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Kuntamung K, Sangthong P, Jakmunee J, Ounnunkad K. Simultaneous immunodetection of multiple cervical cancer biomarkers based on a signal-amplifying redox probes/polyethyleneimine-coated gold nanoparticles/2D tungsten disulfide/graphene oxide nanocomposite platform. Bioelectrochemistry 2024; 160:108780. [PMID: 39018611 DOI: 10.1016/j.bioelechem.2024.108780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/06/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024]
Abstract
To advance cervical cancer diagnostics, we propose a state-of-the-art label-free electrochemical immunosensor designed for the simultaneous detection of multiple biomarker proteins (p16INK4a, p53, and Ki67). This immunosensor is constructed using a polyethyleneimine-coated gold nanoparticles/2D tungsten disulfide/graphene oxide (PEI-AuNPs/2D WS2/GO) composite-modified three-screen-printed carbon electrode (3SPCE) array. The 2D WS2/GO hybrid provides a large specific surface area for supporting well-dispersed PEI-AuNPs and adsorbed redox-active species, enhancing overall performance. The PEI-AuNPs-decorated 2D WS2/GO composite not only improves electrode conductivity but also increases the antibody loading capacity. Redox-active species, including Cd2+ ions, 2,3-diaminophenazine (DAP), and methylene blue (MB), serve as distinct signaling compounds to quantitatively detect the cervical cancer biomarkers p16INK4a, p53, and Ki67, respectively. Additionally, the immunosensor demonstrates the detection with high sensitivity, good storage stability, high selectivity, and acceptable reproducibility. This immunosensor demonstrates a good linear relationship with the logarithm of protein concentrations. Additionally, the immunosensor also demonstrates high sensitivity, good storage stability, high selectivity, and acceptable reproducibility. Our promising results and the successful application of the immunosensor in detecting three tumor markers in human serum highlight its potential for clinical diagnosis of cervical cancer.
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Affiliation(s)
- Kulrisa Kuntamung
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Division of Occupational and Environmental Diseases, Department of Disease Control, Ministry of Public Health, Nonthaburi 11000, Thailand
| | - Padchanee Sangthong
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Jaroon Jakmunee
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Kontad Ounnunkad
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Pateras IS, Igea A, Nikas IP, Leventakou D, Koufopoulos NI, Ieronimaki AI, Bergonzini A, Ryu HS, Chatzigeorgiou A, Frisan T, Kittas C, Panayiotides IG. Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System. Int J Mol Sci 2024; 25:1251. [PMID: 38279253 PMCID: PMC10816510 DOI: 10.3390/ijms25021251] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.
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Affiliation(s)
- Ioannis S. Pateras
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Ana Igea
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain
| | - Ilias P. Nikas
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus
| | - Danai Leventakou
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Nektarios I. Koufopoulos
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Argyro Ioanna Ieronimaki
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Anna Bergonzini
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Alfred Nobels Allé 8, 141 52 Stockholm, Sweden;
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Teresa Frisan
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Christos Kittas
- Department of Histopathology, Biomedicine Group of Health Company, 156 26 Athens, Greece;
| | - Ioannis G. Panayiotides
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
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Pereira Pinto P, Zanine RM. Diagnostic value of p16 and Ki-67 expression in cervical glandular intraepithelial disease: A review. Ann Diagn Pathol 2023; 62:152054. [PMID: 36396551 DOI: 10.1016/j.anndiagpath.2022.152054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/07/2022] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Cervical adenocarcinoma has been increasing in frequency, particularly among young women. Its diagnosis still presents many challenges. In addition to the difficulty in accessing the lesion, the lack of well-established criterias for cytological and histological diagnosis, and colposcopic images that are often not very clear, there are many benign situations that mimic glandular diseases. Immunohistochemistry has been used to aid this diagnosis. The purpose of this review is to evaluate the data available in the literature related to the use of p16 and Ki-67 as an auxiliary tool in the diagnosis of glandular disease. METHODS Original articles were searched in the PUBMED/MEDLINE, EMBASE, SCOPUS and BVS using different combinations of keywords and descriptors. RESULTS Of the 83 initial articles, 10 were selected. The criterias used for immunohistochemical interpretation showed many differences. The studies compared benign pathologies to malignant pathologies and some used panels with different immunomarkers while others used only p16. P16 showed an intense staining pattern in malignant pathologies, despite some studies have shown a negative pattern in adenocarcinoma. This can be explained by the histological subtype, not always related to HPV. Some studies have shown immunopositivity for p16 in normal tissues, tubal metaplasia and cervical endometriosis, but the staining pattern was never intense, as in malignant tissues. Ki-67 showed a more intense staining in AIS and adenocarcinoma tissues and was also present in normal tissues, mainly in tubal metaplasia and cervical endometriosis. CONCLUSIONS Biomarkers have proved to be important tools in aiding the diagnosis of glandular lesions, either alone or in panels. Standardization in the interpretation of immunochemistry is required.
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Affiliation(s)
- Patrícia Pereira Pinto
- Department of Gynecology, Clinical Hospital Complex of the Federal University of Paraná, Rua General Carneiro, 181, Alto da Glória, Curitiba, Paraná, 80060-900, Brazil.
| | - Rita Maira Zanine
- Department of Gynecology, Clinical Hospital Complex of the Federal University of Paraná, Rua General Carneiro, 181, Alto da Glória, Curitiba, Paraná, 80060-900, Brazil
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Buza N. Immunohistochemistry in gynecologic carcinomas: Practical update with diagnostic and clinical considerations based on the 2020 WHO classification of tumors. Semin Diagn Pathol 2021; 39:58-77. [PMID: 34750021 DOI: 10.1053/j.semdp.2021.10.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023]
Abstract
This review provides an update on immunohistochemistry applications-diagnostic, prognostic, and predictive-in the pathology evaluation of gynecologic carcinomas. The 5th edition of the WHO Classification of Female Genital Tumors introduced important changes in the diagnostic classification of lower genital tract, endometrial, and ovarian carcinomas, with major influence on the routine pathology practice. Lower genital tract carcinomas and their precursor lesions are now classified based on their human papillomavirus (HPV)-associated and HPV-independent pathogenesis, reflecting the clinically significant prognostic differences and impacting the therapeutic decision-making. Immunohistochemical markers have an increasing role in the pathology evaluation of endometrial carcinomas: in addition to their traditional use in the differential diagnosis and histologic subtyping, they have also been recently advocated for prognostic classification as surrogates for the TCGA (The Cancer Genome Atlas) molecular groups. New entities - mesonephric-like adenocarcinoma and gastric (gastrointestinal)-type mucinous adenocarcinoma of the endometrium - have also been added and often require immunostains for diagnostic confirmation. Ovarian carcinomas frequently show overlapping morphologic patterns and heterogeneous appearance within the same tumor, necessitating immunohistochemical work-up. Beyond diagnostic applications, there is increasing clinical demand for screening of inherited cancer syndromes, prediction of prognosis and guiding targeted therapy. Practical issues and pitfalls related to mismatch repair protein immunohistochemistry, HER2, and PD-L1 testing are also discussed.
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Affiliation(s)
- Natalia Buza
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
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A Comprehensive Review of Biomarker Use in the Gynecologic Tract Including Differential Diagnoses and Diagnostic Pitfalls. Adv Anat Pathol 2020; 27:164-192. [PMID: 31149908 DOI: 10.1097/pap.0000000000000238] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Morphologic (ie, hematoxylin and eosin) evaluation of the Mullerian tract remains the gold standard for diagnostic evaluation; nevertheless, ancillary/biomarker studies are increasingly utilized in daily practice to assist in the subclassification of gynecologic lesions and tumors. The most frequently utilized "biomarker" technique is immunohistochemistry; however, in situ hybridization (chromogenic and fluorescence), chromosomal evaluation, and molecular analysis can also be utilized to aid in diagnosis. This review focuses on the use of immunohistochemistry in the Mullerian tract, and discusses common antibody panels, sensitivity and specificity of specific antibodies, and points out potential diagnostic pitfalls when using such antibodies.
