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Svarna A, Liontos M, Papatheodoridi A, Papanota AM, Zografos E, Kaparelou M, Zagouri F, Dimopoulos MA. Molecular Prognostic Factors in Uterine Serous Carcinomas: A Systematic Review. Curr Oncol 2025; 32:251. [PMID: 40422510 DOI: 10.3390/curroncol32050251] [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: 02/23/2025] [Revised: 04/05/2025] [Accepted: 04/22/2025] [Indexed: 05/28/2025] Open
Abstract
Uterine serous carcinomas are an aggressive minority of endometrial cancers. They are characterized by mutations in TP53 and extensive copy number alterations and are primarily classified in the copy number-high/p53abn molecular prognostic group, highlighting a unique molecular profile that is crucial for understanding their behavior and treatment responses. Clinical studies have shown that molecular categorization via biomarkers can facilitate proper treatment selection, and this is now widely used. In this context, the scope of this systematic review is to identify molecular characteristics with prognostic significance for these neoplasms to further inform on their treatment needs. We performed a comprehensive literature search of all articles written in English using the PubMed/Medline and Cochrane databases through February 2025. Our review led to the inclusion of 95 studies, from which we identified a total of 66 distinct molecular characteristics along with new cancer signatures that may impact prognosis. These findings have the potential to inform clinical practice by aiding in the development of tailored treatment strategies for patients with uterine serous carcinoma, ultimately improving outcomes in this challenging malignancy.
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Affiliation(s)
- Anna Svarna
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Michalis Liontos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Alkistis Papatheodoridi
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Aristea-Maria Papanota
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Eleni Zografos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Maria Kaparelou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Flora Zagouri
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
| | - Meletios-Athanasios Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, V.Sofias 80, 11528 Athens, Greece
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Li JJX, Ip PPC. Endometrial Cancer: An Update on Prognostic Pathologic Features and Clinically Relevant Biomarkers. Surg Pathol Clin 2022; 15:277-299. [PMID: 35715162 DOI: 10.1016/j.path.2022.02.006] [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] [Indexed: 06/15/2023]
Abstract
The prognosis of endometrial cancers has historically been determined by the evaluation of histologic typing, grading, and staging. Recently, molecular classification, pioneered by the 4 prognostic categories from The Cancer Genome Atlas Research Network, has been shown to independently predict the outcome, correlate with biomarker expression, and predict response to adjuvant chemotherapy. In modern-day pathology practice, it has become necessary to integrate the time-honored prognostic pathologic features with molecular classification to optimize patient management. In this review, the significance of the molecular classification of endometrioid carcinomas, the application of practical diagnostic surrogate algorithms, and interpretation of test results will be addressed. Histologic features and theragnostic biomarkers will also be discussed in relation to the molecular subtypes of endometrial cancers.
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Affiliation(s)
- Joshua J X Li
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR
| | - Philip P C Ip
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong SAR.
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3
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Integrating Precision Medicine into the Contemporary Management of Gynecologic Cancers. Curr Oncol Rep 2022; 24:889-904. [DOI: 10.1007/s11912-021-01163-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2021] [Indexed: 12/24/2022]
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Saito A, Yoshida H, Nishikawa T, Yonemori K. Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives. World J Clin Oncol 2021; 12:868-881. [PMID: 34733610 PMCID: PMC8546653 DOI: 10.5306/wjco.v12.i10.868] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/14/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
Endometrial cancer is the most common gynecological cancer in developed countries, and its incidence has increased. The majority of patients with endometrial cancer have an early disease and favorable prognosis; however, a significant proportion of endometrial cancer, which mainly comprises high-grade or type II endometrial cancer such as serous, clear cell, and carcinosarcoma, shows advanced/recurrent disease and dismal prognosis. Novel therapeutic development is required for patients with aggressive endometrial cancers. Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2 (HER2) overexpression/gene amplification in 20%-40% of patients with type II endometrial cancer. Historically, HER2 targeted therapy has been developed for various major cancers, including breast and gastric cancer. Notably, recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change. Simultaneously, an optimized HER2 test for endometrial cancer as companion diagnostics should be established. In this review, we summarize the recent findings on endometrial cancer, current treatment, optimized HER2 testing, key clinical trials on HER2 targeted therapy, and future directions in aggressive endometrial cancer, including serous carcinoma and carcinosarcoma.
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Affiliation(s)
- Ayumi Saito
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan
| | - Hiroshi Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 1040045, Japan
| | - Tadaaki Nishikawa
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan
| | - Kan Yonemori
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan
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Jamieson A, Thompson EF, Huvila J, Gilks CB, McAlpine JN. p53abn Endometrial Cancer: understanding the most aggressive endometrial cancers in the era of molecular classification. Int J Gynecol Cancer 2021; 31:907-913. [PMID: 33589443 DOI: 10.1136/ijgc-2020-002256] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/20/2021] [Accepted: 01/28/2021] [Indexed: 11/04/2022] Open
Abstract
Over the past decade, our understanding of endometrial cancer has changed dramatically from the two-tiered clinicopathologic classification system of type I and type II endometrial cancer through to the four distinct molecular subtypes identified by The Cancer Genome Atlas (TCGA) in 2013. In both systems there is a small subset of endometrial cancers (serous histotype/high numbers of somatic copy number abnormalities) that account for a disproportionately high percentage of endometrial cancer related deaths. This subset can be identified in routine clinical practice by first identifying the approximately one-third of endometrial cancers that are either ultramutated/POLEmut tumors, with pathogenic mutations in the exonuclease domain of POLE, or hypermutated/MMRd tumors, with loss of DNA mismatch repair. Immunostaining for p53 stratifies the remaining endometrial cancers into those with wild-type staining pattern and those with mutant pattern staining (p53abn endometrial cancer). This latter group of p53abn endometrial cancer is the subject of this review. Most p53abn endometrial cancers are serous type and high grade, but it also includes other histotypes and lower grade tumors, and has consistently been associated with the poorest clinical outcomes. Although it only accounts for 15% of all endometrial cancer cases, it is responsible for 50-70% of endometrial cancer mortality. A better understanding of the molecular alterations in the p53abn subgroup, beyond the ubiquitous and definitional TP53 mutations, is required so we can identify better treatments for these most aggressive endometrial cancers. Recent evidence has shown improved survival outcomes with the addition of chemotherapy compared with radiation alone in p53abn endometrial cancers. Opportunities for targeted therapy for p53abn endometrial cancers also exist with a proportion of p53abn endometrial cancers known to have homologous recombination deficiency (HRD) or human epidermal growth factor 2 (HER2) overexpression/amplification. This review will provide an overview of our current understanding of p53abn endometrial cancer.
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Affiliation(s)
- Amy Jamieson
- Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Emily F Thompson
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Jutta Huvila
- Department of Pathology, University of Turku, Turku, Finland
| | - C Blake Gilks
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Jessica N McAlpine
- Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, The University of British Columbia, Vancouver, British Columbia, Canada
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HER-2 Amplification in Uterine Serous Carcinoma and Serous Endometrial Intraepithelial Carcinoma. Am J Surg Pathol 2021; 45:708-715. [PMID: 33739786 DOI: 10.1097/pas.0000000000001682] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Human epidermal growth factor receptor 2 (HER-2) targeted therapy shows promising results in HER-2-positive uterine serous carcinoma (USC). HER-2 scoring criteria for USC and its associated noninvasive lesion, serous endometrial intraepithelial carcinoma (SEIC), are not well-established. Here, we compare the breast and gastric (GI) HER-2 immunohistochemistry (IHC) scoring criteria for HER-2 with HER-2/neu fluorescence in situ hybridization (FISH) in 68 tumors (17 USC with SEIC, 30 USC, 18 SEIC, 3 metastatic USC). The majority (97%) of lesions displayed intratumoral HER-2 IHC heterogeneity. Breast or GI IHC scoring criteria were performed equivalently. The breast and GI IHC criteria classified 51% and 47% USC as HER-2 negative (IHC 0/1+), 40% and 45% as equivocal (IHC 2+), and 9% each as HER-2 positive (IHC 3+). A quarter of USC classified as HER-2 negative or positive with the breast (25%, n=7/28) or GI IHC criteria (23%, n=6/26) was discordant by FISH. Specifically, 13% to 14% of IHC 0/1+ USC were FISH amplified; 50% of IHC 3+ USC were FISH negative. The majority (77% to 83%) of SEIC were HER-2 IHC 0/1+, and no SEIC was HER-2 IHC 3+. A minority (4% to 7%) of IHC 0/1+ SEIC were FISH positive. Discordant HER-2 status was observed between half (47%,bn=7/15) of synchronous SEIC and USC. In conclusion, USC displays HER-2 intratumoral heterogeneity, a high IHC/FISH discordance rate, and variation in HER-2 status between the SEIC and invasive components. Caution is required when evaluating HER-2 in small biopsies, which should be repeated on excisions. Both IHC and FISH should be performed on USC until clinical trials correlate HER-2 status with clinical response to HER-2-targeted therapy.
