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Publications (162)
Purpose
Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor–independent cyclin D1–CDK4...
The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origi...
Introduction
Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP‐ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score de...
Background
The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system includes lymphovascular invasion quantification as a staging criterion for endometrioid endometrial carcinomas; no lymphovascular invasion and focal invasion (≤4 vessels involved) are grouped as one category, and substantial invasion as another.
Objecti...
Anti‐HER2 therapy is indicated for erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2‐mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2‐mutated EC. From an institutional c...
Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution in cancers with TP53 loss. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed ac...
5511
Background: Inhibition of the Cyclin D-Cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Elevated CDK4 expression is observed in 34–77% of endometrioid endometrial cancers (ECs) and is an early event of neoplastic transformation. Responses to endocrine m...
Objective
We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease.
Methods
Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January...
Serous endometrial carcinoma (SEC) constitutes about 10% of endometrial carcinomas and is one of the most aggressive and lethal types of uterine cancer. Due to the rapid progression of SEC, early detection of this disease is of utmost importance. However, molecular and cellular dynamics during the pre-dysplastic stage of this disease remain largely...
Objectives
To investigate the association of molecular and pathologic factors with concurrent or recurrent ovarian disease to guide ovarian preservation in endometrioid endometrial cancer.
Methods
Patients with endometrial cancer ≤50 years of age at diagnosis were grouped by elective oophorectomy versus ovarian preservation at staging (January 201...
Introduction/Background
Lymphovascular space invasion (LVSI) is a recognized predictor of nodal spread and survival in endometrioid endometrial adenocarcinoma (EEC). However, the impact of LVSI extent on local versus distant recurrence has not been established.
Methodology
We conducted a multicenter retrospective cohort study of patients with FIGO...
Introduction/Background
To identify the anatomic distribution of endometrial cancer recurrences among the different molecular subtypes and evaluate the prognostic significance of molecular subtypes in the recurrent setting.
Methodology
All patients with endometrial cancer who had their initial staging surgery performed at our institution between 2...
Introduction/Background
The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system groups focal lymphovascular space invasion (F-LVSI) and no LVSI (NEG) into one risk category, sparking debate over the prognostic impact of substantial LVSI (S-LVSI). We sought to clarify the prognostic significance of LVSI in patients with...
Background
Many sentinel lymph node (SLN) ultrastaging protocols for endometrial cancer exist, but there is no consensus method.
Objective
This study aims to develop guidelines for size criteria in SLN evaluation for endometrial cancer, to determine whether a single cytokeratin AE1:AE3 immunohistochemical slide provides sufficient data for diagnos...
Journal clubs (JCs) are a common format used in teaching institutions to promote trainee engagement and develop skills in seeking out evidence-based medicine and critically evaluating literature. Digital technology has made JC accessible to worldwide audiences, which allows for increased inclusion of globally diverse presenters and attendees. Herei...
Trastuzumab has demonstrated clinical efficacy in the treatment of HER2‐positive serous endometrial cancer (EC), which led to its incorporation into standard‐of‐care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes tha...
Introduction
Endometroid endometrial cancers (EECs) are clinically and molecularly heterogeneous. We sought to investigate the molecular landscape of stage I, grade 3 EECs.
Methods
Patients with stage I, grade 3 EECs who underwent surgical staging from 1/2014–1/2020 were identified. Clinicopathologic data were curated from electronic medical recor...
Introduction
To further subclassify copy number-low endometrial carcinomas (CNL-EC) based on immunohistochemistry (IHC) with prognostic implications.
Methods
We compiled EC patients who received their primary treatment at our institution from 2014 to 2022, and who had CNL-EC based on a surrogate of The Cancer Genome Atlas (TCGA) prognostic EC mole...
Introduction
While the genomic landscape of untreated primary endometrial carcinoma (EC) is well characterized, the molecular underpinnings of distant metastatic EC are poorly understood. We sought to define genomic alterations associated with distant metastatic EC.
Methods
We obtained sequencing data from distant metastatic ECs from a total of 18...
Introduction
Uterine serous carcinoma (USC) typically arises from atrophic endometrium but may be associated with hyperplasia in 5–10% of cases. We sought to identify USC with concurrent hyperplasia and define if i) they are molecularly related, and ii) USC associated with hyperplasia are genetically distinct from those without.