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Xiao Y, Liang MR, Liu CC, Wang YN, Zeng Y, Zhou J, Zhu HT, Wang Q, Zou Y, Zeng SY. Overexpression of P16 reversed the MDR1-mediated DDP resistance in the cervical adenocarcinoma by activating the ERK1/2 signaling pathway. Cell Div 2019; 14:6. [PMID: 31312250 PMCID: PMC6612198 DOI: 10.1186/s13008-019-0048-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 05/18/2019] [Indexed: 11/27/2022] Open
Abstract
Background To investigate the role of P16 (INK4a)-extracellular signal related kinase 1/2 (ERK1/2) signaling pathway in cisplatin (DDP) resistance induced by multidrug resistance protein 1 (MDR1), also known as P-glycoprotein (P-gp), in cervical adenocarcinoma. Methods A human DDP-resistant HeLa cell line (HeLa/DDP) was constructed using the combination of incremental and intermittent administration of DDP. Cell Counting Kit-8 (CCK-8) assay was used to measure the IC50 and resistance index (RI) of cells. The morphological changes and population doubling time were observed under an inverted microscope. Plate cloning formation assay was performed to evaluate the cell proliferation and tumorigenic ability. Cell invasion and migration were determined by transwell assays. Besides, the expression of P16, phosphorylated extracellular signal related kinase 1 and 2 (pERK1/2), total ERK1/2 and MDR1 were measured using western blot analysis. The ERK-specific inhibitor U0126 and agonist TPA was used to explore the role of ERK. Results The DDP-resistant cervical adenocarcinoma HeLa/DDP cell line was successfully established, which showed stronger cell growth, invasion, and migration. In the HeLa/DDP cells, pERK1/2 was downregulated, P-gp was upregulated and P16 was downregulated. Overexpression of P16 led to a significant decrease in the proliferation rate, migration ability, and invasion ability of the HeLa/DDP cells. Furthermore, overexpression of P16 increased and the decreased expression of pERK1/2 and P-gp in the HeLa/DDP cells, respectively. Treatment of HeLa/DDP cells transfected with P16 plasmid with ERK-specific inhibitor U0126 significantly decreased the expression of pERK1/2 and increased the expression of P-gp from 6 h to 48 h. Moreover, after 72 h, the expression of pERK1/2 was up-regulated and the expression of P-gp was inhibited. Conclusion Overexpression of P16 could partially reverse the MDR1-mediated DDP resistance in the cervical adenocarcinoma by the enhancement of phosphorylation of ERK signaling pathway, which provided a theoretical basis for the treatment of DDP resistance in cervical adenocarcinoma. Electronic supplementary material The online version of this article (10.1186/s13008-019-0048-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yun Xiao
- 1Medical College of Nanchang University, No.461, Bayi Street, Nanchang, 330006 Jiangxi China.,Department of Radiotherapy, Jiangxi Tumor Hospital, No. 519, Beijingdong Street, Nanchang, 330029 Jiangxi China
| | - Mei-Rong Liang
- 1Medical College of Nanchang University, No.461, Bayi Street, Nanchang, 330006 Jiangxi China.,3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Cheng-Cheng Liu
- 3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Ya-Nan Wang
- 3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Yang Zeng
- 3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Jun Zhou
- 3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Hui-Ting Zhu
- 3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Qin Wang
- Department of Obstetrics and Gynecology, Duchang Maternal and Child Health Hospital, No. 79, Dongfeng Street, Duchang, 332600 Jiangxi China
| | - Yang Zou
- 4Center Laboratory, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
| | - Si-Yuan Zeng
- 1Medical College of Nanchang University, No.461, Bayi Street, Nanchang, 330006 Jiangxi China.,3Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi Street, Nanchang, 330006 Jiangxi China
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7
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Darling HS. Metachronous endobronchial metastasis from uterine cervical adenocarcinoma. SOUTH AFRICAN JOURNAL OF ONCOLOGY 2018. [DOI: 10.4102/sajo.v2i0.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Malignant involvement of the lung can be primary or metastatic. Although primary lung cancer may be endobronchial, parenchymal or both, metastases to the lung are generally parenchymal. However, less commonly, they may be endobronchial. The lungs are the most common site of metastases among all the malignancies. Common extrapulmonary malignancies causing endobronchial metastases (EBMs) are breast, colorectal and kidney. EBMs from uterine cervical cancer are very rare. Although there are a few case reports in the medical literature describing EBM from cervical cancer, none are from adenocarcinoma histology. In this study, we report a case of EBM which on histopathological examination and immunohistochemistry were found to be from a prior adenocarcinoma cervix. Differentiating EBM from bronchogenic carcinoma and other more common extrapulmonary solid organ malignancies may present a clinico-pathological and radiological challenge.
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Kawachi A, Yoshida H, Kitano S, Ino Y, Kato T, Hiraoka N. Tumor-associated CD204 + M2 macrophages are unfavorable prognostic indicators in uterine cervical adenocarcinoma. Cancer Sci 2018; 109:863-870. [PMID: 29274107 PMCID: PMC5834786 DOI: 10.1111/cas.13476] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 12/09/2017] [Accepted: 12/18/2017] [Indexed: 12/13/2022] Open
Abstract
Uterine cervical adenocarcinoma is rare, but its prevalence has increased. To improve outcomes and ensure the suitability of recent immunotherapies, the aim of this study was to evaluate the clinicopathological impact of the tumor immune microenvironment of uterine cervical adenocarcinoma. We investigated 148 adenocarcinoma cases, including 21 cases of adenocarcinoma in situ (AIS) and 127 cases of invasive adenocarcinoma, using immunohistochemistry to detect tumor-infiltrating immune cells and the expression of programmed cell death 1 ligand-1 (PD-L1) and p16 on tumor cells. We then carried out correlation and survival analyses. The density of immune cells and expression levels were compared between the tumor cell nest and stroma and between AIS and invasive adenocarcinoma using digital image analysis. A higher density of tumor-infiltrating CD204+ M2 macrophages was significantly associated with shorter disease-free survival, although no other tumor-infiltrating immune cells were prognostic, including CD4+ , CD8+ , FOXP3+ , and PD-1+ lymphocytes and CD68+ macrophages. The density of stroma-infiltrating lymphocytes and macrophages was significantly higher in invasive adenocarcinoma than in AIS. The density of tumor-infiltrating lymphocytes in p16-expressing human papillomavirus (HPV)-positive tumors was significantly higher than that in HPV-negative tumors. The HPV status was not associated with patient outcome. Expression of PD-L1 on tumor cells was found only in invasive adenocarcinoma cases (17.3%). A higher density of stroma-infiltrating lymphocytes and macrophages was found in PD-L1-positive tumors than in negative tumors. Patients with PD-L1-positive tumors tended to experience longer survival. It is suggested that tumor-infiltrating CD204+ M2 macrophages may predict poor prognoses in patients with cervical adenocarcinoma.
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Affiliation(s)
- Asuka Kawachi
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroshi Yoshida
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Shigehisa Kitano
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshinori Ino
- Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Tomoyasu Kato
- Department of Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.,Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
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Buza N, Hui P. Immunohistochemistry in Gynecologic Pathology: An Example-Based Practical Update. Arch Pathol Lab Med 2017; 141:1052-1071. [PMID: 28745567 DOI: 10.5858/arpa.2016-0541-ra] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - Immunohistochemical stains are routinely applied in the pathology diagnostic workup of gynecologic lesions. The rapidly expanding repertoire of available markers helps in refining the diagnostic criteria for each disease entity; however, limitations and pitfalls exist. OBJECTIVE - To provide a practical, relevant update on the use of immunohistochemistry for commonly encountered differential diagnoses in gynecologic pathology. DATA SOURCES - Literature review and authors' diagnostic experience. CONCLUSIONS - Immunohistochemistry is a helpful adjunct tool in gynecologic pathology. Although the primary application is in the diagnostic workup, novel prognostic and predictive markers, and immunostains to screen for genetic cancer syndromes, have also been recently introduced in the field.
