Highlights
- •Pathologists play a central role in the management (including targeted therapy) of women with gynecologic cancer.
- •Pathology is important in identification of targetable tumors based on morphologic features and biomarkers.
- •Pathology is key to monitoring therapeutic response, and to discovery of novel biomarkers and therapeutic targets.
Abstract
The role of the pathologist in the multidisciplinary management of women with gynecologic
cancer has evolved substantially over the past decade. Pathologists' evaluation of
parameters such as pathologic stage, histologic subtype, grade and microsatellite
instability, and their identification of patients at risk for Lynch syndrome have
become essential components of diagnosis, prognostic assessment and determination
of optimal treatment of affected women.
Despite the use of multimodality treatment and combination cytotoxic chemotherapy,
the prognosis of women with advanced-stage gynecologic cancer is often poor. Therefore,
expanding the arsenal of available systemic therapies with targeted therapeutic agents
is appealing. Anti-angiogenic therapies, immunotherapy and poly ADP ribose polymerase
(PARP) inhibitors are now routinely used for the treatment of advanced gynecologic
cancer, and many more are under investigation. Pathologists remain important in the
clinical management of patients with targeted therapy, by identifying potentially
targetable tumors on the basis of their pathologic phenotype, by assessing biomarkers
that are predictive of response to targeted therapy (e.g. microsatellite instability,
PD1/PDL1 expression), and by monitoring treatment response and resistance. Pathologists
are also vital to research efforts exploring novel targeted therapies by identifying
homogenous subsets of tumors for more reliable and meaningful analyses, and by confirming
expression in tumor tissues of novel targets identified in genomic, epigenetic or
other screening studies.
In the era of precision gynecologic oncology, the roles of pathologists in the discovery,
development and implementation of targeted therapeutic strategies remain as central
as they are for traditional (surgery-chemotherapy-radiotherapy) management of women
with gynecologic cancers.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Gynecologic OncologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer statistics, 2017.CA Cancer J. Clin. 2017; 67: 7-30
- Risk group criteria for tailoring adjuvant treatment in patients with endometrial cancer: a validation study of the gynecologic oncology group criteria.J. Gynecol. Oncol. 2015; 26: 32-39
- Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients.J. Pathol. 2000; 192: 328-335
- Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma.Hum. Pathol. 2002; 33: 347-354
- Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis.Int. J. Gynecol. Pathol. 2012; 31: 195-205
- MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas.Oncogene. 1998; 17: 2413-2417
- Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of lynch syndrome.Genes Chromosom. Cancer. 2009; 48: 737-744
- Increased risk for hereditary nonpolyposis colorectal cancer-associated synchronous and metachronous malignancies in patients with microsatellite instability-positive endometrial carcinoma lacking MLH1 promoter methylation.Clin. Cancer Res. 2004; 10: 481-490
- Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma.Cancer. 2006; 106: 87-94
- Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int. J. Cancer. 2015; 136: E359-86
- A brief review of the management of platinum-resistant-platinum-refractory ovarian cancer.Med. Oncol. 2017; 34: 103
- Incorporation of bevacizumab in the primary treatment of ovarian cancer.N. Engl. J. Med. 2011; 365: 2473-2483
- A phase 3 trial of bevacizumab in ovarian cancer.N. Engl. J. Med. 2011; 365: 2484-2496
- OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.J. Clin. Oncol. 2012; 30: 2039-2045
- Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial.J. Clin. Oncol. 2014; 32: 1302-1308
- Improved survival with bevacizumab in advanced cervical cancer.N. Engl. J. Med. 2014; 370: 734-743
- Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG oncology/gynecologic oncology group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2017; 18: 779-791
- Bevacizumab shows activity in patients with low-grade serous ovarian and primary peritoneal cancer.Int. J. Gynecol. Cancer. 2014; 24: 1010-1014
- Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.Lancet Oncol. 2014; 15: 852-861
https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm533891.htm. Accessed 13 September 2017.
https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm548487.htm. Accessed 13 September 2017.
