

Methods

We compared histologic findings, p16^INK4a expression, and human papillomavirus (HPV) DNA status in four patients with primary SCC of the upper genital tract and five patients with primary cervical SCC extending to the mucosa of the upper genital tract.

Results

All five SCCs of cervical origin showed strong expression of p16^INK4a, whereas all four SCCs of the upper genital tract were negative, although one showed weak focal staining. Three of the five cervical SCCs were positive for HPV16 DNA, whereas all four primary SCCs of the upper genital tract were negative for HPV DNA.

Conclusions

Although a thorough histological examination is important, immunonegativity for p16^INK4a and negative for HPV DNA may be useful adjuncts in determining primary SCCs of the upper genital tract.

Citations

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PAX8 Positivity, Abnormal p53 Expression, and p16 Negativity in a Primary Endometrial Squamous Cell Carcinoma: A Case Report and Review of the Literature
Daniela Fanni, Michele Peiretti, Valerio Mais, Elena Massa, Clara Gerosa, Francesca Ledda, Maria Luisa Fais, Gavino Faa, Stefano Angioni
International Journal of Gynecological Pathology.2022; 41(4): 431. CrossRef
Molecular Analysis of HPV-independent Primary Endometrial Squamous Cell Carcinoma Reveals TP53 and CDKN2A Comutations
Mark R. Hopkins, Doreen N. Palsgrove, Brigitte M. Ronnett, Russell Vang, Jeffrey Lin, Tricia A. Murdock
American Journal of Surgical Pathology.2022; 46(12): 1611. CrossRef
Primary squamous cell carcinoma of the endometrium—Case report with cytological characteristics in direct and indirect endometrial samples
Sanda Rajhvajn, Ana Barišić, Lada Škopljanac‐Mačina, Danijela Jurič, Vesna Mahovlić
Cytopathology.2021; 32(6): 823. CrossRef
Überraschung in der Abradatdiagnostik
U. Kellner, A. Kellner, U. Cirkel
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Retropharyngeal Lymph Node Metastasis in 54 Patients with Oropharyngeal Squamous Cell Carcinoma Who Underwent Surgery-Based Treatment
Eun-Jae Chung, Go-Woon Kim, Bum-Ki Cho, Sung-Jin Cho, Dae-Young Yoon, Young-Soo Rho
Annals of Surgical Oncology.2015; 22(9): 3049. CrossRef

Human Papillomavirus Prevalence and Cell Cycle Related Protein Expression in Tonsillar Squamous Cell Carcinomas of Korean Patients with Clinicopathologic Analysis: Miji Lee, Sung Bae Kim, Sang-wook Lee, Jong-Lyel Roh, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim, Kyung-Ja Cho; Korean J Pathol. 2013;47(2):148-157. Published online April 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.148

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Abstract PDF

Background

Human papillomavirus (HPV)-related tonsillar squamous cell carcinoma (TSCC) has recently been characterized as a distinct subset with a favorable prognosis. The prevalence and clinicopathologic significance of HPV-related TSCC in Koreans are not well known.

Methods

HPV in situ hybridization (ISH) accompanied by p53, p16, pRb, and cyclin D1 immunohistochemical staining were performed on 89 resection cases of TSCC from 2000 through 2010.

Results

HPV was detected by ISH in 59 of 89 cases (66.3%). HPV-positive TSCCs were more common in younger ages (p=0.005), and tumor sizes were smaller in the HPV-positive compared to the HPV-negative group (p=0.040). Positive HPV staining was significantly correlated with p16 expression (p<0.001), pRb inactivation (p=0.003), and cyclin D1 down-regulation (p<0.001) but not with p53 expression (p=0.334). Seventeen cases that showed p16-immunopositivity with HPV-negativity by ISH were retested by HPV typing; HPV DNA was not detected in all cases. There was no significant difference between HPV-positive and HPV-negative patients either in the disease-specific survival (DSS, p=0.857) or overall survival (p=0.910). Furthermore, pRb-inactivated cases showed better DSS (p=0.023), and p53-positive cases showed worse DSS (p=0.001).

Conclusions

Although high HPV prevalence was noted, it was not correlated with histopathologic findings or survival benefit. In addition to p53 expression, pRb inactivation along with p16 overexpression and down-regulation of cyclin D1 are thought to be important pathogenetic steps for developing TSCCs.