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Affiliation(s)
| | - Pei Hui
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
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10
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The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review. Clin Exp Metastasis 2017; 34:295-307. [PMID: 28730323 PMCID: PMC5561159 DOI: 10.1007/s10585-017-9856-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022]
Abstract
Secondary tumors of the ovary account for 10-25% of all ovarian malignancies. The most common tumors that give rise to ovarian metastases include breast, colorectal, endometrial, stomach, and appendix cancer. The correct diagnosis of secondary ovarian tumors may be challenging as they are not infrequently misdiagnosed as primary ovarian cancer, particularly in the case of mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extra-ovarian metastases and, furthermore, may suggest the primary tumor site. Despite extensive study, some cases remain equivocal even after assessing a broad spectrum of antigens. Therefore, gene expression profiling represents an approach able to further discriminate equivocal findings, and one that has been proven effective in determining the origin of cancer of unknown primary site. The available data concerning secondary ovarian tumors is rather limited owing to the relative heterogeneity of this group and the practical absence of any prospective trials. However, several intriguing questions are encountered in daily practice, including rational diagnostic workup, the role of cytoreductive surgery, and consequent adjuvant chemotherapy. This review seeks to address these issues comprehensively and summarize current knowledge on the epidemiology, pathogenesis, and management of secondary ovarian tumors, including further discussion on the different pathways of metastatisation, metastatic organotropism, and their possible molecular mechanisms.
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Kammerer-Jacquet SF, Thierry S, Cabillic F, Lannes M, Burtin F, Henno S, Dugay F, Bouzillé G, Rioux-Leclercq N, Belaud-Rotureau MA, Stock N. Differential diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: utility of p16 in combination with MDM2 and CDK4 immunohistochemistry. Hum Pathol 2017; 59:34-40. [DOI: 10.1016/j.humpath.2016.08.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/03/2016] [Accepted: 08/17/2016] [Indexed: 01/01/2023]
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Kaspar HG, Crum CP. The Utility of Immunohistochemistry in the Differential Diagnosis of Gynecologic Disorders. Arch Pathol Lab Med 2015; 139:39-54. [DOI: 10.5858/arpa.2014-0057-ra] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context
Immunohistochemistry has assumed an increasing role in the identification and characterization of gynecologic disorders including lesions with deceptively bland morphology, uncommon and underdiagnosed neoplasms, and neoplasms with specific genetic alterations associated with overexpression or loss of expression of specific proteins. The diagnostic accuracy has been significantly improved owing to the discovery and increasing experience with the tumor-associated biomarkers, and the increasing demand for precise tumor classification to assess suitability for the expanding therapeutic modalities including clinical trials.
Objective
To differentiate lesions of the gynecologic tract through the use of effective immunohistochemical panels.
Data Sources
Literature review and authors' personal practice experience.
Conclusions
The application of diagnostic and prognostic immunohistochemical panels has enabled pathologists to better guide therapeutic decisions and to better predict the clinical outcome. It is now well established that the use of ancillary testing, including immunohistochemistry, has a significant power in the identification, differentiation, and classification of reactive, premalignant, and malignant gynecologic disorders. This article discusses the utilities and pitfalls of the commonly used immunohistochemical markers in the context of overlapping morphologic features encountered in the uterus, ovaries, and fallopian tubes.
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Affiliation(s)
- Hanna G. Kaspar
- From the Department of Laboratory Medicine, Geisinger Health System, Wilkes-Barre, Pennsylvania (Dr Kaspar)
| | - Christopher P. Crum
- and the Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Crum)
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13
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Pabuccu EG, Taskin S, Ustun H, Gungor M, Aytac R, Yalcin I, Ortac F. Diagnostic performance of p16 staining in atypical squamous cells 'cannot exclude high-grade squamous epithelial lesion' in predicting high-grade cervical pathology. J OBSTET GYNAECOL 2014; 34:730-4. [PMID: 24999727 DOI: 10.3109/01443615.2014.930107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Atypical squamous cells 'cannot exclude high-grade squamous epithelial lesion' (ASC-H) cytology represents clear risk and has been a controversial issue in clinical practice. The objective of this study is to investigate the diagnostic performance of p16(INK4A) immunohistochemistry (IHC) among ASC-H Pap smears in predicting high-grade cervical intraepithelial lesions. Decolourisation and staining process with p16(INK4A) is applied to 27 ASC-H diagnosed conventional Pap smears, which were all managed with colposcopy-directed cervical biopsy priorly. Staining characteristics of ASC-H Pap smears were compared with histopathological data and sensitivity-specificity values of p16 triage to detect CIN2 + histopathology were determined. The sensitivity and specificity of positive p16(INK4A) immune staining to detect CIN2 + histopathology were as 87.5% and 68%, respectively. The positive predictive value of p16 triage is found as 53.8% and negative predictive value was as 92.8%. p16(INK4A) IHC seems applicable for conventional Pap smears and may provide an alternative triage option in ASC-H category.
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Affiliation(s)
- E G Pabuccu
- Department of Obstetrics and Gynecology, Ankara University School of Medicine , Ankara , Turkey
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14
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Loureiro J, Oliva E. The spectrum of cervical glandular neoplasia and issues in differential diagnosis. Arch Pathol Lab Med 2014; 138:453-83. [PMID: 24678677 DOI: 10.5858/arpa.2012-0493-ra] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Premalignant and malignant glandular lesions of the cervix are known to often cause diagnostic problems with a variety of benign (more common) as well as other malignant mimics, the latter setting often being represented by secondary involvement by endometrioid endometrial carcinoma especially in small samplings. OBJECTIVE To highlight key histologic features and immunohistochemical markers that may be helpful in the distinction of in situ endocervical carcinoma from benign glandular proliferations, and those that separate different subtypes of invasive endocervical carcinoma, as well as invasive carcinoma from other carcinomas secondarily involving the cervix and nonneoplastic proliferations of the cervix. CONCLUSIONS Clinical and morphologic features as well as immunohistochemistry results should be used in conjunction in the differential diagnosis of glandular proliferations of the cervix, as correct interpretation has major clinical consequences for the patient in most instances (especially benign versus malignant). Immunohistochemical markers should be used as part of a panel of antibodies, as exceptions may occur to the usual pattern of staining, and if used singly, they may mislead the pathologist to establish a wrong diagnosis.
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Affiliation(s)
- Joana Loureiro
- From the Department of Pathology, Instituto Português de Oncologia, Porto, Portugal (Dr Loureiro); and the Department of Pathology, Massachusetts General Hospital, Boston (Dr Oliva)
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15
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Yamauchi M, Fukuda T, Wada T, Kawanishi M, Imai K, Hashiguchi Y, Ichimura T, Yasui T, Sumi T. Comparison of outcomes between squamous cell carcinoma and adenocarcinoma in patients with surgically treated stage I-II cervical cancer. Mol Clin Oncol 2014; 2:518-524. [PMID: 24940487 DOI: 10.3892/mco.2014.295] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 04/30/2014] [Indexed: 11/06/2022] Open
Abstract
To improve our understanding of cervical adenocarcinoma (AD) and evaluate the clinical and pathological variables affecting its prognosis, we retrospectively reviewed the medical records of 455 patients with cervical cancer [International Federation of Gynecology and Obstetrics stage I/II; 91 cases with AD and 364 with squamous cell carcinoma (SCC)] who underwent surgery at our hospital between January, 1995 and August, 2012 and compared the characteristics and prognoses between AD and SCC cases, including age, clinical stage, histological type, lymph node metastasis, lymphovascular space invasion (LVSI), cervical stromal invasion, parametrial invasion, vaginal invasion, corpus invasion, ovarian metastasis and tumor diameter. We used Cox regression analysis to determine independent prognostic factors. AD was found to have a significantly poorer prognosis in all the patients (P=0.001), stage I patients (P=0.001) and stage IB patients (P<0.05). The prognosis did not differ in patients who did not require postoperative treatment; however, patients who received postoperative treatment exhibited a significantly poorer prognosis (P<0.05). Patients with AD who received postoperative irradiation alone had a significantly poorer prognosis (P<0.05). The multivariate analysis identified LVSI (P=0.008), stromal invasion (P=0.024) and ovarian metastasis (P=0.032) as independent predictors of shorter survival. AD was associated with a worse prognosis compared to SCC in patients with stage IB disease, particularly in those who required postoperative treatment. Such patients may benefit from individualized postoperative treatments that differ from those applied for SCC.