Methods
Patients d...
Background
Racial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry‐based variations in germline pathogenic variants (gPVs) is unknown.
Methods
Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor‐normal Memorial Sloan Kettering Cancer Center Integrated Mutat...
Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark, with the highest mortality rates observed among Black patients. Here, analysis of 1,882 prospectively sequenced ECs using a clinical FDA-authorized tumor–normal panel revealed a significantly higher prevalence of high-risk histolo...
Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (EC), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification, or HER2 genetic intratumor heterogeneity (G-ITH), has been associated with resistance to a...
5596
Background: Racial/ethnic disparities in outcomes exist in endometrial cancer (EC), particularly amongst self-reported Black compared to Non-Hispanic White (NH-White) patients. However, the contribution of differences in germline pathogenic variants (gPV) and genetics care to disparities is unknown. We seek to describe the spectrum of gPV in u...
e17624
Background: Uterine sarcomas are rare tumors with diverse morphologic appearances, genetic underpinnings, and clinical behavior. Molecular characterization of these tumors by next generation sequencing (NGS) has improved disease classification and prognostication, but its impact on therapeutic selection remains limited. Analysis of 3D genomi...
Purpose:
Using next generation sequencing (NGS), The Cancer Genome Atlas (TCGA) found that endometrial carcinomas (ECs) fall under one of four molecular subtypes, and a POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)-based surrogate has been developed. We sought to retrospectively classify and characterize a large se...
Objectives:
To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma.
Methods:
Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment o...
Primary mucinous ovarian neoplasms, gastrointestinal-type (GI-type), are composed of mucin-producing tumor cells resembling intestinal goblet cells or gastric foveolar epithelium. In contrast to seromucinous tumors, which exhibit endocervical-type mucinous differentiation and are thought to be derived from endometriosis, the cell/tissue-of-origin o...
Background: Endometrioid endometrial cancer (EC), the most common histologic type of EC, is underpinned by somatic genetic alterations of genes in the PI3K and MAPK pathways, and ARID1A. Here we sought to evaluate the genomic landscape of stage IA, low-volume, non-myometrial invasive ECs to define the earliest drivers and tumor evolution of endomet...
Introduction: Endometrial carcinomas (ECs) of no-specific molecular profile (NSMP-EC) are a large and heterogenous group of tumors. These cancers, in particular endometrioid carcinomas, are thought to be dependent on or benefit from estrogen receptor (ER) signaling. In this study, we sought to determine the sources of ER signaling in patients with...
Objective:
Chromatin remodeling genes (CRGs) encode components of epigenetic regulatory mechanisms and alterations in these genes have been identified in several tumor types, including gynecologic cancers. In this study, we sought to investigate the prevalence and clinicopathological associations of CRG alterations in endometrial carcinoma (EC)....
Background:
We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features.
Methods:
Germline assessment of ≥ 76 cancer predisposition genes was performed in patients with EC unde...
The morphologic assessment of uterine leiomyosarcoma (LMS) may be challenging, and diagnostic immunohistochemical (IHC) analysis is currently lacking. We evaluated the genomic landscape of 167 uterine LMS by targeted next-generation sequencing (NGS) to identify common genomic alterations. IHC analyses corresponding to these genomic landmarks were a...
Uterine corpus cancer is the third most common cancer in women in the United States, with approximately 65,620 new cases in the United States in 2020 and 12,590 estimated deaths. Uterine cancers can be broadly classified into two groups. Cancers of endometrioid histology are common (about 80% of cases), are associated with obesity and estrogen expo...
High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour...
Objectives
We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), determine whether these gPVs were biallelic alterations, and define associations with clinicopathologic features.
Methods
Germline assessment of ≥76 genes was performed in patients with EC undergoing clinical...
Objectives
We sought to determine if Sectioning and Extensively Examining the FIMbriated End (SEE-FIM) of fallopian tubes (FTs) identifies more clinically significant tubal pathology in endometrial cancer (EC) compared to routine sectioning (RS).
