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In this study, the authors sought to describe the cytologic features of primary gynecologic germ cell tumors and carcinomas exhibiting germ cell differentiation because little information currently exists.An institutional database search was performed to identify histologically confirmed gynecologic germ cell tumors and carcinomas with germ cell tumor differentiation. Available cytologic material was reviewed by three observers, and morphologic features were recorded in addition to patient age at original diagnosis, primary tumor site, site(s) from which the examined cytologic material was obtained, and the type of examined cytologic preparations.In total, 15 cytologic specimens from 12 women (aged 19-82 years) were identified and included touch preparations of core biopsies from various sites (n = 6), fine-needle biopsies (n = 2), pelvic washings (n = 1), ascitic fluids (n = 4), pelvic cyst fluid (n = 1), and endometrial aspirate (n = 1). Of the 12 patients, seven had primary gynecologic germ cell tumors, four had gynecologic (ovarian and endometrial) tumors exhibiting somatic yolk sac tumor-like differentiation, and the remaining patient had an intestinal-type adenocarcinoma arising within an ovarian teratoma. There was morphologic overlap among many of the cases, although cytoplasmic vacuolation/granular cytoplasm was seen in 75% of primary yolk sac tumors or carcinomas with yolk sac tumor differentiation, and dense/squamoid cytoplasm was seen in 100% of teratomatous elements that were sampled.Germ cell tumors and somatic neoplasms exhibiting germ cell tumor differentiation occurring in adult women share some cytologic features and may be difficult to distinguish from one another, although some tumor types showed characteristic cytomorphologic findings.

in press Accurate classification of melanocytic tumors is important for prognostic evaluation, treatment and follow-up protocols of patients. The majority of melanocytic proliferations can be classified solely based on clinical and pathological criteria, however in select cases a definitive diagnostic assessment remains challenging and additional diagnostic biomarkers would be advantageous. We analyzed melanomas, nevi, Spitz nevi and atypical spitzoid tumors using parallel sequencing (exons of 611 genes and 507 gene translocation analysis) and methylation arrays (850k Illumina EPIC). By combining detailed genetic and epigenetic analysis with reference-based and reference-free DNA methylome deconvolution we compared Spitz nevi to nevi and melanoma and assessed the potential for these methods in classifying challenging spitzoid tumors. Results were correlated with clinical and histologic features. Spitz nevi were found to cluster independently of nevi and melanoma and demonstrated a different mutation profile. Multiple copy number alterations and TERT promoter mutations were identified only in melanomas. Genome-wide methylation in Spitz nevi was comparable to benign nevi while the Leukocytes UnMethylation for Purity (LUMP) algorithm in Spitz nevi was comparable to melanoma. Histologically difficult to classify Spitz tumor cases were assessed which, based on methylation arrays, clustered between Spitz nevi and melanoma and in terms of genetic profile or copy number variations demonstrated worrisome features suggesting a malignant neoplasm. Comprehensive sequencing and methylation analysis verify Spitz nevi as an independent melanocytic entity distinct from both nevi and melanoma. Combined genetic and methylation assays can offer additional insights in diagnosing difficult to classify Spitzoid tumors.

Overexpression of repetitive elements is an emerging hallmark of human cancers1. Diverse repeats can mimic viruses by replicating within the cancer genome through retrotransposition, or presenting pathogen-associated molecular patterns (PAMPs) to the pattern recognition receptors (PRRs) of the innate immune system2–5. Yet, how specific repeats affect tumor evolution and shape the tumor immune microenvironment (TME) in a pro- or anti-tumorigenic manner remains poorly defined. Here, we integrate whole genome and total transcriptome data from a unique autopsy cohort of multiregional samples collected in pancreatic ductal adenocarcinoma (PDAC) patients, into a comprehensive evolutionary analysis. We find that more recently evolvedShortInterspersedNuclearElements (SINE), a family of retrotransposable repeats, are more likely to form immunostimulatory double-strand RNAs (dsRNAs). Consequently, younger SINEs are strongly co-regulated with RIG-I like receptor associated type-I interferon genes but anti-correlated with pro-tumorigenic macrophage infiltration. We discover that immunostimulatory SINE expression in tumors is regulated by eitherLongInterspersedNuclearElements 1 (LINE1/L1) mobility or ADAR1 activity in aTP53mutation dependent manner. Moreover, L1 retrotransposition activity tracks with tumor evolution and is associated withTP53mutation status. Altogether, our results suggest pancreatic tumors actively evolve to modulate immunogenic SINE stress and induce pro-tumorigenic inflammation. Our integrative, evolutionary analysis therefore illustrates, for the first time, how dark matter genomic repeats enable tumors to co-evolve with the TME by actively regulating viral mimicry to their selective advantage.

HPV42 consensus genomes.