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Affiliation(s)
- Makoto Yamauchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Takeshi Fukuda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Takuma Wada
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Masaru Kawanishi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Kenji Imai
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Yasunori Hashiguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Tomoyuki Ichimura
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Tomoyo Yasui
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
| | - Toshiyuki Sumi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
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16
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Pacchiarotti A, Galeotti S, Bellardini P, Chini F, Collina G, Palma PD, Ghiringhello B, Maccallini V, Musolino F, Negri G, Pisa R, Sabatucci I, Rossi PG. Impact of p16(INK4a) immunohistochemistry staining on interobserver agreement on the diagnosis of cervical intraepithelial neoplasia. Am J Clin Pathol 2014; 141:367-73. [PMID: 24515764 DOI: 10.1309/ajcpcywvl61svkfu] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVES This study aimed to compare the interobserver Cohen κ on H&E staining and on H&E plus p16(INK4a) staining of all cervical biopsy specimens in a population-based screening program. METHODS All the colposcopy-guided biopsies generated by the routine screening of 23,258 women aged 25 to 64 years were stained with H&E and H&E plus p16. Biopsy specimens were reviewed by six external experts. RESULTS The four diagnoses were available in 441 cases. The interobserver κ values were 0.52 (95% confidence interval [CI], 0.45-0.58) and 0.48 (95% CI, 0.42-0.56) with H&E and H&E + p16, respectively, when using a five-group classification (normal, CIN 1, CIN 2, CIN 3, and cancer); adopting a two-group classification (≤CIN 1 and ≥CIN 2), the values were 0.75 (95% CI, 0.66-0.82) and 0.70 (95% CI, 0.61-0.79), respectively. CONCLUSIONS The use of p16 on all cervical biopsy specimens in a screening program showed virtually no effect on reproducibility of the histologic diagnosis.
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Affiliation(s)
- Alberto Pacchiarotti
- Lega Italiana per la Lotta contro i Tumori, Sezione Provinciale di Latina, Latina, Italy
| | - Simona Galeotti
- Servizio Interaziendale di Epidemiologia, AUSL Reggio Emilia, Reggio Emilia, Italy
| | - Paola Bellardini
- Screening, Latina Local Health Authority ASL di Latina, Latina, Italy
| | - Francesco Chini
- Laziosanità, Agenzia di Sanità Pubblica Regione Lazio, Rome, Italy
| | - Guido Collina
- UO Anatomia Patologica, AUSL di Bologna, Bologna, Italy; UO Anatomia Patologica, Ospedale Maggiore, AUSL di Bologna, Bologna, Italy
| | | | | | | | - Fabio Musolino
- Lega Italiana per la Lotta contro i Tumori, Sezione Provinciale di Latina, Latina, Italy
| | - Giovanni Negri
- Dipartimento di Patologia, Central Hospital Bolzano, Bolzano, Italy
| | - Roberto Pisa
- Servizio Anatomia Patologica, Azienda Ospedaliera S. Camillo-Forlanini, Rome, Italy
| | - Ilaria Sabatucci
- Department of Gynecologic–Obstetrical and Urologic Sciences, University of Rome, Rome, Italy
| | - Paolo Giorgi Rossi
- Servizio Interaziendale di Epidemiologia, AUSL Reggio Emilia, Reggio Emilia, Italy
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17
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von Knebel Doeberitz M, Reuschenbach M, Schmidt D, Bergeron C. Biomarkers for cervical cancer screening: the role of p16INK4ato highlight transforming HPV infections. Expert Rev Proteomics 2014; 9:149-63. [DOI: 10.1586/epr.12.13] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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18
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Abstract
Cervical cancer, a potentially preventable disease, remains the second most common malignancy in women worldwide. Human papillomavirus is the single most important etiological agent in cervical cancer, contributing to neoplastic progression through the action of viral oncoproteins, mainly E6 and E7, which interfere with critical cell cycle pathways, p53 and retinoblastoma. However, evidence suggests that human papillomavirus infection alone is insufficient to induce malignant changes and that other host genetic variations are important in the development of cervical cancer. This article will discuss the latest molecular profiling techniques available and review the published literature relating to their role in the diagnosis and management of cervical dysplasia and cancer. It is hoped that these techniques will allow the detection of novel biomarkers at DNA, RNA, microRNA and protein levels, which may ultimately play a role in facilitating early disease diagnosis and in predicting response to therapies, thus allowing the development of personalized treatment strategies.
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Affiliation(s)
- Cara M Martin
- Department of Pathology, Coombe Women's Hospital, Dublin 8, Ireland.
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19
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Koo YJ, Hahn HS, Lee IH, Lim KT, Lee KH, Kim HS, Kim TJ, Chun YK, Kim HS, Hong SR. Dual immunostaining of cervical cytology specimens with atypical squamous cells for p16/Ki-67 does not exclude the existence of a high-grade squamous intraepithelial lesion. Virchows Arch 2013; 463:689-96. [PMID: 24081504 DOI: 10.1007/s00428-013-1483-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 08/03/2013] [Accepted: 09/17/2013] [Indexed: 11/24/2022]
Abstract
This study was conducted to evaluate the accuracy of p16/Ki-67 dual immunostaining compared to high-risk human papillomavirus (HR-HPV) DNA testing for cervical intraepithelial neoplasia (CIN) in women with atypical squamous cells, cytology not excluding high-grade squamous intraepithelial lesion (ASC-H). Data were collected from 73 patients diagnosed to have ASC-H on a Pap smear who were HPV genotyped and had histological examination of a cervical biopsy. The CINtecPLUS kit was used on residual liquid-based material, and the immunoreactivity of dual-stained cells was graded according to the number as follows: G1 (1-5 positive cells), G2 (6-10), G3 (11-20), and G4 (> 20). Accuracy was evaluated based on the histological examination of colposcopy-guided biopsy or cervical conization on follow-up. Of the 70 patients with available data, positive p16/Ki-67 was associated with histological severity as follows: 15% in negative histology, 67% in CIN 1, 90% in CIN 2, and 100% in CIN 3. The average grade of positive p16/Ki-67 staining also increased from 0.2 in histologically negative cases to 1.2 in CIN 1, 2.4 in CIN 2, and 2.9 in CIN 3 (p < 0.01). For patients with CIN 2 or higher, p16/Ki-67 had a sensitivity of 94.6% and a specificity of 75.8%, while HR-HPV testing showed a sensitivity of 67.6% and a specificity of 66.7%. p16/Ki-67 immunostaining demonstrated better accuracy than HR-HPV for detecting CIN 2 or higher in patients with ASC-H cytology. Given the higher concordance with histological diagnosis, the grading system of positive p16/Ki-67 can be a useful adjunct for predicting high-grade lesions in clinical practice.
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Affiliation(s)
- Yu-Jin Koo
- Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea
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20
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Endocervical glandular neoplasia associated with lobular endocervical glandular hyperplasia is HPV-independent and correlates with carbonic anhydrase-IX expression: a Gynaecological Oncology Group Study. Br J Cancer 2013; 108:613-20. [PMID: 23299542 PMCID: PMC3593541 DOI: 10.1038/bjc.2012.578] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background: Lobular endocervical glandular hyperplasia (LEGH) is a rare lesion of the uterine cervix. It has been proposed that LEGH may represent a precursor lesion to a group of mucinous adenocarcinoma with gastric phenotype (GA) that is independent of high-risk human papillomavirus (H-HPV) infection. Carbonic anhydrase-IX (CA-IX) is highly expressed in conventional glandular lesions (CGLs). However, expression of CA-IX in LEGH or GA has not been studied. Methods: In all, 12 CGLs, 7 LEGHs, 6 LEGHs with coexisting adenocarcinoma in situ (AIS, 3) and GA (3) were identified from Japanese women with a cytological diagnosis of atypical glandular cells of undetermined significance. Immunostaining was used to detect CA-IX and p16INK4a (hereafter termed p16) protein expression in the tissues and CA-IX protein expression in the Papanicolaou smears (PSs). Polymerase chain reaction was used to detect H-HPV DNA in liquid-based cytology. Results: Out of 12 (83%) CGLs, 10 were positive with H-HPV and high levels of CA-IX expression were seen in all (100%) cases. P16 protein expression was observed in 11 out of 12 (92%) cases. None of the LEGHs, LEGHs with AIS or GA were positive for H-HPV and only 8 out of 13 (62%) showed focal weak (1+) p16 expression. In contrast, all cases (100%) exhibited strong CA-IX protein expression. Conclusion: Our study suggests that there are different molecular mechanisms of carcinogenesis resulting in CGLs vs LEGHs associated with AIS or GA. There is also a possible link between LEGHs and GAs. Furthermore, CA-IX expression may serve as a useful biomarker for the detection of GAs in the absence of H-HPV infection.