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Robinson CL, Harrison BT, Ligon AH, Dong F, Maffeis V, Matulonis U, Nucci MR, Kolin DL. Detection of ERBB2 amplification in uterine serous carcinoma by next-generation sequencing: an approach highly concordant with standard assays. Mod Pathol 2021; 34:603-612. [PMID: 33077919 DOI: 10.1038/s41379-020-00695-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 01/29/2023]
Abstract
Uterine serous carcinoma is an aggressive subtype of endometrial cancer that accounts for fewer than 10% of endometrial carcinomas but is responsible for about half of deaths. A subset of cases has HER2 overexpression secondary to ERBB2 gene amplification, and these patients may benefit from anti-HER2 therapies, such as trastuzumab. HER2 protein overexpression is currently assessed by immunohistochemistry (IHC) and ERBB2 gene amplification by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing (NGS) is increasingly used to routinely identify predictive and prognostic molecular abnormalities in endometrial carcinoma. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification, we identified cases of uterine serous carcinoma (n = 93) and compared HER2 expression by IHC and copy number assessed by FISH with copy number status assessed by NGS. ERBB2 copy number status using a combination of IHC and FISH was interpreted using the 2018 ASCO/CAP guidelines for breast carcinoma. ERBB2 amplification by NGS was determined by the relative number of reads mapping to ERBB2 in tumor DNA compared to control nonneoplastic DNA. Cases with copy number ≥6 were considered amplified and copy number <6 were non-amplified. By IHC, 70 specimens were classified as negative (0 or 1+), 19 were classified as equivocal (2+), and 4 were classified as positive (3+). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6. In this series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in uterine serous carcinoma and provides an alternative to measurement by IHC and FISH.
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Affiliation(s)
| | - Beth T Harrison
- Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Azra H Ligon
- Department of Pathology, Division of Clinical Cytogenetics, Brigham and Women's Hospital, Boston, MA, USA
| | - Fei Dong
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Valeria Maffeis
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | | | - Marisa R Nucci
- Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - David L Kolin
- Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, MA, USA.
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Abstract
A digital assay is one in which the sample is partitioned into many small containers such that each partition contains a discrete number of biological entities (0, 1, 2, 3, …). A powerful technique in the biologist's toolkit, digital assays bring a new level of precision in quantifying nucleic acids, measuring proteins and their enzymatic activity, and probing single-cell genotypes and phenotypes. Part I of this review begins with the benefits and Poisson statistics of partitioning, including sources of error. The remainder focuses on digital PCR (dPCR) for quantification of nucleic acids. We discuss five commercial instruments that partition samples into physically isolated chambers (cdPCR) or droplet emulsions (ddPCR). We compare the strengths of dPCR (absolute quantitation, precision, and ability to detect rare or mutant targets) with those of its predecessor, quantitative real-time PCR (dynamic range, larger sample volumes, and throughput). Lastly, we describe several promising applications of dPCR, including copy number variation, quantitation of circulating tumor DNA and viral load, RNA/miRNA quantitation with reverse transcription dPCR, and library preparation for next-generation sequencing. This review is intended to give a broad perspective to scientists interested in adopting digital assays into their workflows. Part II focuses on digital protein and cell assays.
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Affiliation(s)
- Amar S Basu
- 1 Department of Electrical and Computer Engineering, and Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA
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Sever E, Döğer E, Kumbasar S, Şık BA, Temur M, Yılmaz HT, Yılmaz Ö, Özbay PO, Yücesoy İ. Chromosome aberrations [dup(1q)] in endometrial cancer: Gene analysis of 54 surgical specimens in Turkey. Taiwan J Obstet Gynecol 2016; 55:357-62. [DOI: 10.1016/j.tjog.2016.02.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2015] [Indexed: 12/18/2022] Open
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Black JD, Lopez S, Cocco E, Bellone S, Altwerger G, Schwab CL, English DP, Bonazzoli E, Predolini F, Ferrari F, Ratner E, Silasi DA, Azodi M, Schwartz PE, Santin AD. PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas. Br J Cancer 2015; 113:1020-6. [PMID: 26325104 PMCID: PMC4651122 DOI: 10.1038/bjc.2015.306] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 08/03/2015] [Accepted: 08/05/2015] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVES We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. METHODS Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. RESULTS Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours. CONCLUSIONS Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment.
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Affiliation(s)
- Jonathan D Black
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Salvatore Lopez
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy
| | - Emiliano Cocco
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Stefania Bellone
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Gary Altwerger
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Carlton L Schwab
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Diana P English
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Elena Bonazzoli
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Federica Predolini
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Francesca Ferrari
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Elena Ratner
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Dan-Arin Silasi
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Masoud Azodi
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Peter E Schwartz
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
| | - Alessandro D Santin
- Department of Obstetrics, Gynecology and Reproductive Sciences Yale University School of Medicine, Yale, CT 06520, USA
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Omar N, Yan B, Salto-Tellez M. HER2: An emerging biomarker in non-breast and non-gastric cancers. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.pathog.2015.05.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Zhang Y, Zhao D, Gong C, Zhang F, He J, Zhang W, Zhao Y, Sun J. Prognostic role of hormone receptors in endometrial cancer: a systematic review and meta-analysis. World J Surg Oncol 2015; 13:208. [PMID: 26108802 PMCID: PMC4511445 DOI: 10.1186/s12957-015-0619-1] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 06/10/2015] [Indexed: 12/19/2022] Open
Abstract
Background The aim of this study was to summarize the global predicting role of hormone receptors for survival in endometrial cancer. Methods Eligible studies were identified and assessed for quality through multiple search strategies. Data were collected from studies comparing overall survival (OS), cancer-specific survival (CSS), or progression-free survival (PFS) in patients with elevated levels of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) with those in patients with lower levels. The combined hazard ratios of ER, PR, and HER2 for survival were calculated. Results A total of 98 studies were included for meta-analysis (44 for ER, 38 for PR, and 16 for HER2). Higher levels of either ER or PR could significantly indicate better survival. The pooled hazard ratios (HRs) of ER for OS, CSS, and PFS were 0.75 (95 % CI, 0.68–0.83), 0.45 (95 % CI, 0.33–0.62), and 0.66 (95 % CI, 0.52–0.85), respectively. The combined HRs of PR for OS, CSS, and PFS reached 0.63 (95 % CI, 0.56–0.71), 0.62 (95 % CI, 0.42–0.93), and 0.45 (95 % CI, 0.30–0.68), respectively. In contrast, elevated levels of HER2 could predict worse outcome with a HR of 1.98 (95 % CI, 1.49–2.62) for OS, and a HR of 2.26 (95 % CI, 1.57–3.25) for PFS. Conclusions In patients with endometrial cancer, higher level of ER and PR predicted favorable survival, and increased level of HER2 was associated with poorer survival. All of the three hormone receptors had prognostic value for survival.
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Affiliation(s)
- Yanli Zhang
- Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Changle Road #536, Shanghai, 200040, People's Republic of China.
| | - Dong Zhao
- Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Changle Road #536, Shanghai, 200040, People's Republic of China.
| | - Changguo Gong
- Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China.
| | - Fengmei Zhang
- Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China.
| | - Jing He
- Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China.
| | - Wei Zhang
- Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China.
| | - Yulan Zhao
- School of Life Science, East China Normal University, North Zhongshan Road #3663, Shanghai, People's Republic of China.
| | - Jing Sun
- Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Changle Road #536, Shanghai, 200040, People's Republic of China.
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Hastings RJ, Bown N, Tibiletti MG, Debiec-Rychter M, Vanni R, Espinet B, van Roy N, Roberts P, van den Berg-de-Ruiter E, Bernheim A, Schoumans J, Chatters S, Zemanova Z, Stevens-Kroef M, Simons A, Heim S, Salido M, Ylstra B, Betts DR. Guidelines for cytogenetic investigations in tumours. Eur J Hum Genet 2015; 24:6-13. [PMID: 25804401 DOI: 10.1038/ejhg.2015.35] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 01/19/2015] [Accepted: 02/03/2015] [Indexed: 12/31/2022] Open
Affiliation(s)
- Rosalind J Hastings
- Women's Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Nick Bown
- Northern Genetics Service, Institute of Genomic Medicine, Central Parkway, Newcastle, UK
| | - Maria G Tibiletti
- UO Anatomia Patologica, Ospedale di Circolo-Polo Universitario, Varese, Italy
| | - Maria Debiec-Rychter
- Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, University Hospital Gasthuisberg, UZ Leuven, Leuven, Belgium
| | - Roberta Vanni
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy
| | - Blanca Espinet
- Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain
| | - Nadine van Roy
- Centre for Medical Genetics, University Hospital Ghent, Ghent, Belgium
| | - Paul Roberts
- Cytogenetics Department, St James's Hospital, Leeds, UK
| | - Eva van den Berg-de-Ruiter
- Department of Genetics, University of Groningen, University Medical Centre Groningen, RB Groningen, The Netherlands
| | - Alain Bernheim
- Génétique des tumeurs (INSERM U985), Laboratoire de Cytogénétique, Pathologie Moléculaire Gustave Roussy, Paris-Villejuif, France
| | - Jacqueline Schoumans
- Cancer Cytogenetic Unit, Lausanne University Hospital, CHUV, Lausanne, Switzerland
| | - Steve Chatters
- Haematology, Cellular and Molecular Diagnostic Service, Great Ormond St Hospital, London, UK
| | - Zuzana Zemanova
- Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Marian Stevens-Kroef
- Radboud University Nijmegen Medical Centre Department of Human Genetics, HB Nijmegen, The Netherlands
| | - Annet Simons
- Radboud University Nijmegen Medical Centre Department of Human Genetics, HB Nijmegen, The Netherlands
| | - Sverre Heim
- Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Marta Salido
- Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain
| | - Bauke Ylstra
- Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, MB Amsterdam, The Netherlands
| | - David R Betts
- Department of Clinical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
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Targeting HER2 in ovarian and uterine cancers: Challenges and future directions. Gynecol Oncol 2014; 135:364-70. [DOI: 10.1016/j.ygyno.2014.09.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 08/28/2014] [Accepted: 09/03/2014] [Indexed: 01/22/2023]
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16
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Black JD, English DP, Roque DM, Santin AD. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer. ACTA ACUST UNITED AC 2014; 10:45-57. [PMID: 24328598 DOI: 10.2217/whe.13.72] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.
