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Endometrial metaplasia

Authors: Evan R.J. Goyette, M.D., Jessica L. Bentz, M.D.

Editorial Board Member: C. Blake Gilks, M.D.

Deputy Editor-in-Chief: Jennifer A. Bennett, M.D.

Last author update: 28 March 2022

Last staff update: 18 October 2022

Copyright: 2002-2022, PathologyOutlines.com, Inc.

PubMed search: Endometrial metaplasia uterus

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Table of Contents

Cite this page: Goyette ERJ, Bentz JL. Endometrial metaplasia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusmetaplasia.html. Accessed December 1st, 2022.

Definition / general

Nonneoplastic cytomorphologic transformation of the epithelial lining of the uterine cavity from its usual endometrial phenotype to other subtypes of Müllerian epithelial differentiation
While rare, endometrial stromal transformation to other mesenchymal elements can also occur

Essential features

Epithelial metaplasia is replacement of the normal endometrium by a differentiated epithelium
Endometrial metaplasia can be associated with hyperestrogenism, inflammation, repeated irritation or endometrial polyps
Be sure to rule out a neoplastic process (endometrial hyperplasia or carcinoma)
Epithelial metaplasias include squamous, mucinous, tubal, eosinophilic, papillary, secretory and hobnail
Stromal metaplasias (while uncommon) include osseous, cartilaginous, myomatous, adipose and synovial-like

Terminology

Epithelial cellular change
Endometrial cytoplasmic change

Epidemiology

Wide age range; most common in perimenopausal to postmenopausal women

Sites

Endometrium, including endometrial polyps

Etiology

Hyperestrogenism
- Exogenous hormone use / unopposed estrogens
- Polycystic ovarian syndrome (PCOS)
- Other causes of persistent anovulation
- Ovarian tumors secreting hormones
- Endometrial hyperplasia or carcinoma
Prolonged irritation
- Mechanical
  - Intrauterine device
  - Previous hysteroscopy and manipulation
    - Curettage
    - Polypectomy
- Infectious / inflammatory
  - Chronic endometritis
  - Pyometria
- Physiologic
  - Breakdown
No obvious cause in a small percentage of cases
Reference: Virchows Arch 2018;472:907

Clinical features

Some epithelial metaplasias (e.g. squamous or mucinous) tend to coexist with endometrial hyperplasia or carcinoma; this is not true for other epithelial metaplastic changes, such as tubal metaplasia or for the stromal metaplasias (Histopathology 2008;53:325)

Diagnosis

Microscopic examination of endometrial biopsy / curettage or hysterectomy

Radiology description

Ultrasound
- Generally no significant findings
- If osseous stromal metaplasia → strongly echogenic endometrial plate with posterior shadowing (Clin Imaging 2018;52:260)

Radiology images

Images hosted on other servers:

Ultrasonographic features of osseous metaplasia

Prognostic factors

If isolated metaplasia → no clinical significance; no follow up necessary
If associated with hyperplasia or frank malignancy → dependent upon associated condition (see endometrial hyperplasia and endometrial endometrioid carcinoma)

Case reports

31 year old woman with osseous metaplasia (Radiol Bras 2016;49:62)
38 year old woman with cartilaginous metaplasia (J Midlife Health 2013;4:195)
38 year old woman with tubal metaplasia (Int J Clin Exp Pathol 2015;8:7610)
63 and 74 year old women with intestinal metaplasia (Int J Gynecol Pathol 2011;30:492)
67 year old woman with ichthyosis uteri (Indian J Pathol Microbiol 2020;63:637)

Frozen section description

Metaplasia might be mistaken for a hyperplasia on frozen section if the clinicians send a uterus to evaluate for carcinoma; awareness of this pitfall is important to avoid diagnosing an endometrial neoplasm on frozen section

