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Relationship: 3608

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Hyperplasia (glandular epithelial cells of endometrium) leads to Increased, adenosquamous carcinomas of endometrium

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Hyperplasia (glandular epithelial cells of endometrium)

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, adenosquamous carcinomas of endometrium

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Early-life estrogen receptor agonism leading to endometrial adenosquamous carcinoma via promotion of sine oculis homeobox 1 progenitor cells	adjacent	Moderate	Not Specified	Travis Karschnik (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	Low	NCBI
mammals	mammals		NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Endometrial hyperplasia (especially atypical) provides the proliferative substrate for glands to undergo malignant transformation. On it’s own, this is diagnosed as endometrioid adenocarcinoma. When co-occuring with malignant squamous differentiation it is classified as adenosquamous carcinoma.

Diagnosing adenosquamous carcinoma can be challenging because each of the components (adenocarcinoma and squamous cell carcinoma) have distinct histological features. Tumors may also be poorly differentiated generally which makes morphological identification difficult.

Subjectivity and interobserver variability aside, atypical hyperplasia and early carcinoma can look very similar, both including features like crowded glands, nuclear enlargement, and loss of polarity.

Finally, there is a lack of reliable biomarkers to definitively distinguish non-cancerous from cancerous hyperplastic activity.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This Key Event Relationship was part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2024) employed by the Endocrine Disruptor Screening Program (EDSP). A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies. Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled and evaluated. The present effort focused primarily on empirical studies with laboratory rodents and other mammals.

Searching for this page began with google scholar searches for hyperplasia and endometrial carcinoma concurrence and progression keywords. The bibliographic information in the studies referenced in the empirical evidence field were then used to broaden the search.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Adenosquamous carcinoma is a malignant tumor with glandular (adenocarcinoma) and squamous carcinoma components.

In the setting of hyperplasia, genetically altered progenitors may expand clonally and undergo differentiation into both glandular and squamous components. The hyperplastic component often accounting for no less than 70% of the tumor (Haqqani & Fox 1976).

Endometrial hyperplasia, especially atypical hyperplasia is a well-established precursor to the most common type of endometrial cancer, endometrioid adenocarcinoma (Boardman et al., 2023; Hecht et al., 2005; Huvila et al., 2021).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The diagnosis of adenosquamous carcinoma, which requires histological findings of adenocarcinoma and squamous cell carcinoma on the same lesion, definitionally limits the ability of a single precursor event to lead to the adverse outcome on its own. The rarity of diagnosed adenosquamous carcinoma also limits studies specifically connecting increased hyperplasia incidence to adenosquamous carcinoma.

There are, however, numerous studies linking endometrial hyperplasia with a progression to endometrial carcinoma broadly as well as studies demonstrating concurrent hyperplasia and carcinoma:

Horn et al., 2004, which found 52% of subjects with atypical hyperplasia progressed into carcinomas.
The National Cancer Institute found in their Study of Endometrial Hyperplasia Progression that the risk of progression among women with atypical hyperplasia is 8% through four years, rising to 28% through 19 years of follow-up and that non-atypical forms of endometrial hyperplasia were far less likely to progress to carcinoma.
Mutter et al., 2008 found that a new diagnosis of endometrial intraepithelial neoplasia (EIN) is associated with a concurrent occult carcinoma in approximately one-third of cases defined as a cancer diagnosis within 1 year. Patients who remain cancer free in the first year have a 45-fold risk of progression to endometrioid endometrial carcinoma compared with patients with non-EIN hyperplasia’s (Baak & Mutter 2005; Hecht et al., 2005; Lacey et al., 2008).
Su et al., 2024, which found 34% of 200 patients with endometrial hyperplasia also had concurrent endometrial cancer.
Trimble et al., 2006, which found 39% of 115 patients previously diagnosed with atypical hyperplasia had carcinoma at hysterectomy.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The evidence presented here derive from human females.

Taxonomic Applicability

The taxonomic applicability could plausibly be extended to other mammals expressing endometrial hyperplasia.

Lifestage Applicability

The lifestage applicability is relevent to adulthood when adenosquamous carcinomas develop and are measured.

Sex Applicability

The sex applicability is limited to females as a consequence of the measurement occuring on endometrial tissue.

References

List of the literature that was cited for this KER description. More help

Baak, J. P. A., & Mutter, G. L. (2005). Ein and who94. Journal of Clinical Pathology, 58(1), 1-6.

Boardman, L., Novetsky, A. P., & Valea, F. (2023). Management of Endometrial Intraepithelial Neoplasia or Atypical Endometrial Hyperplasia. Obstetrical & Gynecological Survey, 78(12), 731-733.

Haqqani, M. T., & Fox, H. (1976). Adenosquamous carcinoma of the endometrium. Journal of clinical pathology, 29(11), 959-966.

Hecht, J. L., Ince, T. A., Baak, J., Baker, H. E., Ogden, M. W., & Mutter, G. L. (2005). Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Modern pathology, 18(3), 324-330.

Horn, L. C., Schnurrbusch, U., Bilek, K., Hentschel, B., & Einenkel, J. (2004). Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment. International Journal of Gynecological Cancer, 14(2), 348-353.

Huvila, J., Pors, J., Thompson, E. F., & Gilks, C. B. (2021). Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis. The Journal of pathology, 253(4), 355-365.

Lacey Jr, J. V., & Chia, V. M. (2009). Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas, 63(1), 39-44.

Lacey Jr, J. V., Mutter, G. L., Nucci, M. R., Ronnett, B. M., Ioffe, O. B., Rush, B. B., ... & Sherman, M. E. (2008). Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer, 113(8), 2073-2081.

Mutter GL, Kauderer J, Baak JPA, Alberts DA. Biopsy histomorphometry predicts uterine myoinvasion by endometrial carcinoma: a gynecologic oncology group study. Hum Pathol. 2008;39(6):866–874

National Cancer Institute, Division of Cancer Epidemiology & Genetics. Study of Endometrial Hyperplasia Progression. U.S. Department of Health and Human Services. Accessed September 8, 2025. https://dceg.cancer.gov/research/cancer-types/endometrium-uterus/study-endometrial-hyperplasia-progression

Su, J., She, L., Fan, Y., Wang, H., Zhang, Q., Zhang, J., & Ma, H. (2024). Model Predicting the Risk of Endometrial Hyperplasia Developing into Endometrial Cancer. Journal of Inflammation Research, 6159-6171.

Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:812–9