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Affiliation(s)
- Jonathan D Black
- Yale University School of Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Room 305 Laboratory for Surgery, Obstetrics & Gynecology, 333 Cedar Street; PO Box 208063, New Haven, CT 06520-8063, USA
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HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.62] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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18
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Farzand S, Siddique T, Saba K, Bukhari MH. Frequency of HER2/neu overexpression in adenocarcinoma of the gastrointestinal system. World J Gastroenterol 2014; 20:5889-5896. [PMID: 24914350 PMCID: PMC4024799 DOI: 10.3748/wjg.v20.i19.5889] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 07/12/2013] [Accepted: 12/04/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the frequency of HER2/neu protein overexpression in gastric (group A), small intestine (group B), and colorectal (group C) adenocarcinoma.
METHODS: A descriptive, cross-sectional study was performed on 50 cases of gastrointestinal adenocarcinoma (stomach, small intestine, and colorectal); 11 from group A, 8 from group B, and 31 from group C. The samples were grossed and processed in the pathology department, and sections were stained with HE (hematoxylin and eosin stain) for histopathological confirmation of malignancy (well-differentiated, moderately-differentiated, and poorly-differentiated). The confirmed samples were processed for immunomarker study of HER2/neu.
RESULTS: HER2/neu protein overexpression was found in 33 (66%) patients overall (P = 0.000). Out of 33 HER2/neu positive subjects, 23 (69.6%) were from group C, while the remaining 10 (30%) were from group A. None of the patients from group B had positive HER2/neu protein overexpression. No protein overexpression or membrane staining in < 10% tumor cells was observed in 17 (34%) patients, which were labeled as score “0” and considered negative for HER2/neu protein overexpression. Faint/weak staining (in ≥ 10% of tumors cells) were observed in 8 (16%) patients and given the “1+” score. Similarly 13 (26%) patients reported moderate staining (in ≥ 10% tumor cells) and were thus labeled as “2+”, and strong staining (in ≥ 10% tumors cells), labeled as “3+”, was observed in 12 (24%) patients. Out of 50 patients, 26 (52%) were suffering from grade-II malignancy, 16 (32%) from grade-I, and 8 (16%) from grade-III. There was highly significant association between tumor grades and HER2/neu protein overexpression (P = 0.0000).
CONCLUSION: HER2/neu protein is credibly overexpressed in colon and gastric adenocarcinomas in immunohistochemistry. There is significant association between grade of tumor and HER2/neu protein overexpression.
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Buza N, Roque DM, Santin AD. HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges. Arch Pathol Lab Med 2014; 138:343-50. [PMID: 24576030 DOI: 10.5858/arpa.2012-0416-ra] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT In the era of targeted cancer therapy, there is growing interest in developing novel therapeutic strategies against endometrial carcinoma, especially its most biologically aggressive variant, serous adenocarcinoma. Several publications have demonstrated that a significant proportion of uterine serous carcinomas show HER2 overexpression and/or amplification, suggesting that HER2 may be a promising therapeutic target. Case reports have already shown clinical response to trastuzumab, a humanized monoclonal immunoglobulin (Ig) G1 antibody against HER2, and patients are currently being enrolled in a multi-institutional prospective randomized trial to evaluate the therapeutic efficacy of trastuzumab. OBJECTIVE To review current data on HER2 testing and targeted therapy against HER2/neu in endometrial carcinoma. DATA SOURCES Review of the literature and personal experience of the authors. CONCLUSIONS Parallel to the clinical studies, there is a need to develop standardized criteria for HER2 testing in endometrial carcinoma that reflect the unique biological and pathogenetic features of these tumors and correlate with clinical response to therapy. This article presents a comprehensive review of the current state of HER2-based therapy and HER2 testing in endometrial carcinoma.
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Affiliation(s)
- Natalia Buza
- From the Departments of Pathology (Dr Buza) and Obstetrics, Gynecology, and Reproductive Sciences (Drs Roque and Santin), Yale University School of Medicine, New Haven, Connecticut; and the Gynecologic Oncology Program, Yale Cancer Center, New Haven, Connecticut (Dr Santin)
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20
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Buza N, English DP, Santin AD, Hui P. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Mod Pathol 2013; 26:1605-12. [PMID: 23765245 DOI: 10.1038/modpathol.2013.113] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 05/08/2013] [Accepted: 05/11/2013] [Indexed: 01/28/2023]
Abstract
HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely--at least in part--resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases--85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component--were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients' medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended, due to the significant heterogeneity of HER2 protein expression.
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Affiliation(s)
- Natalia Buza
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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21
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English DP, Roque DM, Santin AD. HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther 2013; 17:85-99. [PMID: 23529353 DOI: 10.1007/s40291-013-0024-9] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
HER2 or ErbB2 is a member of the epidermal growth factor family and is overexpressed in subsets of breast, ovarian, gastric, colorectal, pancreatic, and endometrial cancers. HER2 regulates signaling through several pathways (Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin pathways) associated with cell survival and proliferation. HER2-overexpressed and/or gene-amplified tumors are generally regarded as biologically aggressive neoplasms. In breast, cervical, endometrial, and ovarian cancer, there have been several studies linking the amplification of the c-erbB2 gene with chemoresistance and overall poor survival. Tyrosine kinase inhibitors and immunotherapy with monoclonal antibodies targeting HER2 hold promise for patients harboring these aggressive neoplasms. Trastuzumab combined with cytotoxic chemotherapy agents or conjugated with radioactive isotopes is currently being investigated in clinical trials of several tumor types.
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Affiliation(s)
- Diana P English
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, LSOG 305, P.O. Box 208063, New Haven, CT 06520-8063, USA
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22
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Rosa FE, Santos RM, Rogatto SR, Domingues MAC. Chromogenic in situ hybridization compared with other approaches to evaluate HER2/neu status in breast carcinomas. Braz J Med Biol Res 2013; 46:207-16. [PMID: 23558859 PMCID: PMC3854374 DOI: 10.1590/1414-431x20132483] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 12/03/2012] [Indexed: 12/12/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) has been evaluated in breast
cancer patients to identify those most likely to benefit from herceptin-targeted
therapy. HER2 amplification, detected in 20-30% of invasive breast tumors, is
associated with reduced survival and metastasis. The most frequently used
technique for evaluating HER2 protein status as a routine procedure is
immunohistochemistry (IHC). HER2 copy number alterations have
also been evaluated by fluorescence in situ hybridization
(FISH) in moderate immunoexpression (IHC 2+) cases. An alternative procedure to
evaluate gene amplification is chromogenic in situ
hybridization (CISH), which has some advantages over FISH, including the
correlation between HER2 status and morphological features.
Other methodologies have also been used, such as silver-enhanced in
situ hybridization (SISH) and quantitative real-time RT-PCR, to
determine the number of HER2 gene copies and expression,
respectively. Here we will present a short and comprehensive review of the
current advances concerning HER2 evaluation in human breast
cancer.
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Affiliation(s)
- F E Rosa
- Departamento de Patologia, Hospital das Clínicas, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil.