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Assessment of the Mutation Profile of Tonsillar Squamous Cell Carcinomas Using Targeted Next-Generation Sequencing
Ha Young Park, Joong Seob Lee, Jee Hye Wee, Jeong Wook Kang, Eun Soo Kim, Taeryool Koo, Hee Sung Hwang, Hyo Jung Kim, Ho Suk Kang, Hyun Lim, Nan Young Kim, Eun Sook Nam, Seong Jin Cho, Mi Jung Kwon
Biomedicines.2023; 11(3): 851. CrossRef
Clinicopathologic characterization of cervical metastasis from an unknown primary tumor: a multicenter study in Korea
Miseon Lee, Uiree Jo, Joon Seon Song, Youn Soo Lee, Chang Gok Woo, Dong-Hoon Kim, Jung Yeon Kim, Sun Och Yoon, Kyung-Ja Cho
Journal of Pathology and Translational Medicine.2023; 57(3): 166. CrossRef
Negative Prognostic Implication of TERT Promoter Mutations in Human Papillomavirus–Negative Tonsillar Squamous Cell Carcinoma Under the New 8th AJCC Staging System
Hyunchul Kim, Mi Jung Kwon, Bumjung Park, Hyo Geun Choi, Eun Sook Nam, Seong Jin Cho, Kyueng-Whan Min, Eun Soo Kim, Hee Sung Hwang, Mineui Hong, Taeryool Koo, Hyo Jung Kim
Indian Journal of Surgical Oncology.2021; 12(S1): 134. CrossRef
Prevalence of high-risk human papillomavirus and its genotype distribution in head and neck squamous cell carcinomas
Yuil Kim, Young-Hoon Joo, Min-Sik Kim, Youn Soo Lee
Journal of Pathology and Translational Medicine.2020; 54(5): 411. CrossRef
Frequent hepatocyte growth factor overexpression and low frequency of c-Met gene amplification in human papillomavirus–negative tonsillar squamous cell carcinoma and their prognostic significances
Mi Jung Kwon, Dong Hoon Kim, Hye-Rim Park, Hyung Sik Shin, Ji Hyun Kwon, Dong Jin Lee, Jin Hwan Kim, Seong Jin Cho, Eun Sook Nam
Human Pathology.2014; 45(7): 1327. CrossRef

Methylation and Immunoexpression of p16^INK4a Tumor Suppressor Gene in Primary Breast Cancer Tissue and Their Quantitative p16^INK4a Hypermethylation in Plasma by Real-Time PCR: Jae Jun Lee, Eunkyung Ko, Junhun Cho, Ha Young Park, Jeong Eon Lee, Seok Jin Nam, Duk-Hwan Kim, Eun Yoon Cho; Korean J Pathol. 2012;46(6):554-561. Published online December 26, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.6.554

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Abstract PDF

Background

The p16^INK4a gene methylation has been reported to be a major tumorigenic mechanism.

Methods

We evaluated the methylation status of the p16^INK4a genes in 231 invasive breast cancer and 90 intraductal carcinoma specimens using a methylation-specific polymerase chain reaction and p16 protein expression using immunohistochemistry. The quantity of cell-free methylated p16^INK4a DNA in the plasma samples of 200 patients with invasive breast cancer was also examined using a fluorescence-based real-time polymerase chain reaction assay.

Results

The frequencies of p16^INK4a methylation in invasive and intraductal tumors were 52.8% (122/231) and 57.8% (52/90), respectively. The p16 protein was overexpressed in 145 of the 231 invasive carcinomas (62.8%) and 63 of the 90 intraductal carcinomas (70%). High p16 expression in invasive carcinomas correlated significantly with a high histologic grade, a negative estrogen receptor and progesterone receptor status, p53 immunoreactivity and high Ki-67 expression with immunohistochemistry. In addition, the methylation index of p16^INK4a was significantly higher in the cancer patients than the normal controls (p<0.001).

Conclusions

High p16 immunoreactivity correlated with a loss of differentiation in breast carcinomas and high frequency of p16^INK4a promoter methylation in both invasive and intraductal carcinomas, suggesting it may be involved in the pathogenesis of breast cancer.