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21
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Ravarino A, Nemolato S, Macciocu E, Fraschini M, Senes G, Faa G, Negri G. CINtec PLUS immunocytochemistry as a tool for the cytologic diagnosis of glandular lesions of the cervix uteri. Am J Clin Pathol 2012; 138:652-6. [PMID: 23086765 DOI: 10.1309/ajcp00inmgifyfnq] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Cytologic findings of glandular lesions of the cervix uteri are often difficult to evaluate. We studied the usefulness of CINtec PLUS p16/Ki-67 double stain (mtm laboratories, Heidelberg, Germany) for the diagnosis of glandular lesions. The study included 47 abnormal results on liquid-based cytologic tests with a subsequent histologic diagnosis of adenocarcinoma in situ or with early invasion, and 16 samples with negative results on follow-up. All samples were stained with CINtec PLUS p16/Ki-67 double stain. Of the neoplastic samples, 7 were excluded because of insufficient residual cellularity or loss of neoplastic cells. Of the samples that were adequate, 92.5% were stained with CINtec PLUS, whereas 7.5% were judged inconclusive. All inconclusive cases were at least 3 years old. Of the 16 negative samples, 15 (93.8%) stained negative and only 1 (6.2%) showed several positive clusters of cells. Our study shows that CINtec PLUS is a robust and useful tool for the diagnosis of glandular lesions of the cervix uteri.
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22
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Alexander RE, Hu Y, Kum JB, Montironi R, Lopez-Beltran A, Maclennan GT, Idrees MT, Emerson RE, Ulbright TM, Grignon DG, Eble JN, Cheng L. p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma. Mod Pathol 2012; 25:1526-33. [PMID: 22684221 DOI: 10.1038/modpathol.2012.103] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.
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Affiliation(s)
- Riley E Alexander
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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23
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van Bogaert LJ. P16INK4a immunocytochemistry/immunohistochemistry: need for scoring uniformization to be clinically useful in gynecological pathology. Ann Diagn Pathol 2012; 16:422-6. [DOI: 10.1016/j.anndiagpath.2012.03.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Revised: 03/21/2012] [Accepted: 03/24/2012] [Indexed: 12/01/2022]
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24
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Izaaks CD, Truter EJ, Khan S. Prevalence of human papilloma virus in cytological abnormalities: Association of risk factors and cytomorphological findings. Cytojournal 2012; 9:19. [PMID: 22993533 PMCID: PMC3440928 DOI: 10.4103/1742-6413.100123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 06/18/2012] [Indexed: 11/15/2022] Open
Abstract
Background: Previous studies demonstrated the etiological role of human papilloma virus (HPV) in cervical carcinogenesis. Assessing the distribution of HPV may elucidate these observations. Materials and Methods: In total, we examined 3839 specimens, of which 187 abnormally classified cervical smears were immunostained using the p16INK4A assay. DNA was extracted from 182 specimens, and polymerase chain reaction (PCR) was performed. Participants’ socio-demographics, sexual and reproductive history, HIV status, contraceptive use, and Pap smear history were recorded. Results: Subject ages, number of sexual partners, and age at first sexual encounter ranged from 15 to 49 years, from 1 to 37 partners, and from 13 to 34 years, respectively. P16 immunoreactivity was detected in 60.4% of cases. The distribution of epithelial lesions and P16 overexpression (bracketed) was: 28 (5) atypical squamous cells of undetermined significance (ASC-US), 96 (50) lower grade squamous intraepithelial lesion (LSIL), 9 (7) atypical squamous cells-cannot exclude HSIL (ASC-H), and 54 (51) higher grade squamous intraepithelial lesion (HSIL). Ninety-four percent of HSIL expressed P16. Fifty-two percent of LSIL expressed P16. P16 expression declined from 61% (25–34 year age group) to 5% (45–49 year age group) for different age groups. HPV-DNA by PCR was detected in 94.5% of P16-positive samples. Type-specific PCR (HPV 16 and 18) was found in 12.2% and 14.5% of abnormal lesions, respectively. Younger age at first sexual encounter and HIV infection predominated in HPV type(s) 16 and/or 18 positive subjects. Conclusion: This study reinforced the value of the p16INK4A surrogate marker in identifying women with progressive cervical disease.
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Affiliation(s)
- Christo D Izaaks
- Address: Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology (CPUT), Bellville Campus, Cape Town 7535, Western Cape, Republic of South Africa
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25
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Lee SJ, Choi HJ. Primary endometrial squamous cell carcinoma: a case report and review of relevant literature on korean women. KOREAN JOURNAL OF PATHOLOGY 2012; 46:395-8. [PMID: 23110036 PMCID: PMC3479822 DOI: 10.4132/koreanjpathol.2012.46.4.395] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 12/22/2011] [Accepted: 12/28/2011] [Indexed: 11/17/2022]
Abstract
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 p16INK4a. 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.
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Affiliation(s)
- Sung Jong Lee
- Department of Obstetrics and Gynecology, St. Vincent's Hospital, The Catholic University of Korea School of Medicine, Suwon, Korea
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26
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Chen ZW, Weinreb I, Kamel-Reid S, Perez-Ordoñez B. Equivocal p16 immunostaining in squamous cell carcinoma of the head and neck: staining patterns are suggestive of HPV status. Head Neck Pathol 2012; 6:422-9. [PMID: 22801997 PMCID: PMC3500888 DOI: 10.1007/s12105-012-0382-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 06/27/2012] [Indexed: 01/03/2023]
Abstract
p16 immunohistochemistry (IHC) is commonly used as a surrogate marker for human papillomavirus (HPV) detection in squamous cell carcinomas of the head and neck (SCCHN). However, the HPV status of tumors not staining strongly for p16 is difficult to interpret and may require the use of PCR, not available in all laboratories, as a final arbiter. We aim to determine if staining pattern in equivocal p16 staining and correlation to the percentage of positively stained tumor cells is predictive of HPV status. A retrospective review was performed on all SCCHN that underwent p16 IHC and PCR in our institution from 2007 to 2010. Descriptors of staining pattern in the original IHC report were retrieved. All available IHC slides were reviewed and reclassified using consensus staining pattern descriptors. Original and reclassified descriptors were compared to the final PCR HPV status for statistical significance using the χ(2) test. An estimate of the percentage of tumor cells that showed any form of staining was performed. Thirty-two SCCHN cases that underwent PCR HPV testing had equivocal p16 IHC results. Twenty-six cases available for review were reclassified into four staining patterns. Comparing age, sex, tumor site and diagnosis to HPV PCR status showed no statistically significant findings. However, comparing original descriptors to HPV status was statistically significant with isolated staining associated with negative HPV status (p = 0.0002). Analysis using reclassified descriptors showed strong association of membranous/cytoplasmic staining of isolated cells with negative HPV status and faint, diffuse nuclear and cytoplasmic staining with positive HPV status (p = 0.00006). HPV-negative cases with the former pattern had no more than 30 % positively-stained tumor cells and HPV-positive cases with the latter pattern had 50-90 % positively-stained cells. Our results suggest that pattern of staining in p16 IHC is associated with HPV status. For instance, a diffuse nuclear and cytoplasmic staining pattern, regardless of intensity, is associated with HPV positivity. The HPV-positive cases determined by staining pattern were also associated with a higher percentage of stained tumor cells.