Methods
From 7/2020–12/2020, FTs from patients undergoing surgical management of EC were variably proc...
Objectives
We sought to investigate if molecular profiles and endometrial cancer (EC)-based molecular subtyping are associated with clinicopathologic variables and outcomes in ovarian clear cell carcinomas (OCCCs).
Methods
Patients with OCCC who underwent clinical panel-based sequencing from 4/2015–1/2021 were identified. Pathogenic somatic altera...
Objectives
Genomic instability is a hallmark of human cancer, with fundamental relevance to cancer etiology and evolution, anti-tumor immunity and therapeutic response. High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability defined by distinct mutational processes, intraperitoneal spread and tumor heterogeneity. As...
Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the upda...
Purpose:
We sought to determine whether sequencing analysis of circulating cell-free (cf)DNA in prospectively accrued endometrial cancer (EC) patients captures the mutational repertoire of the primary lesion and allows for disease monitoring.
Design:
Peripheral blood was prospectively collected from 44 newly diagnosed EC patients over a 24-month...
Objectives: We sought to assess the role of adjuvant therapy in stage I grade 3 endometrioid endometrial carcinomas (EC). The primary objective was to define the agreement between PORTEC-1 high intermediate risk (HIR), GOG 99 HIR, and TCGA molecular subtype classification for these patients. Secondary outcomes included adjuvant treatment received a...
Objectives: To describe endometrial carcinoma (EC) molecular classification utilizing clinical next-generation sequencing (NGS) and immunohistochemistry (IHC) and to assess the clinical, pathologic, and survival outcomes based on molecular data.
Methods: We identified all primary and recurrent EC samples of 341-505 cancer-related genes undergoing N...
Objectives: To assess the prognosis of isolated tumor cells (ITCs) within sentinel lymph nodes (SLN) compared with node-negative (NN) disease in early-stage endometrioid endometrial cancer and to perform additional evaluation by molecular classification.
Methods: Patients (pts) who underwent primary surgical management of uterine cancer from 2007-2...
Objectives: To investigate the association of The Cancer Genome Atlas (TCGA) molecular subtype, CTNNB1 (B-catenin) hotspot mutation, and pathologic factors with concurrent or recurrent ovarian disease in endometrial cancer (EC) patients (pts).
Methods: EC pts aged ≤50 years were grouped by those electing oophorectomy (BO) versus ovarian preservatio...
Purpose:
Microsatellite instability-high (MSI-H) endometrial carcinomas (ECs) are underpinned by distinct mechanisms of DNA mismatch repair deficiencies (MMR-D). We sought to characterize clinical and genetic features of MSI-H ECs harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph).
Design:
Of >1,100 E...
Patients with high-grade serous ovarian cancer suffer poor prognosis and variable response to treatment. Known prognostic factors for this disease include homologous recombination deficiency status, age, pathological stage and residual disease status after debulking surgery. Recent work has highlighted important prognostic information captured in c...
Endometrial carcinomas (ECs) classified by The Cancer Genome Atlas (TCGA) as copy number-low (also referred to as "no specific molecular profile" [NSMP]) have a prognosis intermediate between POLE-mutated and copy number-high ECs. NSMP-ECs are a heterogeneous group, however, comprising both relatively indolent and aggressive ECs. We identified a to...
Objective
To assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND).
Methods
We identified newly diagnosed CS patients who underwent primary surgical management from January 1996–December 2019. The SLN cohort underwent SLN biopsy alon...
HER2 is an established therapeutic biomarker in advanced or recurrent endometrial serous carcinoma. Current clinical guidelines recommend HER2 testing exclusively in this endometrial carcinoma (EC) subtype; however, the full spectrum of ECs harboring HER2 amplification remains ill-defined. The present study characterizes the clinicopathologic and m...
Low-grade, low-stage endometrioid carcinomas (LGLS EC) demonstrate 5-yr survival rates up to 95%. However, a small subset of these tumors recur, and little is known about prognostic markers or established mutation profiles associated with recurrence. The goal of the current study was to identify the molecular profiles of the primary carcinomas and...
Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells. However, their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported this...
Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells. However, their location remains debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported this tissue can b...