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23
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Chromosomal aberrations detected by chromogenic in situ hybridization in abdominal wall endometriosis after cesarean section. Int J Gynecol Pathol 2012; 31:328-34. [PMID: 22653345 DOI: 10.1097/pgp.0b013e318240505e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The goal of this study is to evaluate the chromosomal loss in abdominal wall endometriosis by chromogenic in situ hybridization (CISH). Twenty-four cases of abdominal wall endometriosis that developed after cesarean section at the Korea University Medical Center between January 1997 and December 2006 were selected. CISH was performed in the sections of tissue microarray block using the Zymed CISH centromeric probes for chromosomes 3, 7, 8, 9, 10, 11, 17, and 18. Monosomy was defined when the percentage of the nuclei with a single dot was more than mean+3 SD of the respective probe in normal control endometrium. CISH study was possible in more than half of the endometriosis samples, except for chromosome 9, and was most successful for chromosome 17. The frequency of monosomy was high for chromosomes 9 (75.0%) and 17 (73.9%), moderate for chromosomes 10 (57.1%) and 18 (56.3%), and low for chromosomes 3 (12.5%), 7 (22.2%), 8 (10.5%), and 11 (10.5%). Monosomy for >2 and 3 chromosomes occurred in 66.7% and 42.9% of the cases, respectively. It is concluded that CISH method may be considered a useful laboratory technique in detecting chromosomal loss, and multiple chromosomal loss is involved in the formation of ectopic endometrium in abdominal wall endometriosis.
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Peiró G, Peiró FM, Ortiz-Martínez F, Planelles M, Sánchez-Tejada L, Alenda C, Ceballos S, Sánchez-Payá J, Laforga JB. Association of mammalian target of rapamycin with aggressive type II endometrial carcinomas and poor outcome: a potential target treatment. Hum Pathol 2012; 44:218-25. [PMID: 22955108 DOI: 10.1016/j.humpath.2012.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 04/22/2012] [Accepted: 05/09/2012] [Indexed: 12/11/2022]
Abstract
The classification of endometrial carcinoma divided into types I and II has shown clinical usefulness. Molecular alterations of PTEN and Wnt/β-catenin have been identified in this neoplasia. However, the role of mammalian target of rapamycin according to subcellular localization in the pathogenesis of this neoplasia and its prognostic significance are not well defined. We studied the expression of phosphorylated mammalian target of rapamycin, PTEN, and β-catenin and their relationship with clinicopathologic features, molecular factors (microsatellite instability, mismatch repair, and BRAF genes) and patients' survival in a series of 260 nonconsecutive endometrial carcinomas. Tissue microarrays were manually constructed, and genomic DNA was extracted from paraffin-embedded cylinders (1 mm thick) from preselected tumor areas. The mammalian target of rapamycin in the nuclei (mTORC2; 47%) or cytoplasm (mTORC1; 48%) were seen in type II endometrial carcinoma, the latter also in advanced stages (P ≤ .046). PTEN loss (58%) was detected in type I endometrial carcinoma of grade 1, at early stage, with mismatch repair gene loss (24.4%) and microsatellite instability-positive status (22%; P ≤ .05). Nuclear β-catenin (16%) was found in type I tumors of younger patients (P ≤ .003). In contrast, BRAF-V600E mutations were not detected (0%). Mammalian target of rapamycin cytoplasmic high expression implied poorer prognosis (P = .02; Kaplan-Meier, log-rank test), but grade 3 tumors, vascular invasion, advanced stage, or PTEN presence correlated independently with a negative impact on survival (all P ≤ .036; Cox analysis). Our results show that mammalian target of rapamycin, PTEN, and β-catenin are independently involved in different molecular subtypes of endometrial carcinoma with diverse patients' prognosis and support their distinctive treatment based on targeted drugs.
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Affiliation(s)
- Gloria Peiró
- Research Unit, Hospital General Universitari d'Alacant, Pintor Baeza 12, 03010 Alacant, Spain.
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25
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Alvarez T, Miller E, Duska L, Oliva E. Molecular Profile of Grade 3 Endometrioid Endometrial Carcinoma. Am J Surg Pathol 2012; 36:753-61. [DOI: 10.1097/pas.0b013e318247b7bb] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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De P, Smith BR, Leyland-Jones B. Human epidermal growth factor receptor 2 testing: where are we? J Clin Oncol 2010; 28:4289-92. [PMID: 20697080 DOI: 10.1200/jco.2010.29.5071] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Motoi T, Kumagai A, Tsuji K, Imamura T, Fukusato T. Diagnostic utility of dual-color break-apart chromogenic in situ hybridization for the detection of rearranged SS18 in formalin-fixed, paraffin-embedded synovial sarcoma. Hum Pathol 2010; 41:1397-404. [PMID: 20594581 DOI: 10.1016/j.humpath.2010.02.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 02/22/2010] [Accepted: 02/25/2010] [Indexed: 11/27/2022]
Abstract
Pathological diagnosis of synovial sarcoma is often problematic due to its broad spectrum of histology. Because synovial sarcoma consistently carries a specific chromosomal translocation, t(X;18), and its derivative chimeric gene, either SS18-SSX1 or SS18-SSX2, detecting these abnormalities by reverse transcription polymerase chain reaction or fluorescence in situ hybridization has been recognized as a powerful aid for diagnosis. Recently, chromogenic in situ hybridization, which enables simultaneous visualization of both genomic abnormality and the morphology of tumor cells, has gained attention. This study investigated the diagnostic utility of dual-color break-apart chromogenic in situ hybridization as a novel method for detecting SS18 rearrangement in synovial sarcoma. Formalin-fixed, paraffin-embedded tissue samples from 16 cases of synovial sarcoma and 10 cases of 5 other types of soft tissue sarcoma were collected. Dual-color break-apart probes were designed against the genomic region adjacent to SS18. Fluorescence and chromogenic in situ hybridization studies were performed using the same sections. In both assays, the number of signals was counted for sixty nuclei per sample. Scoring ratios (unpaired signals/paired signals) were calculated. Subsequently, SS18-SSX1 and SS18-SSX2 were examined by reverse transcription polymerase chain reaction. The results of chromogenic in situ hybridization, fluorescence in situ hybridization, and reverse transcription polymerase chain reaction were correlated. Unpaired signals were clearly observed in all the synovial sarcoma samples, which mostly indicated rearranged SS18. Synovial sarcoma and non-synovial sarcoma samples were clearly distinguished from each other by the scoring ratios. Reverse transcription polymerase chain reaction demonstrated SS18 chimeric gene transcripts in all the synovial sarcoma cases, while no fusion genes were detected in the non-synovial sarcoma cases. Taken together, unpaired signals in synovial sarcoma reflected rearranged SS18. The present chromogenic in situ hybridization-based SS18 rearrangement detection system provides a highly sensitive and specific method for the diagnosis of synovial sarcoma. Chromogenic in situ hybridization-based methods have great potential for routine use in the diagnosis of synovial sarcoma.
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Affiliation(s)
- Toru Motoi
- Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan.
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28
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Xu M, Schwartz P, Rutherford T, Azodi M, Santin A, Silasi D, Martel M, Hui P. HER-2/neu receptor gene status in endometrial carcinomas: a tissue microarray study. Histopathology 2010; 56:269-73. [DOI: 10.1111/j.1365-2559.2009.03464.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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29
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Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, Berek JS, Chapman JA, DiSilvestro PA, Horowitz IR, Fiorica JV. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2009; 116:15-20. [PMID: 19840887 DOI: 10.1016/j.ygyno.2009.09.025] [Citation(s) in RCA: 198] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Revised: 09/11/2009] [Accepted: 09/18/2009] [Indexed: 12/19/2022]
Abstract
PURPOSE This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification. PATIENTS AND METHODS Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2). Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio >2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response. RESULTS Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification (r=0.459; p<0.0001). Thirty-four women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification. No major tumor responses were observed. Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response. Neither HER2 overexpression nor HER2 amplification appeared to be associated with progression-free survival or overall survival. CONCLUSION Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment. Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.
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Affiliation(s)
- Gini F Fleming
- University of Chicago Medical Center, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA.
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Penault-Llorca F, Bilous M, Dowsett M, Hanna W, Osamura RY, Rüschoff J, van de Vijver M. Emerging technologies for assessing HER2 amplification. Am J Clin Pathol 2009; 132:539-48. [PMID: 19762531 DOI: 10.1309/ajcpv2i0hgpmgbsq] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Patients with human epidermal growth factor receptor-2 (HER2)+ breast cancer are eligible for trastuzumab treatment; therefore, accurate assessment of HER2 status is essential. Until recently, only 2 methods were validated for determining the HER2 status of breast tumors in the routine diagnostic setting: immunohistochemical analysis and fluorescence in situ hybridization (FISH). Recently, bright-field in situ hybridization techniques such as chromogenic in situ hybridization (CISH) and silver-enhanced in situ hybridization (SISH), which combine features of immunohistochemical analysis and FISH, have been introduced for the determination of HER2 status. These new techniques use a peroxidase enzyme-labeled probe with chromogenic detection, instead of a fluorescent-labeled probe, allowing results to be visualized by standard bright-field microscopy. Thus, the histologic features and HER2 status of a specimen can be evaluated in parallel. Moreover, signals do not decay over time. This review discusses recent publications regarding CISH and SISH testing, including results scoring and concordance between FISH and immunohistochemical analysis.