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Affiliation(s)
- Zhongchuan Will Chen
- Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON Canada
| | - Ilan Weinreb
- Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON Canada
| | - Suzanne Kamel-Reid
- Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON Canada
| | - Bayardo Perez-Ordoñez
- Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON Canada
- Department of Pathology, University Health Network, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON M5G 2C4 Canada
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27
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Differentiating rectal carcinoma by an immunohistological analysis of carcinomas of pelvic organs based on the NCBI Literature Survey and the Human Protein Atlas database. Surg Today 2012; 42:515-25. [PMID: 22441574 DOI: 10.1007/s00595-012-0167-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 08/01/2011] [Indexed: 12/27/2022]
Abstract
The treatments and prognoses of pelvic organ carcinomas differ, depending on whether the primary tumor originated in the rectum, urinary bladder, prostate, ovary, or uterus; therefore, it is essential to diagnose pathologically the primary origin and stages of these tumors. To establish the panels of immunohistochemical markers for differential diagnosis, we reviewed 91 of the NCBI articles on these topics and found that the results correlated closely with those of the public protein database, the Human Protein Atlas. The results revealed the panels of immunohistochemical markers for the differential diagnosis of rectal adenocarcinoma, in which [+] designates positivity in rectal adenocarcinoma and [-] designates negativity in rectal adenocarcinoma: from bladder adenocarcinoma, CDX2[+], VIL1[+], KRT7[-], THBD[-] and UPK3A[-]; from prostate adenocarcinoma, CDX2[+], VIL1[+], CEACAM5[+], KLK3(PSA)[-], ACPP(PAP)[-] and SLC45A3(prostein)[-]; and from ovarian mucinous adenocarcinoma, CEACAM5[+], VIL1[+], CDX2[+], KRT7[-] and MUC5AC[-]. The panels of markers distinguishing ovarian serous adenocarcinoma, cervical carcinoma, and endometrial adenocarcinoma were also represented. Such a comprehensive review on the differential diagnosis of carcinomas of pelvic organs has not been reported before. Thus, much information has been accumulated in public databases to provide an invaluable resource for clinicians and researchers.
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28
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Costa S, Venturoli S, Negri G, Sideri M, Preti M, Pesaresi M, Falasca A, Barbieri D, Zerbini M, Santini D, Sandri MT, Ghiringhello B, Caroppo Venturini N, Syrjänen S, Syrjänen K. Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the uterine cervix: An analysis of 166 cases. Gynecol Oncol 2012; 124:490-5. [DOI: 10.1016/j.ygyno.2011.11.039] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Revised: 11/18/2011] [Accepted: 11/20/2011] [Indexed: 11/25/2022]
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29
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Singh M, Mockler D, Akalin A, Burke S, Shroyer AL, Shroyer KR. Immunocytochemical colocalization of p16INK4a and Ki-67 predicts CIN2/3 and AIS/adenocarcinoma. Cancer Cytopathol 2011; 120:26-34. [DOI: 10.1002/cncy.20188] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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30
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Fuste V, del Pino M, Perez A, Garcia A, Torne A, Pahisa J, Ordi J. Primary squamous cell carcinoma of the vagina: human papillomavirus detection, p16(INK4A) overexpression and clinicopathological correlations. Histopathology 2011; 57:907-16. [PMID: 21166704 DOI: 10.1111/j.1365-2559.2010.03727.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM To determine the role of human papillomavirus (HPV) in the pathogenesis of primary squamous cell carcinoma of the vagina (SCCVa), and to evaluate its clinicopathological significance. METHODS AND RESULTS All cases of SCCVa diagnosed over a 15-year period from two hospitals in Barcelona, Spain (n=32) were retrieved. Patients with a history of carcinoma of the cervix diagnosed <5 years before were excluded. HPV was detected and typed by polymerase chain reaction (PCR) using SPF10 primers. Immunohistochemistry was performed for p16 and p53. HPV was detected in 25 cases (78.1%). HPV16 was the most prevalent type. Patients with HPV-positive tumours were associated frequently with a history of carcinoma or intraepithelial neoplasia of the cervix or vulva diagnosed more than 5 years before (56% versus 0%; P=0.01). HPV-positive tumours were more frequently of non-keratinizing, basaloid or warty type than HPV-negative neoplasms (84% versus 14.3%; P<0.001), and showed diffuse positive immunoreactivity for p16(INK4a) (96%, versus 14.3%; P<0.001). The sensitivity and specificity of p16 to identify HPV-positive tumours were 96% and 85.7%, respectively. CONCLUSIONS A high number of SCCVs are related to HPV infection and may be identified by immunohistochemistry for p16. HPV-positive tumours tend to affect women with history of cervical neoplasia.
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Affiliation(s)
- Victoria Fuste
- Department of Pathology, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain
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31
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Park KJ. Neoplastic Lesions of the Cervix. Surg Pathol Clin 2011; 4:17-86. [PMID: 26837288 DOI: 10.1016/j.path.2010.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
This review presents a discussion of the gross and microscopic features, diagnosis, differential diagnosis, and prognosis of neoplastic lesions of the cervix. Biomarkers are discussed for each entity presented - cervical intraepithelial neoplasia, squamous carcinoma, glandular neoplasms, adenocarcinoma in situ, adenosquamous carcinoma, and others.
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Affiliation(s)
- Kay J Park
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Is the expression of p16INK4A and galectin-3 correlated with disease progression of cervical neoplasia? ACTA ACUST UNITED AC 2011. [DOI: 10.5468/kjog.2011.54.4.192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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The prognostic signifi cance of p16, Ki-67, p63, and CK17 expression determined by immunohistochemical staining in cervical intraepithelial neoplasia 1. ACTA ACUST UNITED AC 2011. [DOI: 10.5468/kjog.2011.54.4.184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study. Br J Cancer 2010; 104:353-60. [PMID: 21157448 PMCID: PMC3031897 DOI: 10.1038/sj.bjc.6606049] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells. Methods: Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen. Results: Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH). Conclusion: The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.
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Huang MZ, Huang S, Li DQ, Nie XM, Li HB, Jiang XM. The study of the combination detection of HPV-DNA and p16INK4a in cervical lesions. Med Oncol 2010; 28 Suppl 1:S547-52. [DOI: 10.1007/s12032-010-9705-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Accepted: 09/25/2010] [Indexed: 11/24/2022]
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Samarawardana P, Dehn DL, Singh M, Franquemont D, Thompson C, Gaido L, Torkko KC, Homer P, Burke S, Titmus MA, Nayi V, Shroyer KR. p16(INK4a) is superior to high-risk human papillomavirus testing in cervical cytology for the prediction of underlying high-grade dysplasia. Cancer Cytopathol 2010; 118:146-56. [PMID: 20544710 DOI: 10.1002/cncy.20078] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The primary goal of this study was to compare the clinical performance of an optimized and rigorously controlled immunocytochemical (ICC) assay for p16(INK4a) to high-risk (HR) human papillomavirus (HPV) detection by polymerase chain reaction (PCR) as diagnostic adjuncts for cytology specimens from colposcopy patients. METHODS : The study included 403 cervical cytology specimens collected within 3 months of colposcopy. The colposcopic impression and cervical biopsy diagnosis served as the standards for correlation with cytological, p16(INK4a), and HPV data. p16(INK4a) was evaluated using an immunoperoxidase-based assay that was linear over 4 logs for the detection of HeLa-spiked positive control cytology specimens, using a threshold for positive test results that was based on receiver operating characteristic curve analysis. HR-HPV was detected by multiplex PCR using genotype-specific primers. RESULTS : In all combined diagnostic categories (negative for intraepithelial lesion and malignancy, atypical glandular cells, atypical squamous cells of undetermined significance, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion), the p16(INK4a) ICC and HR-HPV assays, respectively, had sensitivity of 81.7% and 83.3% (P = .81) and specificity of 78.1% and 50.9% (P < .001) for the detection of underlying > or =grade 2 cervical intraepithelial neoplasia (CIN) lesions on biopsy. Furthermore, the positive predictive value of p16(INK4a) ICC was greater than that of HR-HPV for patients with biopsies > or =CIN-2 (41.2% and 24.2%, respectively, P = .001). CONCLUSIONS : This p16(INK4a) immunocytochemical assay has superior specificity but similar sensitivity to HR-HPV testing to predict underlying high-grade dysplastic lesions in patients who are referred for colposcopy. The determination of the overall performance characteristics of p16(INK4a) immunocytochemistry, as an independent test or in combination with HPV testing in low-risk screening populations, however, will require subsequent large-scale prospective clinical trials.