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Case Report

Primary Endometrial Squamous Cell Carcinoma: A Case Report and Review of Relevant Literature on Korean Women: Sung Jong Lee, Hyun Joo Choi; Korean J Pathol. 2012;46(4):395-398. Published online August 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.4.395

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Abstract PDF

Primary endometrial squamous cell carcinoma (PESCC) is an extremely rare tumor with unclear pathogenesis. A 54-year-old postmenopausal woman presented with a 6-month history of vaginal bleeding. The patient was provisionally diagnosed with uterine submucosal leiomyoma. This was followed by total hysterectomy with a bilateral salpingo-oophorectomy under the laparoscopic guidance. Histopathologically, the tumor was PESCC which was accompanied by a lack of the tumor in the uterine cervix. The tumor showed positive immunoreactivity for p^16INK4a. But there was no evidence of human papillomavirus (HPV) on in situ hybridization and HPV DNA chip analysis. We also present a review of the relevant literature on Korean women.

Citations

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p16 Block Type Overexpression, p53 Wild Type Reactivity, and Cervical Involvement do not Always Exclude the Diagnosis of Primary Endometrial Squamous Cell Carcinoma (PESCC)
Daniela Fanni, Clara Gerosa, Michele Peiretti, Valerio Mais, Elena Massa, Stefano Angioni, Gavino Faa
International Journal of Gynecological Pathology.2024; 43(2): 200. CrossRef
Pathogenetic characteristics of endometrioid adenocarcinoma of uterus at present stage
T. I. Moiseenko, S. V. Shatalova, E. M. Nepomnyashchaya, V. A. Bandovkina, M. L. Adamyan
Medical alphabet.2024; (36): 35. CrossRef
Case report: Clinicopathological characteristic of two cases of primary endometrial squamous cell carcinoma and review of the literature
Hui-Bin Zhang, Li-Hua Lin, Qiu-Ping Lin, Yuan-Qing Lin, Dan Luo, Shu-Xia Xu
Frontiers in Oncology.2024;[Epub] CrossRef
Treatment of primary squamous cell carcinoma of the endometrium and review of previous literature: A case report
Liyun Song, Qi Wu, Suning Bai, Ren Xu, Xiaona Wang, Yanyan Yang
Medicine.2023; 102(17): e33667. CrossRef
Prevalence of human papilloma virus and Chlamydia trachomatis in endometrial and cervical carcinoma: a comparative study in North Indian women
Heena Gautam, Sumita Mehta, Nidhi Nayar, Neha Kumar, Syed Akhtar Husain, Mausumi Bharadwaj
Systems Biology in Reproductive Medicine.2023; 69(6): 399. CrossRef
PAX8 Positivity, Abnormal p53 Expression, and p16 Negativity in a Primary Endometrial Squamous Cell Carcinoma: A Case Report and Review of the Literature
Daniela Fanni, Michele Peiretti, Valerio Mais, Elena Massa, Clara Gerosa, Francesca Ledda, Maria Luisa Fais, Gavino Faa, Stefano Angioni
International Journal of Gynecological Pathology.2022; 41(4): 431. CrossRef
Molecular Analysis of HPV-independent Primary Endometrial Squamous Cell Carcinoma Reveals TP53 and CDKN2A Comutations
Mark R. Hopkins, Doreen N. Palsgrove, Brigitte M. Ronnett, Russell Vang, Jeffrey Lin, Tricia A. Murdock
American Journal of Surgical Pathology.2022; 46(12): 1611. CrossRef
Primary squamous cell carcinoma of the endometrium—Case report with cytological characteristics in direct and indirect endometrial samples
Sanda Rajhvajn, Ana Barišić, Lada Škopljanac‐Mačina, Danijela Jurič, Vesna Mahovlić
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Primary squamous cell carcinoma of the endometrium associated with human papilloma virus in a young woman: a case report
Tchin Darré, Abdoul-Samadou Aboubakari, Lantam Sonhaye, Baguilane Douaguibe, Akila Bassowa, Gado Napo-Koura
Journal of Medical Case Reports.2019;[Epub] CrossRef
Primary squamous cell carcinoma of the endometrium in a woman of perimenopausal age
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Original Articles

The Utility of p16INK4a and Ki-67 as a Conjunctive Tool in Uterine Cervical Lesions: Sangho Lee, Hyunchul Kim, Hyesun Kim, Chulhwan Kim, Insun Kim; Korean J Pathol. 2012;46(3):253-260. Published online June 22, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.3.253

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Abstract PDF

Background

Immunohistochemical staining for p16INK4a and Ki-67 has been used to improve the accuracy in making a diagnosis of the uterine cervix cancer on biopsy. This study was conducted to examine the usefulness of these markers in the pathological diagnosis based on cervical biopsy.