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Affiliation(s)
- Frédérique Penault-Llorca
- Department of Pathology, Centre Jean Perrin and EA 4233, University of Auvergne, Clermont-Ferrand, France
| | - Michael Bilous
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, Australia
| | - Mitch Dowsett
- Department of Biochemistry, the Royal Marsden Hospital, London, England
| | - Wedad Hanna
- Sunnybrook and Women’s College Health Science Centre, Toronto, Canada
| | | | - Josef Rüschoff
- Institute of Pathology, Klinikum Kassel, Kassel, Germany
| | - Marc van de Vijver
- Department of Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
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Castellvi J, Garcia A, Ruiz-Marcellan C, Hernández-Losa J, Peg V, Salcedo M, Gil-Moreno A, Ramon y Cajal S. Cell signaling in endometrial carcinoma: phosphorylated 4E-binding protein-1 expression in endometrial cancer correlates with aggressive tumors and prognosis. Hum Pathol 2009; 40:1418-26. [PMID: 19428047 DOI: 10.1016/j.humpath.2008.12.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Revised: 11/11/2008] [Accepted: 12/01/2008] [Indexed: 12/21/2022]
Abstract
In the oncogenic process, cell growth control plays a crucial role, and growth factor receptors and their signaling pathways are known to be altered in endometrial cancer, mostly in type I carcinomas. Two main pathways are involved in transmitting the proliferative signal from the membrane receptors to the nucleus: phosphatydil-inositol-3-kinase-protein kinase B-mammalian target of rapamycin and RAS-RAF-ERK pathways. A final effector of these signaling cascades is the cap-dependent mRNA translation initiation complex, which is negatively regulated by 4E-BP1. The aim of our work was to study the relative importance of the factors involved in these pathways and to see their correlation with the clinicopathologic features of the tumors and their prognosis. We studied 120 endometrial carcinomas, including 93 type I and 27 type II carcinomas, and 18 control cases. Tissue microarrays were constructed and immunohistochemistry was performed for HER2, p53, and the phosphorylated forms of protein kinase B, extracellular signal-regulated kinase, and 4E-BP1. HER2 was overexpressed in 11% of carcinomas but not in control cases, and 30% of carcinomas showed activation of protein kinase B and extracellular signal-regulated kinase, mostly in type II carcinomas. The phosphorylated form of 4E-BP1 was found to be cytoplasmic in 31% of cases, and in 63% of cases it showed nuclear expression; the latter was only found in carcinomas. p53 positivity was found in type II and in grade 3 type I carcinomas. This nuclear expression of phospho-4E-BP1 and HER2 overexpression were the only characteristics with prognostic significance. The activation of the signaling pathways that control cell growth is a common event in endometrial carcinomas. 4E-BP1 is a downstream effector of these pathways whose activation status correlates with aggressive phenotypes and prognosis. This factor can reflect the activity of these pathways, regardless of the upstream molecular alterations, and, therefore, it can be a hallmark of the transmission of the oncogenic signal to the nucleus.
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Affiliation(s)
- Josep Castellvi
- Department of Pathology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
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32
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Nitta H, Hauss-Wegrzyniak B, Lehrkamp M, Murillo AE, Gaire F, Farrell M, Walk E, Penault-Llorca F, Kurosumi M, Dietel M, Wang L, Loftus M, Pettay J, Tubbs RR, Grogan TM. Development of automated brightfield double in situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) for breast carcinomas and an assay performance comparison to manual dual color HER2 fluorescence in situ hybridization (FISH). Diagn Pathol 2008; 3:41. [PMID: 18945356 PMCID: PMC2577627 DOI: 10.1186/1746-1596-3-41] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2008] [Accepted: 10/22/2008] [Indexed: 11/10/2022] Open
Abstract
Background Human epidermal growth factor receptor 2 (HER2) fluorescence in situ hybridization (FISH) is a quantitative assay for selecting breast cancer patients for trastuzumab therapy. However, current HER2 FISH procedures are labor intensive, manual methods that require skilled technologists and specialized fluorescence microscopy. Furthermore, FISH slides cannot be archived for long term storage and review. Our objective was to develop an automated brightfield double in situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) and test the assay performance with dual color HER2 FISH evaluated breast carcinomas. Methods The BDISH assay was developed with the nick translated dinitrophenyl (DNP)-labeled HER2 DNA probe and DNP-labeled CEN 17 oligoprobe on the Ventana BenchMark® XT slide processing system. Detection of HER2 and CEN 17 signals was accomplished with the silver acetate, hydroquinone, and H2O2 reaction with horseradish peroxidase (HRP) and the fast red and naphthol phosphate reaction with alkaline phosphatise (AP), respectively. The BDISH specificity was optimized with formalin-fixed, paraffin-embedded xenograft tumors, MCF7 (non-amplified HER2 gene) and BT-474 (amplified HER2 gene). Then, the BDISH performance was evaluated with 94 routinely processed breast cancer tissues. Interpretation of HER2 and CEN 17 BDISH slides was conducted by 4 observers using a conventional brightfield microscope without oil immersion objectives. Results Sequential hybridization and signal detection for HER2 and CEN 17 ISH demonstrated both DNA targets in the same cells. HER2 signals were visualized as discrete black metallic silver dots while CEN 17 signals were detected as slightly larger red dots. Our study demonstrated a high consensus concordance between HER2 FISH and BDISH results of clinical breast carcinoma cases based on the historical scoring method (98.9%, Simple Kappa = 0.9736, 95% CI = 0.9222 – 1.0000) and the ASCO/CAP scoring method with the FISH equivocal cases (95.7%, Simple Kappa = 0.8993%, 95% CI = 0.8068 – 0.9919) and without the FISH equivocal cases (100%, Simple Kappa = 1.0000%, 95% CI = 1.0000 – 1.0000). Conclusion Automated BDISH applications for HER2 and CEN 17 targets were successfully developed and it might be able to replace manual two-color HER2 FISH methods. The application also has the potential to be used for other gene targets. The use of BDISH technology allows the simultaneous analyses of two DNA targets within the context of tissue morphological observation.
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Affiliation(s)
- Hiroaki Nitta
- Office of Medical Affairs, Ventana Medical Systems Inc., Tucson, AZ, USA.
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Grushko TA, Filiaci VL, Mundt AJ, Ridderstråle K, Olopade OI, Fleming GF. An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2007; 108:3-9. [PMID: 17945336 DOI: 10.1016/j.ygyno.2007.09.007] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2007] [Revised: 08/24/2007] [Accepted: 09/04/2007] [Indexed: 01/28/2023]
Abstract
OBJECTIVES To investigate the frequency and potential prognostic or predictive value of HER-2 amplification or overexpression in advanced and recurrent endometrial cancers. METHODS Immunohistochemical staining (IHC; DAKO Herceptest) and fluorescence in situ hybridization (FISH; Vysis Inc. PathVysion DNA Probe Kit) were performed on specimens collected on a randomized Gynecologic Oncology Group (GOG) protocol testing the addition of paclitaxel to doxorubicin/cisplatin. RESULTS HER-2 overexpression (either 2+ (moderate) or 3+ (strong) immunostaining) and HER-2 gene amplification (a ratio of HER-2 copies to chromosome 17 (CEP17) copies > or = 2) were detected in 44% (104 of 234; 58 were 2+ and 46 were 3+) and 12% (21 of 182) of specimens, respectively. There was a significant increased frequency of overexpression in serous tumors vs. all others (23 of 38, 61% vs. 81 of 196, 41%, respectively, P=0.03). HER-2 amplification also appeared to be more common in serous tumors, but results were not significant (6 of 28, 21% vs. 15 of 141, 11%, P=0.12). There was a significant association between grade and HER-2 amplification among nonserous tumors, with grades 1, 2, and 3 cancers demonstrating 3%, 2%, and 21% amplification, respectively (P=0.003). Neither overexpression nor amplification predicted overall survival (OS) after adjusting for treatment and performance status. CONCLUSIONS HER-2 amplification was more common in high grade tumors with a trend to being more common in serous tumors. There was no clear evidence for a survival difference or a difference in benefit from the addition of paclitaxel for women with HER-2 amplified or overexpressed tumors; however, power to detect clinically meaningful differences was low.
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Affiliation(s)
- T A Grushko
- University of Chicago Medical Center, Chicago, IL 60637, USA
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Lambropoulou M, Stefanou D, Alexiadis G, Tamiolakis D, Tripsianis G, Chatzaki E, Vandoros GP, Kiziridou A, Papadopoulou E, Papadopoulos N. Cytoplasmic expression of c-erb-B2 in endometrial carcinomas. Oncol Res Treat 2007; 30:495-500. [PMID: 17890888 DOI: 10.1159/000107734] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND The aim of this study was to investigate the expression of c-erb-B2 in endometrial cancer with attention to both membranous and cytoplasmic staining, and to elucidate the significance of cytoplasmic signaling. MATERIALS AND METHODS c-erb-B2 reactivity was assessed by immunohistochemistry in 110 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. Correlation was made with tumor stage, grade, myometrial invasion, histologic type, and disease outcome. RESULTS c-erb-B2 overexpression, indicated by membranous and cytoplasmic staining of at least 10% of the tumor cells, was found in 47 (42.7%) cases. Cytoplasmic expression of c-erb-B2 was observed more frequently than membranous (69.1 vs. 5.5%). Synchronous cytoplasmic and membranous signaling was noticed in 7.9% of cases. Interestingly, patients with cytoplasmic c-erb-B2-positive tumors had a significantly shorter survival (p = 0.047). CONCLUSIONS These results indicate that c-erb-B2 is a specific marker of endometrial cancer. It is also an independent prognostic indicator of poor outcome. Cytoplasmic staining is as important as membranous staining, and is also a specific finding.