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Affiliation(s)
- Panduka Samarawardana
- Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794-8691, USA
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Stewart CJR, Little L. Diagnostic value and implications of vimentin expression in normal, reactive and neoplastic endocervical epithelium. Pathology 2010; 42:217-23. [PMID: 20350213 DOI: 10.3109/00313021003631353] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
AIMS To assess vimentin immunoreactivity in normal, reactive and neoplastic endocervical epithelium, and compare the results with p16 protein, Ki-67 and bcl-2 expression. METHODS Sixty-two cervical biopsy specimens including normal endocervical epithelium, tubo-endometrioid metaplasia, adenocarcinoma in situ, stratified mucin producing intraepithelial lesions (SMILE), and invasive adenocarcinomas were stained immunohistochemically for vimentin and for p16 protein, Ki-67 and bcl-2. Twelve cases also included areas of high grade cervical intraepithelial neoplasia (CIN). RESULTS Normal endocervical epithelium usually showed subtle but distinct sub-nuclear and delicate lateral cell border vimentin expression while tubo-endometrioid metaplasia exhibited more diffuse cytoplasmic immunoreactivity. Usually adenocarcinoma in situ was completely negative and therefore vimentin staining sharply distinguished the benign and neoplastic epithelial elements. The SMILE lesions and high grade CIN were also vimentin negative in most cases. Most invasive adenocarcinomas were not stained but focal vimentin immunoreactivity was observed in 7/18 cases, and was restricted to small glands and infiltrating cell clusters at the deep (advancing) tumour margin. CONCLUSIONS Normal endocervical cells often exhibit vimentin staining, and this is increased in reactive and metaplastic situations, whereas adenocarcinoma in situ is usually completely negative. Therefore vimentin is a useful additional diagnostic marker in the assessment of problematic cervical glandular lesions. The localised re-expression of vimentin at the deep margin of some endocervical adenocarcinomas may be relevant to the process of tumour progression and invasion in these cases.
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Affiliation(s)
- C J R Stewart
- Department of Histopathology, King Edward Memorial Hospital, Perth, Western Australia
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Glandular neoplasms of the cervix. Diagn Cytopathol 2010. [DOI: 10.1016/b978-0-7020-3154-0.00024-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Value of p16(INK4a) as a marker of progression/regression in cervical intraepithelial neoplasia grade 1. Am J Obstet Gynecol 2009; 201:488.e1-7. [PMID: 19683687 DOI: 10.1016/j.ajog.2009.05.046] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2008] [Revised: 02/12/2009] [Accepted: 05/26/2009] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The objective of this study was to evaluate the usefulness of p16(INK4a) staining to classify cervical intraepithelial neoplasia grade 1 according to its progression/regression risk. STUDY DESIGN Patients with a histologic diagnosis of cervical intraepithelial neoplasia grade 1 were prospectively recruited (n = 138). Simultaneous detection of high-risk human papillomaviruses and p16(INK4a) evaluation were performed. Follow-up was conducted every 6 months by cytology and colposcopy and annually by high-risk human papillomavirus testing, for at least 12 months (mean, 29.0). Progression was defined as a histologic diagnosis of cervical intraepithelial neoplasia grades 2-3, regression as a negative cytology and high-risk human papillomaviruses, and persistence as a cytologic result of low-grade squamous intraepithelial lesions and/or a positive test for high-risk human papillomaviruses. RESULTS Progression was observed in 14 women (10.1%), 66 (47.6%) regressed, and 58 (42.0%) had a persistent disease. p16(INK4a) was positive in 77 (55.8%) initial biopsy specimens. Progression to cervical intraepithelial neoplasia grades 2-3 was identified in 14 of 77 (18.2%) women with positive and none of 61 (0.00%) women with negative p16(INK4a) immunostaining (P < .001). CONCLUSION p16(INK4a) negative cervical intraepithelial neoplasia grade 1 lesions rarely progress and may benefit from a less intensive follow-up.
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A pilot evaluation of a novel immunohistochemical assay for topoisomerase II-alpha and minichromosome maintenance protein 2 expression (ProEx C) in cervical adenocarcinoma in situ, adenocarcinoma, and benign glandular mimics. Int J Gynecol Pathol 2009; 28:114-9. [PMID: 19188825 DOI: 10.1097/pgp.0b013e3181895573] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The histopathologic distinction of cervical adenocarcinoma in situ (AIS) and invasive adenocarcinoma (AC) from some benign endocervical lesions can be challenging. The ProEx C antibody reagent targets nuclear proteins (minichromosome maintenance protein 2, MCM2 and topoisomerase II-alpha, TOP2A), which are over expressed during the aberrant S-phase induction of HPV infected and neoplastic cells. In this immunohistochemical study the utility of the ProEx C reagent in distinguishing AIS and AC from a variety of non-neoplastic glandular lesions was examined. ProEx C immunohistochemical staining was performed on sections from formalin-fixed, paraffin-embedded tissue of 65 cervical tissues including 48 non-neoplastic cervices (normal [n=10], microglandular hyperplasia [n=10], tubal metaplasia [n=11], cervical endometriosis [n=7], reactive endocervix [n=10]) and 17 cervices with glandular malignancy (AIS [n=12] and AC [n=5]). Both intensity and prevalence of immunoreactivity was scored. The median and distribution of scores for both prevalence and intensity was compared for AIS versus each of the 5 benign cervical lesions using a Mann-Whitney U test. The median and distribution of prevalence of immunohistochemical staining for AIS was different from all benign mimics, but the intensity of staining for AIS did overlap with some mimics as it was not significantly different from endometriosis, microglandular hyperplasia, and reactive endocervix. ProEx C reagent has potential as an adjunctive testing tool in the histopathologic diagnosis of both AIS and AC, particularly in difficult cases with small biopsies or foci of disease.
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Utility of p16 Expression for Distinction of Uterine Serous Carcinomas From Endometrial Endometrioid and Endocervical Adenocarcinomas. Am J Surg Pathol 2009; 33:1504-14. [DOI: 10.1097/pas.0b013e3181ac35f5] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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p16 INK4A in routine practice as a marker of cervical epithelial neoplasia. Gynecol Oncol 2009; 115:127-131. [DOI: 10.1016/j.ygyno.2009.06.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2009] [Revised: 05/31/2009] [Accepted: 06/04/2009] [Indexed: 11/22/2022]
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Watanabe J, Nishimura Y, Tsunoda S, Kawaguchi M, Okayasu I, Kuramoto H. Liquid-based preparation for endometrial cytology--usefulness for predicting the prognosis of endometrial carcinoma preoperatively. Cancer 2009; 117:254-63. [PMID: 19562745 DOI: 10.1002/cncy.20035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND The authors evaluated the applicability and usefulness of immunocytochemical staining for cyclin A, p53, estrogen receptor alpha (ER-alpha), and progesterone receptor B (PR-B) as a preoperative prognostic indicators for endometrial carcinoma using endometrial cytology with the liquid-based cytology (LBC) method. METHODS Cytologic specimens from 44 patients who had endometrial carcinoma were prepared with the LBC method. The results of immunocytochemical and immunohistochemical staining for cyclin A, p53, ER-alpha, and PR-B were compared with clinicopathologic parameters and prognosis. RESULTS Patients who had positive results for cyclin A and p53 and negative results for ER-alpha and PR-B appeared to have unfavorable clinicopathologic characteristics, such as high-grade histology, advanced clinical stage, lymphovascular space involvement (LVSI), and deeper myometrial invasion (MI), and had a poor prognosis. In contrast, patients who had positive results for ER-alpha and PR-B, and negative results for cyclin A and p53 had favorable characteristics, such well differentiated tumor, early clinical stage, negative LVSI, and less MI, and had a good prognosis. Immunostaining results from cytologic specimens obtained in the clinic and at surgery and from histologic specimens obtained at surgery were correlated positively. CONCLUSIONS Consistent specimens that were prepared using the LBC method facilitated multiple immunocytochemical analyses. Endometrial cytology with the LBC method was useful for predicting the prognosis of patients with endometrial carcinoma before therapy.
