Journal of Pathology and Translational Medicine

Original Articles

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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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

Citations to this article as recorded by

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
Der Pathologe.2015; 36(3): 317. CrossRef
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

Expression of CHOP in Squamous Tumor of the Uterine Cervix: Hyun Hee Chu, Jun Sang Bae, Kyoung Min Kim, Ho Sung Park, Dong Hyu Cho, Kyu Yun Jang, Woo Sung Moon, Myoung Jae Kang, Dong Geun Lee, Myoung Ja Chung; Korean J Pathol. 2012;46(5):463-469. Published online October 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.5.463

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Abstract PDF

Background

High-risk human papillomavirus (HR-HPV) infection and abnormal p53 expression are closely involved in carcinogenesis of squamous cell carcinoma (SqCC) of uterine cervix. Recent studies have suggested that virus-induced endoplasmic reticulum (ER) stress modulates various cell survival and cell death signaling pathways. The C/EBP homologous protein (CHOP) is associated with ER stress-mediated apoptosis and is also involved in carcinogenesis of several human cancers. We hypothesized that CHOP is involved in the carcinogenesis of uterine cervical cancer in association with HR-HPV and/or p53.

Methods

Immunohistochemistry was used to analyze CHOP and p53 protein expression of tissue sections from 191 patients with invasive cancer or preinvasive lesions of the uterine cervix (61 cases of SqCC, 66 cases of cervical intraepithelial neoplasia [CIN] III, and 64 cases of CIN I).

Results

CHOP was expressed in 59.4% of CIN I, 48.5% of CIN III, and 70.5% of SqCC cases. It was also significantly more frequent in invasive SqCC than in preinvasive lesions (p=0.042). Moreover, CHOP expression significantly correlated with HR-HPV infection and p53 expression (p=0.009 and p=0.038, respectively).

Conclusions

Our results suggest that CHOP is involved in the carcinogenesis of the uterine cervix SqCC via association with HR-HPV and p53.

Citations

Citations to this article as recorded by

Expression of GRP78 and its copartners in HEK293 and pancreatic cancer cell lines (BxPC-3/PANC-1) exposed to MRI and CT contrast agents
Ali Ahmed Azzawri, Ibrahim Halil Yildirim, Zeynep Yegin, Abdurrahim Dusak
Nucleosides, Nucleotides & Nucleic Acids.2024; 43(5): 391. CrossRef
Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology
Elif Guzel, Sefa Arlier, Ozlem Guzeloglu-Kayisli, Mehmet Tabak, Tugba Ekiz, Nihan Semerci, Kellie Larsen, Frederick Schatz, Charles Lockwood, Umit Kayisli
International Journal of Molecular Sciences.2017; 18(4): 792. CrossRef
Endoplasmic reticulum stress pathway PERK‐eIF2α confers radioresistance in oropharyngeal carcinoma by activating NF‐κB
Qiao Qiao, Chaonan Sun, Chuyang Han, Ning Han, Miao Zhang, Guang Li
Cancer Science.2017; 108(7): 1421. CrossRef
Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells
Boyun Kim, Hee Seung Kim, Eun-Ji Jung, Jung Yun Lee, Benjamin K. Tsang, Jeong Mook Lim, Yong Sang Song
Molecular Carcinogenesis.2016; 55(5): 918. CrossRef
Down-regulation of C/EBP homologous protein (CHOP) expression in gastric cardia adenocarcinoma: Their relationship with clinicopathological parameters and prognostic significance
Xiao-Juan Zhu, She-Gan Gao, San-Qiang Li, Zhen-Guo Shi, Zhi-Kun Ma, Shan-Shan Zhu, Xiao-Shan Feng
Clinics and Research in Hepatology and Gastroenterology.2015; 39(3): 391. CrossRef
MG289 in <i>Mycoplasma genitalium</i> Enhances Microbial Invasion and Bacterial Persistence in Benign Human Prostate Cells
Wasia Rizwani, Leticia Reyes, Jeongsoon Kim, Steve Goodison, Charles J. Rosser
Open Journal of Urology.2013; 03(06): 232. 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 Self-collected Pad Sampling for the Detection of HPV In Cervicovaginal Secretion.: Seong Rim Kim, Sang Yong Song, Dae Shick Kim, Jung Won Lee, Chang Soo Park, Duk Soo Bae, Hyen Ji Lee, Kyung Tae Kim, Oh Joong Kwon, Eun Seop Song, Hee Jae Joo, Gheungwhan Ahn; Korean J Pathol. 2004;38(4):258-264.

