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An analysis of HER2 amplification in cervical adenocarcinoma: correlation with clinical outcomes and the International Endocervical Adenocarcinoma Criteria and Classification.

ABSTRACT: Few studies have explored HER2 status in cervical adenocarcinoma, particularly in the gastric-type adenocarcinoma (GAC), a nonhuman-papillomavirus-related subtype with poor clinical outcomes. In this study, we investigated HER2 expression and amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 209 well annotated cervical adenocarcinomas diagnosed using the International Endocervical Adenocarcinoma Criteria and Classification. IHC identified HER2 protein expression in 57.4% (123/209) of adenocarcinomas, of which 62 were IHC 1+ (negative), 38 2+ (equivocal) and 23 3+ (positive). HER2 amplification was found in 13 cases (6.2%) including 10 with IHC 3+ and 3 with IHC 2+. Among all the major histotypes of cervical adenocarcinoma, HER2 amplification was most common in GAC cases with a frequency of 14.7% (5/34). Moreover, HER2 amplification was more frequently associated with 2018 International Federation of Gynecology & Obstetrics (FIGO) stage III/IV, perineural involvement and ovarian spread (p?

SUBMITTER: Shi H

PROVIDER: S-EPMC7737776 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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An analysis of HER2 amplification in cervical adenocarcinoma: correlation with clinical outcomes and the International Endocervical Adenocarcinoma Criteria and Classification.

Shi Haiyan H Shao Ying Y Lu Weiguo W Lu Bingjian B

The journal of pathology. Clinical research 20201022 1

Few studies have explored HER2 status in cervical adenocarcinoma, particularly in the gastric-type adenocarcinoma (GAC), a nonhuman-papillomavirus-related subtype with poor clinical outcomes. In this study, we investigated HER2 expression and amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 209 well annotated cervical adenocarcinomas diagnosed using the International Endocervical Adenocarcinoma Criteria and Classification. IHC identified HER2 protein e ...[more]

PMID: 33089969

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Project description:We sought to classify endocervical adenocarcinomas (ECAs) based on morphologic features linked to etiology (ie, human papillomavirus [HPV] infection), unlike the World Health Organization 2014 classification. The International Endocervical Adenocarcinoma Criteria and Classification (IECC criteria), described herein, distinguishes between human papillomavirus-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification, and no or limited HPVA features (nonhuman papillomavirus-associated adenocarcinoma [NHPVA]). HPVAs were then subcategorized based on cytoplasmic features (mostly to provide continuity with preexisting classification schemes), whereas NHPVAs were subclassified based on established criteria (ie, gastric-type, clear cell, etc.). Complete slide sets from 409 cases were collected from 7 institutions worldwide. Tissue microarrays representing 297 cases were constructed; immunohistochemistry (p16, p53, vimentin, progesterone receptor) and chromogenic in situ hybridization using an RNA-based probe set that recognizes 18 varieties of high-risk HPV were performed to validate IECC diagnoses. The 5 most common IECC diagnoses were usual-type (HPVA) (73% of cohort), gastric-type (NHPVA) (10%), mucinous adenocarcinoma of HPVA type, including intestinal, mucinous not otherwise specified, signet-ring, and invasive stratified mucin-producing carcinoma categories (9%), clear cell carcinoma (NHPVA) (3%) and adenocarcinoma, not otherwise specified (2%). Only 3 endometrioid carcinomas were recognized and all were NHPVA. When excluding cases thought to have suboptimal tissue processing, 90% and 95% of usual-type IECC cases overexpressed p16 and were HPV, whereas 37% and 3% of NHPVAs were p16 and HPV, respectively. The 1 HPV gastric-type carcinoma was found to have hybrid HPVA/NHPVA features on secondary review. NHPVA tumors were larger and occurred in significantly older patients, compared with HPVA tumors (P<0.001). The high-risk HPV chromogenic in situ hybridization probe set had superior sensitivity, specificity, and positive and negative predictive values (0.955, 0.968, 0.992, 0.833, respectively) compared with p16 immunohistochemistry (0.872, 0.632, 0.907, 0.545, respectively) to identify HPV-related usual carcinoma and mucinous carcinoma. IECC reliably segregates ECAs into HPVA and NHPVA types using morphology alone. This study confirms that usual-type ECAs are the most common type worldwide and that mucinous carcinomas comprise a mixture of HPVA and NHPVA, with gastric-type carcinoma being the major NHPVA type. Endometrioid and serous carcinomas of the endocervix are extraordinarily rare. Should clinical outcomes and genomic studies continue to support these findings, we recommend replacement of the World Health Organization 2014 criteria with the IECC 2017.