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Affiliation(s)
- Maria Lambropoulou
- Department of Histology/Embryology, Democritus University of Thrace, Alexandroupolis, Greece
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Powell RD, Pettay JD, Powell WC, Roche PC, Grogan TM, Hainfeld JF, Tubbs RR. Metallographic in situ hybridization. Hum Pathol 2007; 38:1145-59. [PMID: 17640553 DOI: 10.1016/j.humpath.2007.05.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Revised: 04/30/2007] [Accepted: 05/01/2007] [Indexed: 11/29/2022]
Abstract
Metallographic methods, in which a target is visualized using a probe or antibody that deposits metal selectively at its binding site, offers many advantages for bright-field in situ hybridization (ISH) detection as well as for other labeling and detection methods. Autometallographically enhanced gold labeling procedures have demonstrated higher sensitivity than conventional enzyme chromogens. Enzyme metallography, a novel procedure in which an enzymatic probe is used to deposit metal directly from solution, has been used to develop bright-field ISH methods for HER2 gene determination in breast cancer and other biopsy specimens. It provides the highest level of sensitivity and resolution, both for visualizing endogenous gene copies in nonamplified tissues and for resolving multiple gene copies to allow copy enumeration in amplified tissues without the need for oil immersion or fluorescence optics. An automated enzyme metallography procedure, silver ISH, has been developed for use in slide-staining instruments. Metallographic staining also provides excellent results for immunohistochemistry and may be combined with other staining procedures for the simultaneous detection of more than one gene or combinations of genes and proteins.
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Affiliation(s)
- Richard D Powell
- Nanoprobes, Incorporated, 95 Horseblock Road, Unit 1, Yaphank, NY 11980, USA.
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Rushing EJ, Cooper PB, Quezado M, Begnami M, Crespo A, Smirniotopoulos JG, Ecklund J, Olsen C, Santi M. Subependymoma revisited: clinicopathological evaluation of 83 cases. J Neurooncol 2007; 85:297-305. [PMID: 17569000 DOI: 10.1007/s11060-007-9411-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Accepted: 05/03/2007] [Indexed: 12/16/2022]
Abstract
OBJECT Subependymomas are rare ependymal neoplasms. To date, a large clinicopathologic study of these benign neoplasms treated with modern neurosurgical techniques has not been reported. METHODS Eighty-three cases of subependymoma were retrieved from the files of the Armed Forces Institute of Pathology. Clinicopathological features were reviewed; chromogenic in situ hybridization analysis for chromosome 22 was performed (n = 8), and patient follow-up was obtained (n = 34). Overall, the patients included 68 males and 15 females, 1.5 to 85 years of age (mean, 51.0 years). Twenty-seven cases were discovered at autopsy and the remaining were surgical specimens (n = 56). Tumors arose in the posterior fossa (n = 43), lateral ventricles (n = 37), spinal cord (2) and only one arose in the temporal horn. Tumors ranged in size from 2.0 mm to 60 mm in greatest dimension (mean, 23.0 mm). Eighteen-percent (15/83) of subependymomas exhibited a mixed histologic pattern; that is, subependymoma together with another glial tumor. The most common mixture (13/15) was subependymoma and ependymoma. Surgical excision was used in all symptomatic patients; 10 patients received radiation. Four patients developed a recurrence due to incomplete excision. All patients were without evidence of disease at the last follow-up: alive (n = 28) or dead (n = 8). CONCLUSIONS Age is the only variable found to be significantly associated with survival. Currently, surgical methods result in an excellent long-term clinical outcome. Subependymomas do not appear to be associated with NF2 mutations.
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MESH Headings
- Adolescent
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Cerebral Ventricle Neoplasms/complications
- Cerebral Ventricle Neoplasms/mortality
- Cerebral Ventricle Neoplasms/pathology
- Cerebral Ventricle Neoplasms/surgery
- Child
- Child, Preschool
- Cohort Studies
- Ependymoma/complications
- Ependymoma/mortality
- Ependymoma/pathology
- Ependymoma/surgery
- Female
- Glioma, Subependymal/complications
- Glioma, Subependymal/mortality
- Glioma, Subependymal/pathology
- Glioma, Subependymal/surgery
- Humans
- Hydrocephalus/etiology
- Hydrocephalus/pathology
- Infant
- Infratentorial Neoplasms/complications
- Infratentorial Neoplasms/mortality
- Infratentorial Neoplasms/pathology
- Infratentorial Neoplasms/surgery
- Lateral Ventricles/pathology
- Male
- Middle Aged
- Mixed Tumor, Malignant/complications
- Mixed Tumor, Malignant/mortality
- Mixed Tumor, Malignant/pathology
- Mixed Tumor, Malignant/surgery
- Retrospective Studies
- Survival Rate
- Treatment Outcome
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Affiliation(s)
- Elisabeth J Rushing
- Department of Neuropathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
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Tsiambas E, Karameris A, Tiniakos DG, Karakitsos P. Evaluation of topoisomerase IIa expression in pancreatic ductal adenocarcinoma: a pilot study using chromogenic in situ hybridization and immunohistochemistry on tissue microarrays. Pancreatology 2007; 7:45-52. [PMID: 17449965 DOI: 10.1159/000101877] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2005] [Accepted: 03/20/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS To co-evaluate topoisomerase IIa (Topo IIa) protein expression and gene status in pancreatic ductal adenocarcinoma, determining the potential prognostic impact of its alterations. METHODS Using tissue microarrays, 50 sporadic, primary pancreatic ductal adenocarcinomas were cored twice and re-embedded into one paraffin block with a core diameter of 1 mm. Immunohistochemistry and chromogenic in situ hybridization were performed in serial tissue sections for the detection of protein expression levels, chromosome 17 and Topo IIa gene status, respectively. Finally using a semi-automated image analysis system we evaluated the levels of protein expression. RESULTS A significant proportion of the tumors showed Topo IIa overexpression (32/50 or 64%). Gene amplification and deletion were detected in 9 and 4 cases, respectively, associated with protein overexpression. Aneuploidy regarding chromosome 17 was observed in 19/50 tumors and correlated with poor survival rate (Cox regression test: p = 0.001). Topo IIa protein expression was strongly correlated with stage (p = 0.021) and grade (p = 0.034). CONCLUSIONS Topo IIa gene amplification correlates with protein overexpression, but not vice versa. This is a crucial observation for the application of targeted chemotherapies, such as anthracyclines, only in subgroups of patients, according to molecular deregulation criteria and not only to immunohistochemical results. Also, chromosome 17 and not Topo IIa gene instability can be used as a potential independent prognostic factor.
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MESH Headings
- Adenocarcinoma/enzymology
- Adenocarcinoma/pathology
- Antigens, Neoplasm/analysis
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Carcinoma, Pancreatic Ductal/enzymology
- Carcinoma, Pancreatic Ductal/pathology
- Chromogenic Compounds/analysis
- Chromosomes, Human, Pair 17/genetics
- DNA/analysis
- DNA Topoisomerases, Type II/analysis
- DNA Topoisomerases, Type II/genetics
- DNA Topoisomerases, Type II/metabolism
- DNA-Binding Proteins/analysis
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Female
- Gene Amplification
- Humans
- Immunohistochemistry
- In Situ Hybridization
- Male
- Pancreatic Neoplasms/enzymology
- Pancreatic Neoplasms/pathology
- Pilot Projects
- Tissue Array Analysis
- Up-Regulation
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Affiliation(s)
- Evangelos Tsiambas
- Department of Pathology, Tissue Microarrays and Computerized Image Analysis Laboratories, 417 VA Hospital, Athens, Greece.