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Abstract PDF: BACKGROUND
Self-collection of secretion samples for HPV testing is a feasible alternative method for women who would decline to participate in population based cervical cancer programs. The purpose of this study was to determine the sensitivity and specificity of self-sampling for HPV in determining high grade squamous intraepithelial lesion (HSIL) using the pad, and we also wished to compare the results from samples collected by women themselves and those results from samples collected by physicians.
METHODS
Fifty patients voluntarily participated in the sensitivity and specificity study at the university hospitals and 290 volunteers participated in the agreement study at local clinics. DNA was extracted and amplified using HPV L1 consensus primers for the direct sequencing of the pad samples.
RESULTS
For the detection of HSIL, self-collected pad sampling showed good sensitivity (75.0%) and excellent specificity (100%). Two hundreds eighty-six samples from the pads and concurrent physicians?samples showed the agreement at 98.6% with the Kappa, 0.9622 (p=0.0000).
CONCLUSIONS
A self-sampling method using the pad for the detection of HPV DNA is suggested to be an efficient method to access many women for screening easily, rapidly and conveniently. Testing the pad method? utility for a country- or large area-based mass screening study will be necessary in the future.

Detection of Chromosome Aberration in Interphase Nuclei of Tumor Cells by Nonradioactive In Situ Hybridization Using Chromosome-specific Probes.: Sang Sook Lee; Korean J Pathol. 1993;27(6):573-580.

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Abstract PDF: An improved protocol for in situ hybridization(ISH) to routinely processed, paraffin-embedded tissue sections from lung carcinoma is presented. For this study, DNA probes for alpha-satellite chromosome 7 and 17 were used. The protocol to detect numerical chromosome aberrations involved treatment of sections with 1 M sodium thiocyanate prior to pepsin digestion, resulting in reproducible ISH reactions. The effect of avidin-biotin detection system. Four layer avidin methods and triple biotin methods, using avidin-PO, goat antiavidin, biotinylated antigoat IgG, avidin-PO or anti-biotin, biotinylated antirabbit IgG, avidin-PO, markedly enhanced the intensity of positive signals. More than 80% of the tumor and stromal cells showed distinct chromosome hybridization signals in 6 micrometer-thick sections. Lung carcinoma cells showed multiple chromosome signals(2~5 spots), contrasted by one or two signals in the stromal cells in the same section. These results suggest that chromosome polysomy can be reliably detected in tissue sections using in situ hybridization. This capability will prove to be an important tool for determining the underlying genetic basis for tumor development, tissue phenotype heterogeneity and progression by allowing genetic determination to be made on paraffin-embedded tissue sections where tumor histologic architecture is preserved.

Detection of Human Papillomavirus DNA by In Situ Hybridization using Biotinylated DNA Probes in Cervical Intraepithelial Neoplasias and Squamous Cell Carcinomas.: Sang Sook Lee, Ki Kwon Kim, Chai Hong Chung, Seung Won Jin, U Ik Sohn; Korean J Pathol. 1990;24(1):16-26.

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Abstract PDF: The authors examined 9 condylomas, 26 cervical intraepithelial neoplasms(CIN) and 22 invasive squamous cell carcinomas for the presence of human papillomavirus(HPV) DNA sequences by DNA-DNA in situ hybridization. In situ hybridization revealed target HPV DNA sequences mostly in the nuclei of the superficial cells from epithelium which contained either maturation or koilocytotic atypias. With the use of biotinylated HPV DNA probes 6/11, 16/18 and 31/33/35, 42 of the 57(73.7%) were positive with HPV-6/11, 23 with HPV-16/18, 32 with HPV-31/33/35 and 18 with two or more mixed probes. HPV-31/33/35 was wht most prevalent in CIN and invasive squamous cell carcinomas, follwed by HPV-16/18. The incidence of HPV DNA increased from 66.7% to 86.4% with increasing severity of the lesions from condylomas to invasive squamous cell carcinomas. Flat condyloma was most freuently accompanied by CIN.

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