Project description:Previously, our international team proposed a three-tiered pattern classification (Pattern Classification) system for endocervical adenocarcinoma of the usual type that correlates with nodal disease and recurrence. Pattern Classification-A tumors have well-demarcated glands lacking destructive stromal invasion or lymphovascular invasion, Pattern Classification-B tumors show localized, limited destructive invasion arising from A-type glands, and Pattern Classification-C tumors have diffuse destructive stromal invasion, significant (filling a 4 × field) confluence, or solid architecture. Twenty-four cases of Pattern Classification-A, 22 Pattern Classification-B, and 38 Pattern Classification-C from the tumor set used in the original description were chosen using the reference diagnosis originally established. One H&E slide per case was reviewed by seven gynecologic pathologists, four from the original study. Kappa statistics were prepared, and cases with discrepancies reviewed. We found a majority agreement with reference diagnosis in 81% of cases, with complete or near-complete (six of seven) agreement in 50%. Overall concordance was 74%. Overall kappa (agreement among pathologists) was 0.488 (moderate agreement). Pattern Classification-B has lowest kappa, and agreement was not improved by combining B+C. Six of seven reviewers had substantial agreement by weighted kappas (>0.6), with one reviewer accounting for the majority of cases under or overcalled by two tiers. Confluence filling a 4 × field, labyrinthine glands, or solid architecture accounted for undercalling other reference diagnosis-C cases. Missing a few individually infiltrative cells was the most common cause of undercalling reference diagnosis-B. Small foci of inflamed, loose or desmoplastic stroma lacking infiltrative tumor cells in reference diagnosis-A appeared to account for those cases up-graded to Pattern Classification-B. In summary, an overall concordance of 74% indicates that the criteria can be reproducibly applied by gynecologic pathologists. Further refinement of criteria should allow use of this powerful classification system to delineate which cervical adenocarcinomas can be safely treated conservatively.

Project description:The majority of endocervical adenocarcinomas (EAs) are caused by human papillomavirus (HPV). Gastric-type EA, the second most common EA and unrelated to HPV, is biologically different with a more aggressive clinical course. Our knowledge of the molecular fingerprint of these important EA types and its role in diagnosis, prognosis and management is still evolving. Thus, we sought to evaluate the genomic profile of HPV-related and gastric EA. Clinical information including patient outcome was gathered for 56 tumors (45 HPV-associated and 11 gastric-type) surveying evaluated by a targeted massively parallel sequencing assay (OncoPanel platform) which surveys exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. KRAS, TP53, and PIK3CA were the most commonly mutated genes (10, 10, and 9 cases, respectively). Alterations in TP53, STK11, CDKN2A, ATM, and NTRK3 were significantly more common in gastric-type EA (P<0.05, Fisher exact test). Disease recurrence and/or death occurred in 14/49 (29%) cases with clinical information available 7 HPV-related (18% of HPV-related cases with clinical information available) and 7 gastric-type (64% of gastric-type cases with clinical information available). Tumors associated with adverse outcome, regardless of histotype, more commonly had alterations in KRAS (2 HPV-related, 4 gastric-type), GNAS (3 HPV-related, 1 gastric-type), and CDKN2A (0 HPV-related, 3 gastric type) compared with indolent-behaving cases (P<0.05, Fisher exact test). A total of 8/56 (14%) tumors harbored at least one actionable mutation; of these, 6 (75%) were associated with recurrence and/or cancer-related death. Copy number variations were detected in 45/56 cases (80%). The most frequent were chromosome 20 gain and 16q loss, identified in 7 cases each (all HPV-associated EA). The mutational profile of EA is diverse and correlates with clinical behavior and EA subtype. Thus, targeted sequencing assays can potentially serve as a diagnostic and prognostic tool. It can also identify targetable alterations, which may benefit patients with recurrent/metastatic disease.