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Wang X, Jones TD, Zhang S, Eble JN, Bostwick DG, Qian J, Lopez-Beltran A, Montironi R, Harris JJ, Cheng L. Amplifications of EGFR gene and protein expression of EGFR, Her-2/neu, c-kit, and androgen receptor in phyllodes tumor of the prostate. Mod Pathol 2007; 20:175-82. [PMID: 17192792 DOI: 10.1038/modpathol.3800724] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Phyllodes tumor of the prostate is a rare neoplasm with an unpredictable clinical behavior. It may undergo early recurrence with sarcomatous transformation or may even metastasize. Because targeted therapies have shown great success against several malignancies, there is hope that these same therapies may show similar promise in the treatment of other neoplasms. This study was undertaken to investigate both amplification of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridization and the overexpression of EGFR, Her-2/neu, CD117 (c-kit), and androgen receptor by immunohistochemical staining in a series of 11 phyllodes tumors of the prostate. In the stromal elements, EGFR gene amplification was present in four of 11 tumors and polysomy chromosome 7 was present in two of 11 tumors. No amplification was present in the epithelial components. Only one of 11 tumors had polysomy of chromosome 7 in the epithelial components. Immunohistochemically, in the stromal components, EGFR expression was demonstrable in four of 11 tumors and androgen receptor was demonstrated in six of 10 tumors. Neither Her-2/neu nor c-kit expression was seen in the stromal components of any of the 11 tumors. In the epithelial components, EGFR expression was present in all 11 tumors with strong staining in the basal cell layers and weak or no staining in luminal epithelium; androgen receptor expression was seen in seven of 10 tumors; Her-2/neu was weakly positive in four of 11 tumors; and c-kit expression was present focally and weakly in two of 11 cases with only 2-5% of cells staining. The highest staining intensity and the highest percentage of positively staining cells were seen with EGFR immunostaining in both the stromal and epithelial (mainly basal cells) components. Androgen receptor staining showed the next highest staining intensity and percentage of positive cells in both components. Her-2/neu and c-kit were only weakly or infrequently expressed in the epithelial components of prostatic phyllodes tumors. Our data indicate that EGFR and androgen receptor are frequently and strongly expressed in both epithelial and stromal components of prostatic phyllodes tumors. EGFR gene amplification is frequently present in prostatic phyllodes tumors and may account for one of the mechanisms leading to protein overexpression in some but not all cases. Anti-EGFR and/or antiandrogen agents may be potentially useful for management of patients with tumors expressing EGFR and/or androgen receptor.
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Affiliation(s)
- Xiaoyan Wang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Balmer NN, Richer JK, Spoelstra NS, Torkko KC, Lyle PL, Singh M. Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: Correlation with clinicopathologic parameters and biomarkers. Mod Pathol 2006; 19:1593-605. [PMID: 16980945 DOI: 10.1038/modpathol.3800696] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Members of the p160 steroid receptor cofactor family, including AIB1 (Amplified in Breast Cancer 1) (also known as SRC-3/RAC3/ACTR/pCIP/TRAM-1), are of interest in endometrial carcinoma as they affect the function of estrogen (ER) and progesterone receptors (PR). Since it is feasible that alterations in the expression levels of coregulators can either augment ER activity or reduce the ability of PR to oppose ER action in endometrial cancers, our primary aim was to analyze expression of the AIB1 protein in endometrial carcinoma, carcinoma-associated complex atypical hyperplasia, and carcinoma-associated normal endometrium using immunohistochemistry and tissue microarrays. Expression of AIB1 was compared with other biomarkers and clinicopathologic parameters. We also tested AIB1 expression in non-carcinoma associated hyperplastic, normal secretory and proliferative endometrium to determine baseline AIB1 levels. In endometrial carcinoma, there is a higher expression of AIB1 compared to carcinoma-associated complex atypical hyperplasia (0.007) or carcinoma-associated normal endometrium (<0.001). AIB1 expression correlates with older age (P = 0.003), peri- or postmenopausal status (P = 0.002) and a higher grade of carcinomas (P = 0.04). There were no differences in the expression of additional steroid hormone receptor co-activators (SRC-1 and p300/CBP) and the co-repressor SMRT between histologic categories. AIB1 expression correlated with ER (r = 0.30, P = 0.006). The strongest correlation was between ER and PR-B isoform nuclear expression (r = 0.52, P < 0.0001). AIB1 levels were higher in non-carcinoma associated normal and hyperplastic endometrium compared to carcinoma-associated complex atypical hyperplasia and carcinoma-associated normal endometrium, and were the highest in normal secretory endometrium. In conclusion, high AIB1 expression in endometrial carcinoma is associated with parameters of poor prognosis. We propose that when AIB1 is overexpressed in endometrial carcinoma, ER action is augmented, leading to endometrial hyperplasia and progression to malignancy. Future studies correlating expression with response to hormonal therapy may be beneficial.
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Affiliation(s)
- Nicole N Balmer
- Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80045, USA
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Peiró G, Aranda FI, Adrover E, Niveiro M, Alenda C, Payá A, Seguí J. Analysis of HER2 by chromogenic in situ hybridization and immunohistochemistry in lymph node-negative breast carcinoma: Prognostic relevance. Hum Pathol 2006; 38:26-34. [PMID: 17056098 DOI: 10.1016/j.humpath.2006.07.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2006] [Revised: 07/24/2006] [Accepted: 07/31/2006] [Indexed: 01/28/2023]
Abstract
In patients with lymph node-negative breast carcinoma (LNNBC), the prevalence of HER2 overexpression and gene amplification and their prognostic value have not been extensively evaluated. We examined 162 patients with LNNBC with complete follow-up. Immunohistochemistry (IHC) for HER2, Ki67, and p53 was performed. HER2 gene status was analyzed by chromogenic in situ hybridization (CISH) and discordant cases by fluorescence in situ hybridization. HER2 overexpression was seen in 24.7% of cases (40/162) and amplification by CISH in 17.6% (28/159). Agreement between IHC and CISH was achieved in 147 (92.5%) cases. Amplification was seen in 21 (100%) of 21 (3+), 6 (35.3%) of 17 (2+), and 1 (0.6%) of 121 (0-1+) tumors. Fluorescence in situ hybridization detected 3 (1.8%) additional cases. HER2 overexpression and amplification were present in tumors of high grade, with necrosis and lymph-vascular invasion (LVI) (all P < .027). In addition, amplified tumors showed Ki67 of more than 20% and p53 overexpression (P < .05). By univariate analysis, shorter disease-free survival (DFS) and overall survival (OS) were seen for patients with tumors showing HER2 amplification, LVI, and Ki67 of more than 20% (P < .05) (Kaplan-Meier). However, the multivariate analysis (Cox regression) demonstrated only Ki67 as an independent prognostic factor for both DFS (P = .017) and OS (P = .010), and as a trend for HER2 gene status (OS, P = .087) and LVI (DFS, P = .11; OS, P = .063). We conclude that IHC is a reliable method for detecting HER2 expression that can be complemented by CISH in nondefinitive cases (2+). Moreover, CISH is a valuable tool for the assessment of HER2 gene status with potential prognostic value and, therefore, in clinical decision making for treatment of high-risk LNNBC.
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Affiliation(s)
- Gloria Peiró
- Research Unit, Hospital General Universitari d'Alacant, 03010 Alacant, Spain.
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Tsiambas E, Alexopoulou D, Lambropoulou S, Gerontopoulos K, Karakitsos P, Karameris A. Targeting topoisomerase IIa in endometrial adenocarcinoma: a combined chromogenic in situ hybridization and immunohistochemistry study based on tissue microarrays. Int J Gynecol Cancer 2006; 16:1424-31. [PMID: 16803541 DOI: 10.1111/j.1525-1438.2006.00562.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Topoisomerase IIa is a nucleic enzyme that affects the topological structure of DNA and also is a target for chemotherapy (ie, anthracyclines). In this study, we coevaluated its protein expression with chromosome 17 and gene status. Using tissue microarrays, 40 cases of sporadic, primary endometrial adenocarcinomas, 5 cases of atypical hyperplasia, and 5 cases of benign hyperplasia were obtained and reembedded into two paraffin blocks with a core diameter of 1 mm. Immunohistochemistry combined with chromogenic in situ hybridization was performed in 2 and 5 microm sections, respectively. Finally using a semiautomated Image Analysis System, we evaluated the levels of Nuclear labeling index of topoisomerase IIa expression. Statistical analysis was performed by SPSS version 11.0 software. The results indicate that chromosome 17 instability (aneuploidy in 7/40 cases) and Topo IIa gene deregulation (amplification in 3/40 and deletion in 1/40 cases) are significant genetic events correlated with biologic behavior in endometrial adenocarcinoma. Because protein overexpression was observed in a significant proportion of the tumors (18/40), detection of the specific gene deregulation mechanism is a crucial process for application of targeted chemotherapies, which are characterized by different levels of cardiotoxicity and other serious effects.
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Affiliation(s)
- E Tsiambas
- Department of Cytopathology, Evangelismos Hospital, 18B Symis Str., Ag Paraskevi, pc 15341 Athens, Greece.