The skin is exposed to viral pathogens, but whether they contribute to the oncogenesis of skin cancers has not been systematically explored. Here we investigated 19 skin tumor types by analyzing off-target reads from commonly available next-generation sequencing data for viral pathogens. We identified human papillomavirus 42 (HPV42) in 96% (n = 45/47) of digital papillary adenocarcinoma (DPA), an aggressive cancer occurring on the fingers and toes. We show that HPV42, so far considered a nononcogenic, “low-risk” HPV, recapitulates the molecular hallmarks of oncogenic, “high-risk” HPVs. Using machine learning, we find that HPV-driven transformation elicits a germ cell–like transcriptional program conserved throughout all HPV-driven cancers (DPA, cervical carcinoma, and head and neck cancer). We further show that this germ cell–like transcriptional program, even when reduced to the top two genes (CDKN2A and SYCP2), serves as a fingerprint of oncogenic HPVs with implications for early detection, diagnosis, and therapy of all HPV-driven cancers.Significance:We identify HPV42 as a uniform driver of DPA and add a new member to the short list of tumorigenic viruses in humans. We discover that all oncogenic HPVs evoke a germ cell–like transcriptional program with important implications for detecting, diagnosing, and treating all HPV-driven cancers.See related commentary by Starrett et al., p. 17.This article is highlighted in the In This Issue feature, p. 1

The costimulatory molecules B7-H3 and B7-H4 are overexpressed in a variety of human tumors and have been hypothesized as possible biomarkers and immunotherapeutic targets. Despite this potential, the predominating uncertainty about their functional implication in tumor–host interaction hampers their evaluation as a target for cancer therapy. By means of a highly physiologic, spontaneous tumor model in mice, we establish a causal link between B7-H3 and host tumor control and found B7-H4 to be redundant. Cancer Immunol Res; 3(8); 849–54. ©2015 AACR.

Supplementary Figure Legend

Supplementary Figure 1. Increased B7-H3 and B7-H4 protein expression in murine prostate tumors. Supplementary Figure 2. Higher abundance of neoplastic epithelium in the absence of B7-H3. Supplementary Figure 3. Comparable levels of serum testosterone and AR expression in TRAMP+/- wt and TRAMP+/- B7-H3-/- mice. Supplementary Figure 4. B7-H3 does not influence tumor cell proliferation in a cell-intrinsic manner. Supplementary Figure 5. Immunosuppressive environment in TRAMP+ tumors in the absence of B7-H3. Supplementary Figure 6. B7-H3 does not affect T-cell proliferation or NK or CD8+ T-cell function directly. Supplementary Figure 7. Percentages of FoxP3+ cells in control (brachial) and tumor-draining (periaortic) lymph nodes are the same in TRAMP+wt and TRAMP+B7-H3-/- mice. Supplementary Figure 8. Percentages of NK1.1+, CD8+, CD4+ and CD11c+ cells among TILs in TRAMP+wt and TRAMP+B7-H3-/- mice. Supplementary Figure 9. B7-H3 is expressed by tumor-infiltrating lymphocytes.

Purpose:To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental Design:We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.Results:We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.Conclusions:Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness.See related commentary by Lheureux, p. 4838

Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

List of 143 genes included in the targeted capture massively parallel sequencing assay.

Progression-free survival and hazard ratios by histology

Supplemental Figure 2: Copy Number Profiles of GNA11 and BAP1 mutated tumors

Repertoire of non-synonymous somatic mutations in plasma DNA derived from breast cancer patients with BRCA1/2 germline mutations previously treated with platinum-based chemotherapy and/or PARP inhibitors.

Supplementary Table 1

PDF file - 68K

PDF file - 48K, Supplemental Figure 2. Comparison of array-CGH profiles hybridized using non-amplified and amplified DNA.

Purpose:Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials.Experimental Design:We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center.Results:Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit.Conclusions:Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.

Supplemental Figure 1. Copy number alterations in blue nevus-like melanoma

Additional clinical information for patients in MSKCC cohort

Purpose: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis.Experimental Design: Targeted next-generation sequencing, array-based genome-wide methylation analysis, and BAP1 IHC were performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, including 47 primary tumors of the central nervous system, 16 uveal melanomas, 13 cutaneous melanoma metastases, and 2 blue nevus–like melanomas. Gene mutation, DNA-methylation, and copy-number profiles were correlated with clinicopathologic features.Results: Combining mutation, copy-number, and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas, and blue nevus–like melanoma showed common DNA-methylation, copy-number alteration, and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group.Conclusions: Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma, and blue nevus–like melanoma share molecular similarity with chromosome 3 and BAP1 alterations, markers of poor prognosis. Clin Cancer Res; 24(18); 4494–504. ©2018 AACR.