Since the publication of the 1/e in 1977, Blaustein's Pathology of the Female Genital Tract has consolidated its position as the leading textbook of gynecological pathology. An essential reference for all pathologists and residents, this thoroughly updated Seventh Edition includes more than 1400 illustrations in color, informative tables and 22 rev...
Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Ptenf/fPgrCre/+) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myome...
Pten is efficiently deleted in Ptenf/fLtfCre/+ epithelial cells.
A, Genotyping of Ltf-iCre, Pten and Pten deletion (Δ5) in Ptenf/f and Ptenf/fLtfCre/+ uteri. B, In situ hybridization of Pten in Ptenf/f and Ptenf/fLtfCre/+ uteri. Experiments were performed in three individual mice with the representative results presented. Bar, 400 μm. le, luminal e...
Immunofluorescence of α-SMA and E-cad in uteri of Ptenf/f and Ptenf/fLtfCre/+ mice at 6 and 12 months of age.
Representative results from three individual mice are shown. Bar, 400 μm. le, luminal epithelium; ge, glandular epithelium; s, stroma; myo, myometrium.
(JPG)
Expression of CK8 and PTEN in uteri of Ptenf/f and Ptenf/fLtfCre/+ mice at 4 months of age.
A, Expression of CK8 in uteri of Ptenf/fLtfCre/+ mice with myometrial invasion at 4 months of age. Images of Ptenf/f and Ptenf/fLtfCre/+ uteri without myometrial invasion are presented in Fig 1B. B, Expression of PTEN in uteri of Ptenf/fLtfCre/+ mice with or...
Expression of p-AKT, pS6, and COX-2 in uteri of Ptenf/f and Ptenf/fLtfCre/+ mice at 2 and 3 months of age.
The left panel represents uteri from 2-month-old mice, and the right panel shows uteri from 3-month-old mice. A-C, Immunohistochemistry of p-AKT, pS6 and COX-2 in uteri from 2- and 3-month-old Ptenf/fLtfCre/+ and Ptenf/f mice. p-AKT and pS6 si...
No EMT is observed in uteri of 3-month-old Ptenf/f, Ptenf/fLtfCre/+ and Ptenf/fPgrCre/+ mice.
A and B, Immunostaining of Desmin (a mesenchymal cell marker) and E-cad in uteri from Ptenf/f, Ptenf/fLtfCre/+ and Ptenf/fPgrCre/+ mice at 3 months of age. Sections are counterstained with Hoechst. C, Immunofluorescence of p63 and epithelium marker E-cad i...
Immunostaining of F4/80 with Ki67 or Cleaved-caspase-3 in uteri of 3-month-old Ptenf/fLtfCre/+ mice.
A, Immunofluorescence of F4/80 and Ki67 shows no colocalization. B, Immunofluorescence of Cleaved-caspase-3 and F4/80. Scale bars, 200 μm. le, luminal epithelium; s, stroma; myo, myometrium.
(JPG)
List of antibodies used for immunohistochemistry, immunofluorescence and western blotting.
(XLSX)
Western blot analysis of PTEN, p-AKT, and pS6 using protein lysates from 2-month-old Ptenf/f and Ptenf/fLtfCre/+ uteri.
AKT, S6 and β-ACTIN serve as loading controls.
(JPG)
Proliferation and apoptosis in uteri of Ptenf/f and Ptenf/fAmhr2Cre/+ mice at 5 months of age.
A and B, Immunostaining of Cleaved-caspase-3 and E-cad and Ki67 in uteri of 5-month-old Ptenf/f and Ptenf/fAmhr2Cre/+ mice, respectively. Experiments were repeated in three mice with representative images presented. Scale bars, 400 μm. le, luminal epithel...
Expression of ESR1 and PR in uteri of 3-month-old Ptenf/f, Ptenf/fLtfCre/+ and Ptenf/fPgrCre/+ mice.
A, Immunostaining of ESR1 and E-cad. Nuclei are counterstained with Hoechst (blue). B, Immunofluorescence of PR and E-cad in uteri of 3-month-old Ptenf/f, Ptenf/fLtfCre/+ and Ptenf/fPgrCre/+ mice. All experiments were performed in three mice. Scale...