Methods

We selected a consecutive series of 111 colposcopically directed cervical punch biopsies. Using these biopsy samples, we performed an immunohistochemical staining for p16INK4a and Ki-67 to establish a diagnosis. The slides were circulated among four pathologists in a sequential order: the hematoxylin and eosin (H&E) slide, H&E slide and p16INK4a-stained slide, and H&E slide, p16INK4a- and Ki-67-stained slides.

Results

The overall rates of the concordance in the first, the second, and the third diagnoses were 77.5%, 82.0%, and 82.0%, respectively. The rate of the concordance in the diagnosis of cervical intraepithelial neoplasm (CIN) 2/3 was increased from 62.2% to 73.0%. But there was a variability in the rate of the revision of the diagnosis between the pathologists. With the application of criteria for interpreting the expressions of p16INK4a and Ki-67, benign and CIN 1 lesions showed a p16INK4a expression score of 0 or 1. But CIN 2 and CIN 3 lesions showed a p16INK4a expression score of 2 and 3, respectively.

Conclusions

The immunostain for p16INK4a and Ki-67 might be useful in reducing an inter-observer variability. But criteria for interpreting both markers should be strictly applied.

Citations

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Possible role of negative human papillomavirus E6/E7 mRNA as a predictor of regression of cervical intraepithelial neoplasia 2 lesions in hr-HPV positive women
Maria Teresa Bruno, Nazario Cassaro, Salvatore Giovanni Vitale, Arianna Guaita, Sara Boemi
Virology Journal.2022;[Epub] CrossRef
Evaluation of p16, human papillomavirus capsid protein L1 and Ki-67 in cervical intraepithelial lesions: Potential utility in diagnosis and prognosis
Hanan AlSaeid Alshenawy
Pathology - Research and Practice.2014; 210(12): 916. CrossRef
Distribution of Human Papillomavirus 52 and 58 Genotypes, and Their Expression of p16 and p53 in Cervical Neoplasia
Tae Eun Kim, Hwal Woong Kim, Kyung Eun Lee
Korean Journal of Pathology.2014; 48(1): 24. CrossRef
Detection and pathological value of papillomavirus DNA and p16INK4A and p53 protein expression in cervical intraepithelial neoplasia
JINGBO WU, XIAO-JING LI, WEI ZHU, XIU-PING LIU
Oncology Letters.2014; 7(3): 738. CrossRef
p16INK4a Immunohistochemistry in Cervical Biopsy Specimens
Miriam Reuschenbach, Nicolas Wentzensen, Maaike G. Dijkstra, Magnus von Knebel Doeberitz, Marc Arbyn
American Journal of Clinical Pathology.2014; 142(6): 767. CrossRef

Expression of Human Papillomavirus-Related Proteins and Its Clinical Implication in Tonsillar Squamous Cell Carcinoma: Joon Seon Song, Min-Sik Kim, Joon Wook Park, Youn Soo Lee, Chang Suk Kang; Korean J Pathol. 2012;46(2):177-186. Published online April 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.2.177

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Abstract PDF

Background

Human papillomavirus (HPV) is known to cause of oropharyngeal squamous cell carcinoma (SqCC). HPV positive SqCCs overexpress p16 and are associated with better survival. Several markers of cell cycles and apoptosis have been reported as a prognostic value. We examined the prognostic value of HPV status, p16, cyclin D1, and Bcl-2 in patients with tonsillar SqCC.

Methods

Tissue microarrays were constructed in 56 cases of tonsillar SqCC for which we performed an immunohistochemistry and an in situ hybridization (ISH) of the HPV.

Results

Of the 56 cases, 31 (55.3%) were positive for p16 and 20 (35.7%) were positive for HPV ISH. The expressions of p16, cyclin D1, and Bcl-2 were not correlated with the clinicopathologic variables including smoking status, differentiation and pT- and pN-stages. The HPV ISH positive group showed a better overall survival than the HPV negative group (p=0.04), and the p16 positive group showed a better disease free survival (DFS) than the negative group (p=0.016). Cox regression analysis showed that only p16 positivity was an independent prognostic factor for DFS (p=0.03; hazard ratio, 10.1).

Conclusions

Our results indicate that both p16 expression and HPV status are useful indicators for risk stratification in patients with tonsillar SqCC.