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Affiliation(s)
- Jun Watanabe
- Department of Clinical Cytology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.
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Carico E, Fulciniti F, Giovagnoli MR, Losito NS, Botti G, Benincasa G, Farnetano MG, Vecchione A. Adhesion molecules and p16 expression in endocervical adenocarcinoma. Virchows Arch 2009; 455:245-51. [DOI: 10.1007/s00428-009-0811-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 07/01/2009] [Accepted: 07/13/2009] [Indexed: 01/05/2023]
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Endocervical Adenocarcinomas With Prominent Endometrial or Endomyometrial Involvement Simulating Primary Endometrial Carcinomas. Am J Surg Pathol 2009; 33:914-24. [PMID: 19295407 DOI: 10.1097/pas.0b013e3181971fdd] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Tsoumpou I, Arbyn M, Kyrgiou M, Wentzensen N, Koliopoulos G, Martin-Hirsch P, Malamou-Mitsi V, Paraskevaidis E. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev 2009; 35:210-20. [PMID: 19261387 DOI: 10.1016/j.ctrv.2008.10.005] [Citation(s) in RCA: 201] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 10/12/2008] [Accepted: 10/23/2008] [Indexed: 12/16/2022]
Abstract
BACKGROUND P16(INK4a) is a biomarker for transforming HPV infections that could act as an adjunct to current cytological and histological assessment of cervical smears and biopsies, allowing the identification of those women with ambiguous results that require referral to colposcopy and potentially treatment. MATERIAL AND METHODS We conducted a systematic review of all studies that evaluated the use of p16(INK4a) in cytological or histological specimens from the uterine cervix. We also estimated the mean proportion of samples that were positive for p16(INK4a) in cytology and histology, stratified by the grade of the lesion. RESULTS Sixty-one studies were included. The proportion of cervical smears overexpressing p16(INK4a) increased with the severity of cytological abnormality. Among normal smears, only 12% (95% CI: 7-17%) were positive for the biomarker compared to 45% of ASCUS and LSIL (95% CI: 35-54% and 37-57%, respectively) and 89% of HSIL smears (95% CI: 84-95%). Similarly, in histology only 2% of normal biopsies (95% CI: 0.4-30%) and 38% of CIN1 (95% CI: 23-53%) showed diffuse staining for p16(INK4a) compared to 68% of CIN2 (95% CI: 44-92%) and 82% of CIN3 (95% CI: 72-92%). CONCLUSION Although there is good evidence that p16(INK4a) immunostaining correlates with the severity of cytological/histological abnormalities, the reproducibility is limited due to insufficiently standardized interpretation of the immunostaining. Therefore, a consensus needs to be reached regarding the evaluation of p16(INK4a) staining and the biomarker needs to be assessed in various clinical settings addressing specific clinical questions.
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Affiliation(s)
- I Tsoumpou
- Department of Obstetrics and Gynaecology, St Mary's Hospital, CMMC University Hospitals, Manchester M13 0JH, UK
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P16 Immunostaining Patterns in Microglandular Hyperplasia of the Cervix and Their Significance. Int J Gynecol Pathol 2009; 28:107-13. [DOI: 10.1097/pgp.0b013e3181877a73] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am J Surg Pathol 2009; 32:1835-53. [PMID: 18813124 DOI: 10.1097/pas.0b013e3181758831] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Most endocervical adenocarcinomas ( approximately 90%) are high-risk human papillomavirus (HPV)-related neoplasms, with the remainder being unrelated to HPV; both types infrequently metastasize to the ovaries. Clinicopathologic features of 29 cases of synchronous and metachronous endocervical and ovarian tumors (26 HPV-related, 3 unrelated to HPV) were analyzed. In 18 cases, the cervical tumors were clearly invasive; these included 5 clinically evident tumors diagnosed before the ovarian metastases (immediately preoperatively to 7 y), 11 clinically unsuspected tumors diagnosed concurrently in specimens obtained for evaluation of ovarian/pelvic masses, 1 case with concurrent clinically evident cervical and ovarian masses, and 1 clinically occult tumor diagnosed subsequent to the ovarian metastasis. In 11 cases, the cervical tumors were more limited; these included 5 tumors comprised predominantly of adenocarcinoma in situ with small foci of superficial invasion ("microinvasive carcinomas") diagnosed before the ovarian metastases (3 mo to 7 y) and 6 tumors comprised of extensive adenocarcinoma in situ lacking unequivocally recognizable stromal invasion diagnosed before (9 mo to 7 y, n=4), concurrently with (n=1), or subsequent to (n=1) the ovarian metastases. Fifteen cervical tumors involved lower uterine segment corpus endometrium or endomyometrium, including 4 tumors that were minimally invasive or not recognizably invasive in the cervix. The ovarian tumors ranged in size from 2.1 to 30.0 cm (mean/median=12.7/13.5); they were unilateral in 19 cases (65.5%) and 12 of these were unilateral and 10 cm or greater. In 26 cases, including the 19 unilateral tumors, the ovarian tumors exhibited "borderlinelike," confluent glandular, cribriform, and/or villoglandular patterns simulating primary ovarian atypical proliferative (borderline) tumors or well-differentiated carcinomas; these patterns were pure in 24 and admixed with minor infiltrative foci in 2. The ovarian tumors had features typical of metastases (bilateral and infiltrative) in only 3 cases. In all HPV-related cases the paired endocervical and ovarian tumors contained identical HPV types, establishing the ovarian tumors as metastases. Endocervical adenocarcinomas, including microinvasive forms and some not recognizably invasive, have the potential to metastasize to the ovaries; extension into the lower uterine segment/corpus endometrium may be a risk factor, with retrograde uterine/transtubal spread as a possible mechanism.
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p16 Immunohistochemistry as an Alternative Marker to Distinguish Atypical Lipomatous Tumor From Deep-seated Lipoma. Appl Immunohistochem Mol Morphol 2009; 17:51-6. [DOI: 10.1097/pai.0b013e3181719223] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Cuschieri K, Wentzensen N. Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev 2008; 17:2536-45. [PMID: 18842994 DOI: 10.1158/1055-9965.epi-08-0306] [Citation(s) in RCA: 177] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED Human papillomavirus (HPV) infection of the genital tract is very common and normally follows a benign clinical course; however, in an unfortunate minority of infected individuals, it can cause disease that sometimes leads to cancer. It is accepted that HPV DNA testing has a role in the management of cervical disease both in a prevaccination and postvaccination era; however, to improve the specificity of this approach, there is a requirement to develop and validate tools/assays that can identify women at risk for progressive disease. There is evidence to suggest that detection of viral gene expression both directly and indirectly may constitute a more specific approach for delineating clinically significant infection compared with HPV DNA-based assays. HPV oncogene expression and evidence of its deregulation can be monitored through direct detection of viral mRNA transcripts or through detection of the cellular protein p16. For both approaches, commercial assays have been introduced and numerous studies have been conducted. The present article describes the scientific theory underpinning these approaches, their amenability to routine-diagnostic specimens/settings, and the clinical data that has been garnered through their application thus far. Currently, there is promising data indicating that HPV mRNA and p16 might play an important role in future cervical cancer screening scenarios. Still, large randomized studies are necessary to confirm the preliminary data. METHODS PubMed and OVID were interrogated with search terms "HPV RNA;" "HPV mRNA;" "HPV transcript-detection, testing, and methods;" "p16" AND "cervical cancer;" "p16" AND "CIN;" "p16" AND "histology"; "p16" AND "cytology;" "p16;" and "screening."
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Affiliation(s)
- Kate Cuschieri
- Specialist Virology Centre, Royal Infirmary of Edinburgh, United Kingdom.
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