Project description:BackgroundCervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are among the most prevalent gynecologic malignancies globally. The prognosis is abysmal once cervical cancer progresses to lymphatic metastasis. Anoikis, a specialized form of apoptosis induced by loss of cell adhesion to the extracellular matrix, plays a critical role. The prediction model based on anoikis-related genes (ARGs) expression and clinical data could greatly aid clinical decision-making. However, the relationship between ARGs and CESC remains unclear.MethodsARGs curated from the GeneCards and Harmonizome portals were instrumental in delineating CESC subtypes and in developing a prognostic framework for patients afflicted with this condition. We further delved into the intricacies of the immune microenvironment and pathway enrichment across the identified subtypes. Finally, our efforts culminated in the creation of an innovative nomogram that integrates ARGs. The utility of this prognostic tool was underscored by Decision Curve Analysis (DCA), which illuminate its prospective benefits in guiding clinical interventions.ResultsIn our study, We discerned a set of 17 survival-pertinent, anoikis-related differentially expressed genes (DEGs) in CESC, from which nine were meticulously selected for the construction of prognostic models. The derived prognostic risk score was subsequently validated as an autonomous prognostic determinant. Through comprehensive functional analyses, we observed distinct immune profiles and drug response patterns among divergent prognostic stratifications. Further, we integrated the risk scores with the clinicopathological characteristics of CESC to develop a robust nomogram. DCA corroborated the utility of our model, demonstrating its potential to enhance patient outcomes through tailored clinical treatment strategies.ConclusionThe predictive signature, encompassing nine pivotal genes, alongside the meticulously constructed nomogram developed in this research, furnishes clinicians with a sophisticated tool for tailoring treatment strategies to individual patients diagnosed with CESC.

Project description:BackgroundInvasion and metastasis of cervical cancer are the main factors affecting the prognosis of patients with cervical squamous cell carcinoma (CESC). Therefore, it is of vital importance to find novel biomarkers that are associated with CESC invasion and metastasis, which will aid in the amelioration of individualized therapeutic methods for advanced patients.MethodsThe gene expression profiles of 10 metastatic and 116 non-metastatic samples were downloaded from The Cancer Genome Atlas (TCGA), where differentially expressed genes (DEGs) were defined. Weighted gene correlation network analysis (WGCNA) was employed to identify the stemness-related genes (SRGs). Univariate and multivariate regression analyses were used to identify the most significant prognostic key genes. Differential expression analysis of transcription factor (TF) and Gene Set Variation Analysis (GSVA) were utilized to explore the potential upstream regulation of TFs and downstream signaling pathways, respectively. Co-expression analysis was performed among significantly enriched TFs, key SRGs, and signaling pathways to construct a metastasis-specific regulation network in CESC. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for the network. Additionally, direct regulatory patterns of key genes were validated by ChIP-seq and ATAC-seq data.ResultsDEGs in yellow module acquired via WGCNA were defined as key genes which were most significantly related to mRNAsi. A multivariate Cox regression model was constructed and then utilized to explore the prognostic value of key SRGs by risk score. Area under curve (AUC) of the receiver operating characteristic (ROC) curve was 0.842. There was an obvious co expression pattern between the TF NR5A2 and the key gene VIM (R = 0.843, p < 0.001), while VIM was also significantly co-expressed with hallmark epithelial mesenchymal transition (EMT) signaling pathway (R = 0.318, p < 0.001). Naringenin was selected as the potential bioactive small molecule inhibitor for metastatic CESC based on CMap analysis.ConclusionsVIM positively regulated by NR5A2 affected EMT signaling pathways in metastatic CESC, and naringenin was the inhibitor for the treatment of metastatic CESC via suppressing cancer stemness. This hypothetical signaling axis and potential inhibitors provide biomarkers and novel therapeutic targets for metastatic CESC.

Dataset Information

An analysis of HER2 amplification in cervical adenocarcinoma: correlation with clinical outcomes and the International Endocervical Adenocarcinoma Criteria and Classification.

Publications

An analysis of HER2 amplification in cervical adenocarcinoma: correlation with clinical outcomes and the International Endocervical Adenocarcinoma Criteria and Classification.

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