Citations

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Positive Rate of Human Papillomavirus and Its Trend in Head and Neck Cancer in South Korea
Hyun Woong Jun, Yong Bae Ji, Chang Myeon Song, Jae Kyung Myung, Hae Jin Park, Kyung Tae
Frontiers in Surgery.2022;[Epub] CrossRef
Negative Prognostic Implication of TERT Promoter Mutations in Human Papillomavirus–Negative Tonsillar Squamous Cell Carcinoma Under the New 8th AJCC Staging System
Hyunchul Kim, Mi Jung Kwon, Bumjung Park, Hyo Geun Choi, Eun Sook Nam, Seong Jin Cho, Kyueng-Whan Min, Eun Soo Kim, Hee Sung Hwang, Mineui Hong, Taeryool Koo, Hyo Jung Kim
Indian Journal of Surgical Oncology.2021; 12(S1): 134. CrossRef
In situ hybridization for high risk HPV E6/E7 mRNA in oropharyngeal squamous cell carcinoma
Krish Suresh, Parth V. Shah, Sydney Coates, Borislav A. Alexiev, Sandeep Samant
American Journal of Otolaryngology.2021; 42(1): 102782. CrossRef
Prevalence of high-risk human papillomavirus and its genotype distribution in head and neck squamous cell carcinomas
Yuil Kim, Young-Hoon Joo, Min-Sik Kim, Youn Soo Lee
Journal of Pathology and Translational Medicine.2020; 54(5): 411. CrossRef
Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists
James S. Lewis, Beth Beadle, Justin A. Bishop, Rebecca D. Chernock, Carol Colasacco, Christina Lacchetti, Joel Todd Moncur, James W. Rocco, Mary R. Schwartz, Raja R. Seethala, Nicole E. Thomas, William H. Westra, William C. Faquin
Archives of Pathology & Laboratory Medicine.2018; 142(5): 559. CrossRef
Detection of HPV infection in head and neck cancers: Promise and pitfalls in the last ten years: A meta-analysis
Carolin G�tz, Clara Bischof, Klaus-Dietrich Wolff, Andreas Kolk
Molecular and Clinical Oncology.2018;[Epub] CrossRef
Frequent hepatocyte growth factor overexpression and low frequency of c-Met gene amplification in human papillomavirus–negative tonsillar squamous cell carcinoma and their prognostic significances
Mi Jung Kwon, Dong Hoon Kim, Hye-Rim Park, Hyung Sik Shin, Ji Hyun Kwon, Dong Jin Lee, Jin Hwan Kim, Seong Jin Cho, Eun Sook Nam
Human Pathology.2014; 45(7): 1327. CrossRef
Human papillomavirus‐stratified analysis of the prognostic role of miR‐21 in oral cavity and oropharyngeal squamous cell carcinoma
Yoon Ho Ko, Hye Sung Won, Der Sheng Sun, Ho Jung An, Eun Kyoung Jeon, Min Sik Kim, Han Hong Lee, Jin Hyoung Kang, Chan Kwon Jung
Pathology International.2014; 64(10): 499. CrossRef
Human Papillomavirus Prevalence and Cell Cycle Related Protein Expression in Tonsillar Squamous Cell Carcinomas of Korean Patients with Clinicopathologic Analysis
Miji Lee, Sung Bae Kim, Sang-wook Lee, Jong-Lyel Roh, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim, Kyung-Ja Cho
Korean Journal of Pathology.2013; 47(2): 148. CrossRef

Genetic Analysis of Epstein-Barr Virus Latent Membrane Protein 1 and Immunohistochemical Expression of Transforming Growth Factor (TGF)-beta1, TGF-betaRII, p21, p16, E2F1, Thymidylate Synthase, and NF-kappaB in Epstein-Barr Virus Encoded RNA-positive Gastric Adenocarcinoma: Mee Yon Cho, Minseob Eom, Kwang Hwa Park, Mee Dong Kim, Seung Hoon Sung, Myoung Soo Kim, Dae Sung Kim, Sun Ju Choi; Korean J Pathol. 2006;40(3):176-184.