- Association of polymerase e-mutated and microsatellite-instable endometrial cancers with Neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1.JAMA Oncol. 2015; 1: 1319-1323
- Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer.J. Clin. Invest. 2016; 126: 2334-2340
- Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type.Cancer Epidemiol. Biomark. Prev. 2014; 23: 2965-2970
- Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413
- Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study.J. Clin. Oncol. 2017; 35: 2535-2541
- Hormonal therapy in advanced or recurrent endometrial cancer.Cochrane Database Syst. Rev. 2010; 8 (CD007926)
- Tamoxifen in combination with cytotoxic chemotherapy in advanced epithelial ovarian cancer. A prospective randomized trial.Cancer. 1989; 63: 1074-1078
- Antiestrogen therapy in recurrent ovarian cancer resulting in 28 months of stable disease: a case report and review of the literature.Arch. Oncol. 2010; 18: 32-35
- Recurrent epithelial ovarian cancer and hormone therapy.World J Clin Cases. 2013; 1: 187-190
- Tamoxifen for relapse of ovarian cancer.Cochrane Database Syst. Rev. 2001; 17 (CD001034)
- Ovarian cancer evolution through stochastic genome alterations: defining the genomic role in ovarian cancer.Syst Biol Reprod Med. 2014; 60: 2-13
- Classification and characterization of microsatellite instability across 18 cancer types.Nat. Med. 2016; 22: 1342-1350
- Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer.Cancer Res. 2001; 61: 4371-4374
- Clear cell ovarian cancers with microsatellite instability: a unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression.Oncoimmunology. 2017; 6e1277308
- Routinely assessed morphological features correlate with microsatellite instability status in endometrial cancer.Hum. Pathol. 2008; 39: 116-125
- Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome.Am. J. Surg. Pathol. 2014; 38: 793-800
- Mucinous differentiation with tumor infiltrating lymphocytes is a feature of sporadically methylated endometrial carcinomas.Int. J. Gynecol. Pathol. 2017; 36: 205-216
- Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability.Am. J. Surg. Pathol. 2012; 36: 163-172
- Ovarian and endometrial endometrioid adenocarcinomas have distinct profiles of microsatellite instability, PTEN expression, and ARID1A expression.Histopathology. 2015; 66: 517-528
- Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas.Gynecol. Oncol. 2015; 137: 306-310
- Programmed death Ligand-1 immunohistochemistry--a new challenge for pathologists: a perspective from members of the pulmonary pathology society.Arch. Pathol. Lab. Med. 2016; 140: 341-344
- Integrated genomic characterization of endometrial carcinoma.Nature. 2013; 497: 67-73
- Polymerase epsilon exonuclease domain mutations in ovarian Endometrioid carcinoma.Int. J. Gynecol. Cancer. 2015; 25: 1187-1193
- Frequent POLE1 p.S297F mutation in Chinese patients with ovarian endometrioid carcinoma.Mutat. Res. 2014; 761: 49-52
- Mutational heterogeneity in non-serous ovarian cancers.Sci. Rep. 2017; 7: 9728
- Molecular-based classification algorithm for endometrial carcinoma categorizes ovarian endometrioid carcinoma into prognostically significant groups.Mod. Pathol. 2017; https://doi.org/10.1038/modpathol.2017.81
- Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations.Mod. Pathol. 2015; 28: 505-514
- Histopathological features of endometrial carcinomas associated with POLE mutations: implications for decisions about adjuvant therapy.Histopathology. 2016; 68: 916-924
- The genetic landscape of endometrial clear cell carcinomas.J. Pathol. 2017; 243: 230-241
- Undifferentiated endometrial carcinomas show frequent loss of Core switch/sucrose nonfermentable complex proteins.Am. J. Surg. Pathol. 2017; https://doi.org/10.1097/PAS.0000000000000941
- Interobserver agreement in endometrial carcinoma histotype diagnosis varies depending on the cancer genome atlas (TCGA)-based molecular subgroup.Am. J. Surg. Pathol. 2017; 41: 245-252
