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Event: 1070

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased, adenosquamous carcinomas of endometrium

Short name

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term
endometrium

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
	adenosquamous carcinoma	increased
Endometrial carcinoma	adenosquamous carcinoma	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Early-life ER agonism and endometrial adenosquamous carcinoma via SIX1 expression	AdverseOutcome	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI
mammals	mammals	Low	NCBI

Life Stages

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

Life stage	Evidence
Adult, reproductively mature	High

Sex Applicability

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

Term	Evidence
Female	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

An adenosquamous carcinoma of the endometrium is one which contains both malignant glandular and malignant squamous components (Haqqani & Fox 1976). They occur in the epithelial compartment of the endometrium. The epithelial lining is affected by hormonal changes and cyclical regeneration in normal physiology. In cancer, it becomes the site of malignant epithelial proliferation, including divergent differentiation paths; glandular and squamous.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

OECD (2007), Test No. 440: Uterotrophic Bioassay in Rodents: A short-term screening test for oestrogenic properties, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, https://doi.org/10.1787/9789264067417-en

Primarily measured through histopathological examination including:

Tissue sampling (biopsy, curettage, or hysterectomy specimen)
Hematoxylin and Eosin staining
Immunohistochemistry to confirm the nature of each component via marker profiling.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic Applicability

Endometrial adenosquamous carcinoma has been described in:

Humans
Rats and mice (Dixon et al., 2014)

While there isn’t confirmed experimental evidence of endometrial adenosquamous carcinoma in non-humans, mice or rats, there are some mechanistic arguments to support the idea that it is possible in other species. Such as:

All simple epithelial tissues express certain types of keratin, which is a hallmark of squamous cells (Wonodirekso et al., 1993)
Mammals share similar basic endometrial epithelial architecture and cellular differentiation programs are broadly conserved (Cooper 2000).

Lifestage Applicability

Endometrial adenosquamous carcinoma predominantly affects adults in the peri and post-menopause stages. One epidemiological study in humans reported onset in the 30-49 yr old age group (32.5% of cases), highest levels at 50-69 yrs old (44% of cases), and falling at 70-89 yrs old (20.4% of cases) (Benesch et al., 2024). Another histopathologic review of all cases of endometrial carcinoma diagnosed in Norway between 1970 and 1978 showed that the mean age for patients with adenosquamous carcinoma was 62.8 years with a range of 43 to 84 years (Abeler & Kjørstad 1992).

Sex Applicability

Endometrial adenosquamous carcinoma is a female only condition, as it affects the endometrium, which the lining of the uterus.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

This event is related to Test No. 440: Uterotrophic Bioassay in Rodents and, as such, is part of an international regulatory framework being used by the European Chemicals Agency (ECHA), the U.S. Environmental Protection Agency (EPA), and various other OECD member countries as part of chemical safety evaluation.

The data could be used to identify potential endocrine disrupting chemicals and to support regulatory decisions, pesticide registration, industrial chemical approvals, and consumer product safety decisions. It could also be used to identify chemicals for further testing in the Endocrine Screening Disrupter Program (EDSP) Tier 2 tests.

References

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

Abeler, V. M., & Kjørstad, K. E. (1992). Endometrial adenocarcinoma with squamdus cell differentiation. Cancer, 69(2), 488-495.

Benesch, M. G., Ramos-Santillan, V. O., Rog, C. J., Nelson, E. D., & Takabe, K. (2024). Epidemiology of adenosquamous carcinomas. World Journal of Oncology, 15(3), 432.

Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Signaling in Development and Differentiation. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9918/

Dixon, D., Alison, R., Bach, U., Colman, K., Foley, G. L., Harleman, J. H., ... & Yoshida, M. (2014). Nonproliferative and proliferative lesions of the rat and mouse female reproductive system. Journal of toxicologic pathology, 27(3-4 Suppl), 1S.

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

Wonodirekso, S., Au, C. L., Hadisaputrat, W., Affandi, B., & Rogers, P. A. (1993). Cytokeratins 8, 18 and 19 in endometrial epithelial cells during the normal menstrual cycle and in women receiving Norplant®. Contraception, 48(5), 481-493.