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Abstract PDF: BACKGROUND
:Although clinicopathologic differences have been described between Epstein-Barr virus (EBV)-positive and negative gastric adenocarcinomas, the pathogenetic basis for these differences remains unclear. In this study, efforts were made to confirm that expression of EBV-latent membrane protein (LMP1) and immunohistochemical characteristics of EBVpositive gastric adenocarcinomas.
METHODS
We investigated genomic deletion, and RNA & protein expression of the EBV-LMP1, as well as immunohistochemical protein expression of transforming growth factor (TGF)-beta1, TGF-bata RII, p21, p16, E2F1, thymidylate synthase, and NF-kappaB in relation to EBV positive gastric adenocarcinoma.
RESULTS
A total of 38 Epstein-Barr Virus Encoded RNA-positive and 80 negative gastric carcinomas were examined. A 30 bp DNA deletion in the EBV-LMP1 gene, initiating at codon 342, was detected in 94.4% of EBVpositive cases. By RT-PCR and western blotting, EBV-LMP1 mRNA and protein expressions were absent in all cases, re-gardless of DNA deletion. No significant differences in TGF-bata1, TGF-betaRII, p21, NF-kappaB, E2F1, or thymidylate synthase expression were identified. However, the decreased expression of p16 was found in 84.2% of EBV-positive carcinomas, relative to only 57.5% of EBV-negative tumors (p=0.024).
CONCLUSION
EBV-LMP1 DNA deletion, mRNA and protein losses are highly prevalent in EBV-positive gastric adenocarcinoma among Korean patients, along with decreased p16 expression.

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

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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

The Overexpression of Histone Deacetylase 1 and Its Relationship with p16INK4a Gene Hypermethylation in Pulmonary Squamous Cell Carcinoma and Adenocarcinoma.: Jong Hyeok Park, Young Seoub Hong, Phil Jo Choi, Na Young Kim, Kyung Eun Lee, Mee Sook Roh; Korean J Pathol. 2009;43(2):107-112.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.2.107

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Abstract PDF

BACKGROUND
DNA methylation and histone modification are dynamically linked in the epigenetic control of gene silencing and they play an important role in tumorigenesis.
METHODS
To evaluate the role of histone deacetylase 1 (HDAC1) in the development of lung cancer and the relationship between a HDAC1 overexpression and p16INK4a hypermethylation, we performed immunohistochemical staining for HDAC1 in 76 lung cancer specimens (39 squamous cell carcinomas and 37 adenocarcinomas) that had been previously evaluated for their p16INK4a methylation status by real-time quantitative polymerase chain reaction.
RESULTS
A HDAC1 overexpression (>50% of HDAC1 immunoreactive cells) was detected in 65 (85.5%) out of the 76 cases and it was more frequently seen in the squamous cell carcinomas (97.4%) than in the adenocarcinomas (73.0%) (p=0.002). The incidence of HDAC1 overexpression tended to be higher in the heavy smokers with more than 20 pack-years (p=0.067). Although there was no statistical significance, the frequency of p16INK4a hypermethylation in the cases with a HDAC1 overexpression (27.7%) tended to be higher than that in the cases without a HDAC1 overexpression (9.0%) (p=0.175).
CONCLUSIONS
A HDAC1 overexpression might be involved in lung carcinogenesis, and especially in a subgroup of smoking and squamous cell carcinoma patients, and a HDAC1 overexpression may be associated with p16INK4a hypermethylation.

Citations

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Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases
Yulia Aleksandrova, Margarita Neganova
International Journal of Molecular Sciences.2023; 24(19): 14766. CrossRef
Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy
Faizan Haider Khan, Basharat Ahmad Bhat, Bashir Ahmad Sheikh, Lubna Tariq, Roshan Padmanabhan, Jay Prakash Verma, Amritesh Chandra Shukla, Afshin Dowlati, Ata Abbas
Seminars in Cancer Biology.2022; 86: 732. CrossRef
Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer
Lin-Lin Cao, Xiaoxu Song, Lin Pei, Lianhua Liu, Hui Wang, Mei Jia
Medicine.2017; 96(31): e7663. CrossRef
The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer
Brian M. Zeglis, NagaVaraKishore Pillarsetty, Vadim Divilov, Ronald A. Blasberg, Jason S. Lewis
Nuclear Medicine and Biology.2011; 38(5): 683. CrossRef

Methylation Abnormality in Body Fluid Cytology: A Supplemental Molecular Marker for the Diagnosis of Malignant Mesothelioma.: Joon Seon Song, Jin Kyung Jung, Ji Hye Kang, Ilseon Hwang, Se Jin Jang; Korean J Cytopathol. 2008;19(2):126-135.; DOI: https://doi.org/10.3338/kjc.2008.19.2.126