- Improved risk assessment by integrating molecular and Clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts.Clin. Cancer Res. 2016; 22: 4215-4224
- Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment.Gynecol. Oncol. 2016; 143: 46-53
- Integrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615
- Homologous recombination deficiency and ovarian cancer.Eur. J. Cancer. 2016; 60: 49-58
- Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.Mod. Pathol. 2012; 25: 625-636
- Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.Am. J. Surg. Pathol. 2015; 39: 287-293
- Morphologic correlates of molecular alterations in extrauterine Mullerian carcinomas.Mod. Pathol. 2016; 29: 893-903
- Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation.Investig. New Drugs. 2015; 33: 1267-1270
- Extreme outlier analysis identifies occult mitogen-activated protein kinase pathway mutations in patients with low-grade serous ovarian cancer.J. Clin. Oncol. 2015; 33: 4099-4105
- Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.Int. J. Gynecol. Cancer. 2013; 23: 1231-1236
- Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas.J. Pathol. 2013; 229: 111-120
- Marked heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma.Genes Chromosom. Cancer. 2013; 52: 1178-1186
- Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy.Cancer Res. 1993; 53: 1489-1492
- KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.Gynecol. Oncol. 2006; 103: 883-887
- BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas.Am. J. Pathol. 2010; 177: 1611-1617
- BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer.Cancer. 2013; 119: 548-554
- Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study.Lancet Oncol. 2013; 14: 134-140
- Impact of mutational status on survival in low-grade serous carcinoma of the ovary or peritoneum.Br. J. Cancer. 2015; 113: 1254-1258
https://clinicaltrials.gov/ct2/show/NCT01849874. Accessed on 13 September 2017.
- BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors.Am. J. Surg. Pathol. 2014; 38: 1603-1611
- Detection of the BRAF V600E mutation in serous ovarian tumors: a comparative analysis of immunohistochemistry with a mutation-specific monoclonal antibody and allele-specific PCR.Hum. Pathol. 2013; 44: 329-335
- Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.Am. J. Surg. Pathol. 2013; 37: 874-881
- The challenge of intratumour heterogeneity in precision medicine.J. Intern. Med. 2014; 276: 41-51
- Roles of tumor heterogeneity in the development of drug resistance: a call for precision therapy.Semin. Cancer Biol. 2017; 42: 13-19
- The diagnostic and prognostic role of liquid-based cytology: are we ready to monitor therapy and resistance?.Expert. Rev. Anticancer. Ther. 2015; 15: 911-921
- High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 2544-2549
- Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.Nat. Genet. 2014; 46: 424-426
- Work With New Electronic ‘Brains’ Opens Field For Army Math Experts. The Hammond Times, 1957
- Molecular alterations of TP53 are a defining feature of ovarian high-grade serous carcinoma: a rereview of cases lacking TP53 mutations in the cancer genome atlas ovarian study.Int. J. Gynecol. Pathol. 2016; 35: 48-55
- Integrated genomic and molecular characterization of cervical cancer.Nature. 2017; 543: 378-384
- Landscape of genomic alterations in cervical carcinomas.Nature. 2014; 506: 371-375
- Gastric-type endocervical adenocarcinoma: an aggressive tumor with unusual metastatic patterns and poor prognosis.Am. J. Surg. Pathol. 2015; 39: 1449-1457
- The genomic landscape of gastric-type cervical adenocarcinomas.Int. J. Gynecol. Cancer. 2016; 26: 412
Article info
Publication history
Published online: November 23, 2017
Accepted:
November 15,
2017
Received in revised form:
November 14,
2017
Received:
September 18,
2017
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