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Hanna WM, Kwok K. Chromogenic in-situ hybridization: a viable alternative to fluorescence in-situ hybridization in the HER2 testing algorithm. Mod Pathol 2006; 19:481-7. [PMID: 16444193 DOI: 10.1038/modpathol.3800555] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Assessment of human epidermal growth factor receptor-2 status is standard practice in women with breast cancer. Most laboratories use immunohistochemistry as a screening test, with equivocal results confirmed by fluorescence in-situ hybridization (FISH). Chromogenic in-situ hybridization (CISH) is a relatively new method for detection of gene amplification using a peroxidase reaction, which can be viewed using a standard light microscope. This study was undertaken to validate CISH as a method for assessing human epidermal growth factor receptor-2 gene amplification. The gene amplification status of human epidermal growth factor receptor-2 immunohistochemistry negative (0/1+, n = 69; Group 1), immunohistochemistry positive (3+, n = 50; Group 2) and equivocal tumor samples (2+, n = 135; Group 3) was evaluated by FISH and CISH, and the concordance between FISH and CISH results calculated. In Group 1, 67/69 cases did not show amplification by CISH and 69/69 showed no amplification by FISH. Two cases were discordant; therefore, fluorescence/CISH concordance was 97%. In Group 2, 46/50 cases were amplified by FISH and 47/50 cases were amplified by CISH; three cases were not amplified by either method (immunohistochemistry false-positives). Only one case showed discordant FISH and CISH results, making the fluorescence/CISH concordance 98%. In Group 3, 89/135 cases were not amplified and 37/135 were amplified by both methods. Nine cases were discordant, giving a fluorescence/CISH concordance of 93%. The discordant cases were those with very low or borderline amplification with FISH. The high level of concordance between FISH and CISH seen in this study suggests that CISH may be a viable alternative to FISH for use in the human epidermal growth factor receptor-2 testing algorithm.
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Affiliation(s)
- Wedad M Hanna
- Department of Anatomic Pathology, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada.
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Mayr D, Kanitz V, Amann G, Engel J, Burges A, Löhrs U, Diebold J. HER-2/neu gene amplification in ovarian tumours: a comprehensive immunohistochemical and FISH analysis on tissue microarrays. Histopathology 2006; 48:149-56. [PMID: 16405663 DOI: 10.1111/j.1365-2559.2005.02306.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS Data on HER-2/neu overexpression, its correlation to prognosis and the success of treatment with Herceptin((R)) in ovarian carcinomas are scarce and contradictory. Therefore we assessed HER-2/neu expression and amplification in a large series of ovarian tumours by using tissue microarrays (TMAs). METHODS AND RESULTS Two TMAs containing 173 invasive carcinomas, 36 borderline tumours, 20 granulosa cell tumours, 14 carcinosarcomas, 11 benign cystadenoms and eight other pelvic tumours were constructed to assess HER-2/neu gene amplification by fluorescence in-situ hybridization (FISH) and immunohistochemistry. Immunohistochemistry was successful in 94.3%; 81.8% were HercepTest negative, 11.3% were scored as 1+, 4.1% as 2+ and 2.8% as 3+, including 3.1% of invasive carcinomas, 2.8% of borderline tumours and 7.7% of carcinosarcomas; 83.6% could be analysed successfully by FISH revealing no aberration in 75.8%, low amplification in 2.7% and high amplification in 3.7% of the cases. In 17.8% monosomy, trisomy, polysomy or deletion could be detected. All cases with high-level amplification had 2+ or 3+ scores on immunohistochemistry. CONCLUSIONS TMA is a feasible tool to study a large number of ovarian cases. Correlation between immunohistochemistry and FISH was excellent. HER-2/neu overexpression or gene amplification does not correlate with histological tumour type, stage, grade or prognosis.
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Affiliation(s)
- D Mayr
- Sloning Biotechnology GmbH, Puchheim, Germany.
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Santin AD, Bellone S, Van Stedum S, Bushen W, Palmieri M, Siegel ER, De Las Casas LE, Roman JJ, Burnett A, Pecorelli S. Amplification of c-erbB2 oncogene. Cancer 2005; 104:1391-7. [PMID: 16116605 DOI: 10.1002/cncr.21308] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Overexpression of the epidermal growth factor type II receptor HER-2/neu has been associated with resistance to chemotherapy and poor survival in several human tumors. In the current study, the authors have determined the frequency and clinical significance of HER-2/neu gene amplification in uterine serous papillary endometrial carcinoma (USPC), a highly aggressive variant of endometrial carcinoma. METHODS Fluorescence in situ hybridization (FISH) assay was used to analyze gene amplification in paraffin blocks from 30 women harboring Stage IA-IV USPC treated at the University of Arkansas for Medical Sciences (Little Rock, AR) from 1997 to 2004. Chromosome 17 polysomy status by FISH was also assessed in all specimens. USPC patient survival in relation to HER-2/neu gene amplification was analyzed using Kaplan-Meier curves in conjunction with the log-rank test. RESULTS Amplification of the HER-2/neu gene by FISH was observed in 14 of the 30 (47%) cases. Heterogeneity was noted in 4 of 14 cases in the amplification of the HER-2/neu gene within the same tumor samples with pockets of amplified tumor cells amidst nonamplified tumor cells. Patients with USPC harboring tumors with HER-2/neu gene amplification had a significantly shorter survival time from diagnosis to disease-related death when compared with FISH-negative patients (P = 0.0008). African-American (AA) patients were found to have a poorer prognosis compared with Caucasian (C) women (P = 0.01) and to harbor USPC with significantly higher levels of HER-2/neu gene amplification (P = 0.02). CONCLUSIONS HER-2/neu gene amplification in USPC was found to be an important prognostic indicator for poor outcome that occurs more frequently in AA when compared with C patients. Determination of HER-2/neu gene amplification may guide clinical management of patients with USPC and may have important implications for the implementation of novel treatment strategies.
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MESH Headings
- Age Factors
- Aged
- Biomarkers, Tumor/analysis
- Biopsy, Needle
- Cystadenocarcinoma, Papillary/genetics
- Cystadenocarcinoma, Papillary/mortality
- Cystadenocarcinoma, Papillary/pathology
- Female
- Gene Amplification
- Gene Expression Regulation, Neoplastic
- Genes, erbB-2/genetics
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Middle Aged
- Probability
- Prognosis
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Risk Assessment
- Sampling Studies
- Sensitivity and Specificity
- Statistics, Nonparametric
- Survival Analysis
- Uterine Neoplasms/genetics
- Uterine Neoplasms/mortality
- Uterine Neoplasms/pathology
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Affiliation(s)
- Alessandro D Santin
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
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Santi M, Quezado M, Ronchetti R, Rushing EJ. Analysis of chromosome 7 in adult and pediatric ependymomas using chromogenic in situ hybridization. J Neurooncol 2005; 72:25-8. [PMID: 15803371 DOI: 10.1007/s11060-004-3117-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Few studies have yielded reliable data that distinguish between ependymal neoplasms based on molecular genetic attributes. The present study utilizes chromogenic in situ hybridization (CISH), a relatively recent hybridization technique, to retrospectively examine chromosome 7-copy number in pediatric and adult ependymomas. Of the 27 hybridizations, polysomy of chromosome 7 was detected in 10 out of 15 (66%) adult ependymomas, and in only three out of 12 (25%) pediatric lesions. All myxopapillary ependymomas showed polysomy. The remaining tumors were diploid. The authors conclude that (1) there are distinct genetic subsets of ependymoma, in particular, increases in copy number of chromosome 7 are almost exclusively found in myxopapillary ependymoma, and that (2) CISH is a rapid and sensitive method of stratifying morphological variants of ependymoma and potentially other central nervous system (CNS) tumors. These results encourage further investigations with CISH on a larger scale to determine its merit as an ancillary diagnostic and prognostic tool.
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Affiliation(s)
- Mariarita Santi
- Department of Pathology, Children's Hospital National Medical Center, Washington, DC, USA
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Pan CX, Yang XJ, Lopez-Beltran A, MacLennan GT, Eble JN, Koch MO, Jones TD, Lin H, Nigro K, Papavero V, Tretiakova M, Cheng L. c-kit Expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol 2005; 18:320-3. [PMID: 15502806 DOI: 10.1038/modpathol.3800318] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The prognosis for small cell carcinoma of the urinary bladder is poor, and strategies for improved therapy are needed. Targeted therapy against the c-kit proto-oncogene has been successful in the management of gastrointestinal stromal tumor. We investigated the expression of c-kit in 52 cases of small cell carcinoma of the urinary bladder. Specimens with more than 10% of cells demonstrating strong membrane staining were considered to have positive immunostaining for c-kit. c-kit expression was detected in 21 of 52 specimens from these patients. Among the 21 specimens, seven had less than 10% staining, and were considered to be negative. Nine had 11-50% staining, and five had more than 50% staining. Overall, 14 of 52 (27%) small cell carcinomas of the urinary bladder were positive for c-kit expression. During a median follow-up of 11 months, 60% of the patients died of bladder cancer. No association was found between c-kit expression and survival or other clinicopathologic parameters. Five-year cancer-specific survivals for c-kit-positive and c-kit-negative tumors were 9 and 15%, respectively (P=0.36). A significant proportion (27%) of small cell carcinomas of the urinary bladder expressed c-kit, suggesting that it may prove useful as a therapeutic target in small cell carcinoma of the urinary bladder.
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Affiliation(s)
- Chong-Xian Pan
- Department of Medicine, Indiana University, Indianapolis, IN 46202, USA
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