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Abstract PDF

Malignant mesothelioma (MM) is a highly lethal neoplasm arising in pleura and the peritoneum and a rapid and accurate diagnosis is crucial for treatment of the disease. However, the sensitivity of cytological analysis using pleural or ascitic fluid is relatively low, yielding an accurate diagnosis in only 32~79% of cases. We tested the diagnostic value of epigenetic alterations in body fluid cytology as a supplement to conventional methods. Paraffin-embedded tissue blocks from 21 MM patients and associated body fluid cytology slides considered no evidence of malignancy were used to test for epigenetic alteration. Using methylation-specific PCR, we detected methylation of RASSF1A and p16 in 47.6% (10/21) of both surgically resected tumor samples, respectively. Body fluid samples of MM also showed abnormal methylation of RASSF1A and p16INK4a genes in 38.1% (8/21) and 33.3% (7/21) of cases. The concordance in the rates of RASSF1A and p16INK4a gene-methylation abnormalities determined from cytology samples and tissue samples were 61.9% (13/21) and 66.7% (14/21), respectively. Combining both genes increases the sensitivity of the test to 57.1% (12 of 21) of cases. Our results suggest that testing for methylation abnormalities in selected individual genes or gene combinations has diagnostic value as an alternative or adjunct method to conventional cytological diagnosis.

Citations

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Utility of Promoter Hypermethylation for Differentiating Malignant and Benign Effusions in Liquid-Based Cytology Specimens
Ga-Eon Kim, Jo-Heon Kim, Yeong-Hui Kim, Chan Choi, Ji Shin Lee
The Korean Journal of Pathology.2010; 44(3): 315. CrossRef

Loss of Heterozygosity at VHL, FHIT, and p16 Loci in Nonpapillary Renal Cell Carcinoma.: Won Sang Park, Seung Myung Dong, Yong Hyun Cho, Tae Gon Hwang, Su Young Kim, Min Sun Shin, Jae Ho Pi, Suk Hyung Lee, Nam Jin Yoo, Jung Young Lee; Korean J Pathol. 1999;33(1):8-14.

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Abstract PDF: The objectives of this study were to characterize the alterations of 3p and 9p in sporadic renal cell carcinomas (RCC) and to assess the relationship between the clinical stages or tumor size and the alteration of these chromosomes. Thirty eight archival, paraffin embedded tissue sections from 38 patients with RCC were analyzed for loss of heterozygosity (LOH) at 3p and 9p with 11 microsatellite markers. LOH was detected in 81.6% (31/38) and 37.8% (14/37) at 3p and 9p, respectively. The frequencies of LOH at VHL and FHIT locus were 75.6% and 72.2%, respectively. Twelve cases out of 38 showed LOH at both 9p21 and 3p. The loss of 3p in the samples tested was not related to clinical stages and tumor size, but that of 9p21 was significantly associated with advanced stage and larger tumor size. These results support that 3p deletion, including VHL and FHIT gene, play a critical role in the tumorigenesis of sporadic RCC, especially at early stage, and that 9p21 may contribute to the progression of sporadic RCC.

Expression of p16 and Rb in 9,10-Dimethyl-1,2-Benzanthracene Induced Rat Ovarian Carcinogenesis.: Ki Kwon Kim, Dong Hun Kim; Korean J Pathol. 2001;35(2):144-150.

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Abstract PDF: BACKGROUND
In order to investigate the roles of p16 and Rb, their expression was evaluated in 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced ovarian cancers of rats.
METHODS
DMBA-coated silk was inserted into both ovaries of 20 9-week-old Sprague-Dawley rats. The experimental period lasted 20 weeks. The tumor histology was classified and the expression of p16 and Rb in the ovarian tumors was analyzed by immunohistochemistry and Western blot.
RESULTS
The p16 and Rb labeling index was significantly lower in the ovarian cancers than the normal ovarian surface epithelium of a rat. There were no differences among the cancer types. In Western blot analysis, the expressions of p16 and Rb in ovarian cancers were lower than those in normal ovarian tissue. No correlation was present between p16 and Rb.
CONCLUSION
The abnormal expression of p16 and Rb occurs in DMBA-induced rat ovarian cancer and might be involved in carcinogenesis.

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