Purpose:We examined whether prospective molecular characterization of advanced metastatic disease can reveal grade and/or histology-specific differences to inform diagnosis and facilitate enrollment onto clinical trials.Experimental Design:Patients with uterine sarcoma consented to a prospective study of next-generation sequencing (NGS). Clinical annotations were extracted from their medical record. Tumor and matched normal DNA were subjected to NGS, and the genomic landscape was explored for survival correlations and therapeutic targetability.Results:Tumors from 107 women were sequenced and included leiomyosarcoma (n = 80), high-grade non-leiomyosarcoma (n = 22), low-grade endometrial stromal sarcoma (LG-ESS, n = 4), and smooth muscle tumor of uncertain malignant potential (STUMP, n = 2). Genomic profiling influenced histologic diagnosis in three cases. Common uterine leiomyosarcoma alterations were loss-of-function mutations in TP53 (56%), RB1 (51%), and ATRX (31%). Homozygous deletions of BRCA2 were present in 5% of these patients. PTEN alteration frequency was higher in the metastases samples as compared with the primary samples. Genomes of low-grade tumors were largely silent, while 50.5% of high-grade tumors had whole-genome duplication. Two metastatic uterine leiomyosarcoma cases were hypermutated. Both had prolonged disease-free survival. Potentially actionable mutations were identified in 48 patients (45%), 8 (17%) of whom received matched therapy with 2 achieving clinical responses. Among patients with uterine leiomyosarcoma with somatic BRCA2 alterations, sustained partial responses were observed with PARP inhibitor–containing therapy.Discussion:Prospective genomic profiling can contribute to diagnostic precision and inform treatment selection in patients with uterine sarcomas. There was evidence of clinical benefit in patients with uterine leiomyosarcoma with somatic BRCA2 alterations treated with PARP inhibitors.

PDF file - 74K, Supplemental Figure 6. Individual chromosome penetrance blots of uveal melanomas.

PDF file - 71K, Supplemental Figure 4. Individual chromosome penetrance blots of conjunctival melanomas.

Purpose:Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types.Experimental Design:TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution).Results:TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%–18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival.Conclusions:TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

Supplementary Methods Supplementary Figures S1-S5 Supplementary Tables S1, S2

PDF file - 62K, Supplemental Figure 10. Analysis of the GNA11-mutant tumor.

Purpose: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas.Experimental Design: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples.Results:BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma.Conclusions: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents. Clin Cancer Res; 19(12); 3143–52. ©2013 AACR.

Supplementary Table and Figure Legends

SUPPLEMENTAL FIGURE LEGENDS Supplemental Table 1. Genes covered in the 29 gene sequencing panel Supplemental Table 2. Genes covered in the 10 gene uveal melanoma panel Supplemental Table 3. Distribution of tumors with available follow-up data Supplemental Table 4. Comparison of 47 tumors categorized using the Brat et al. classification (grey) and the genetic risk-based classification outlined in the present study (black)

PDF file - 72K, Supplemental Figure 9. Individual chromosome penetrance blots of BRAF/NRAS wild type conjunctival melanomas.

Supplementary Figures

PDF file - 91K, Supplemental Figure 5. Significance of gains and losses calculated using GISTIC 2.0.

Purpose: Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors.Experimental Design: cfDNA from 24 prospectively accrued patients with germline BRCA1 or BRCA2 mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function.Results: Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.Conclusions: Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy. Clin Cancer Res; 23(21); 6708–20. ©2017 AACR.

PDF file - 72K, Supplemental Figure 7. Individual chromosome penetrance blots of BRAF-mutant conjunctival melanomas.

PDF file - 502K, Supplemental Figure 3. Summary blots of individual arrays.

Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.

Background NF1-mutated tumours represent a small subset (10–15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date. Methods This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432). Results Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively). Conclusions Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy.

Urinary cytology is indispensable both for the evaluation of gross hematuria and surveillance of patients with urothelial neoplasms. A positive urine cytology usually indicates the presence of urothelial carcinoma somewhere in the urinary tract. However, in women, it may also signal urothelial carcinoma involvement of the lower gynecologic tract or be the presenting sign for a primary cancer of the lower gynecologic tract or rectum. Guidelines for the evaluation of women with a positive cytology and normal urinary tract are lacking. We present a review of the current literature with case scenarios to bring clinicians attention to this diagnostic dilemma.

Gastric-type endocervical adenocarcinoma (GEA) is a rare form of cervical cancer not associated with human papilloma virus (HPV) infection. We summarize our experience with GEA at a large cancer center.Clinical and demographic information on all patients diagnosed with GEA between June 1, 2002 and July 1, 2019 was obtained retrospectively from clinical charts. Kaplan-Meier survival analysis was performed to describe progression-free survival (PFS) and overall survival (OS). Tumors from a subset of patients underwent next generation sequencing (NGS) analysis.A total of 70 women with GEA were identified, including 43 who received initial treatment at our institution: of these 4 (9%) underwent surgery alone, 15 (35%) underwent surgery followed by adjuvant therapy, 10 (23%) were treated with definitive concurrent chemoradiation (CCRT), 7 (16%) with chemotherapy alone, and 3 (7%) with neoadjuvant CCRT and hysterectomy with or without chemotherapy. One-third (n = 14) of patients experienced disease progression, of whom 86% (n = 12) had prior CCRT. The median PFS and OS for patients with stage I GEA were 107 months (95% CI 14.8-199.2 months) and 111 months (95% CI 17-205.1 months) respectively, compared to 17 months (95% CI 5.6-28.4 months) and 33 months (95% CI 28.2-37.8 months) for patients with stages II-IV, respectively. On NGS, 4 patients (14%) had ERBB2 alterations, including 2 patients who received trastuzumab.GEA is an aggressive form of cervical cancer with poor PFS and OS when diagnosed at stage II or later. Further investigation is needed to identify the optimal management approach for this rare subtype.