Microscopic (histologic) description

Squamous metaplasia:
- Subtypes:
  - Morular (Gynecol Endocrinol 2020;36:460):
    - Rounded to polygonal nests of immature squamous cells that fill the glandular lumen
    - Rarely demonstrates keratinization, mitoses and central necrosis
    - Generally cytologically bland but can obscure examination of the glandular architecture
    - Morular borders are not well defined
    - Characteristic intercellular bridges are not identified
    - More commonly associated with endometrioid adenocarcinoma
  - Squamous metaplasia:
    - Intercellular bridges
    - With or without histiocystic or giant cell reaction to the keratin
    - Ichthyosis uteri (Eur J Gynaecol Oncol 2011;32:699)
      - Extensive replacement of surface endometrium with mature, keratinizing, squamous epithelium as a result of chronic inflammation or cervical obstruction
      - Rarely becomes invasive squamous cell carcinoma (Eur J Gynaecol Oncol 2012;33:552)
Mucinous metaplasia (Gynecol Oncol 2015;136:389, Diagn Pathol 2017;12:39):
- Cuboidal to columnar cells, most commonly resembling endocervical epithelium
  - Rarely, resembling gastric and intestinal type metaplasia
  - Generally cytologically bland
  - Subtypes (Mod Pathol 1999;12:1137):
    - Type A: single cell layer lining the epithelial surface, with or without glandular involvement
    - Type B: focal / patchy papillary / micropapillary changes
    - Type C: extensive papillary, cribriform or microacinar architecture
  - Mucinous metaplasia may be found in the ovaries or cervix of patients with endometrial mucinous metaplasia
Tubal metaplasia (Mod Pathol 2011;24:1254):
- Resembling fallopian tube epithelium; pseudostratified with ciliated eosinophilic cells and clear round cells
Eosinophilic metaplasia:
- Cuboidal to columnar cells with prominent eosinophilic cytoplasm, ranging from granular to dense
- Round nuclei with or without degenerative atypia
Papillary metaplasia (Am J Surg Pathol 2013;37:167):
- Subtypes:
  - Papillary syncytial: pseudostratified eosinophilic cells with indistinct cell borders and loss of nuclear polarity (Int J Gynecol Pathol 2012;31:206)
    - Sometimes termed as pseudopapillary due to the absence of fibrovascular cores
    - Generally located on the surface
    - Associated with stromal breakdown
  - Papillary proliferations: true papillae with fibrovascular cores (Am J Surg Pathol 2001;25:1347)
    - Simple / localized: short, nonbranching
    - Complex / diffuse: numerous branching with papillae and micropapillae
      - Analogous to endometrial intraepithelial neoplasia / atypical hyperplasia
Secretory metaplasia:
- Resembling early to late secretory endometrium, with subnuclear to supranuclear vacuolization
Hobnail metaplasia:
- Glandular, often eosinophilic cells with apically located nuclei that protrude into the lumen
  - Can have cytoplasmic vacuolization
- Generally cytologically bland
Stromal metaplasias:
- Subtypes:
  - Osseous
  - Cartilaginous
  - Myomatous
  - Adipose
  - Synovial-like (Int J Gynecol Pathol 2015;34:570)

Microscopic (histologic) images

Contributed by Jessica L. Bentz, M.D.

Squamous morular metaplasia

Tubal and mucinous metaplasia

Endometrioid adenocarcinoma with mucinous differentiation

Tubal (ciliated cell) metaplasia

Endometrioid adenocarcinoma with cilia

Eosinophilic metaplasia in complex atypical hyperplasia

Papillary syncytial metaplasia

Complex papillary metaplasia

Secretory metaplasia

Hobnail metaplasia

Virtual slides

Images hosted on other servers:

Squamous morular metaplasia

Positive stains

Morular metaplasia:
- CD10, CDX2, SATB2, beta catenin (nuclear and cytoplasmic)
Mucinous metaplasia (Mod Pathol 2012;25:1496):
- Simple: PAX2, ER, PR (weak), p53 (normal / wild type)
- Complex (papillary): PAX2 (weak), p16, ER, p53 (normal / wild type)
Hobnail metaplasia:
- ER, PR
Papillary syncytial metaplasia (Int J Gynecol Pathol 2012;31:206):
- ER (weak), p53 (normal to increased / wild type), p16 (patchy to diffuse)

Negative stains

Morular metaplasia:
- ER, p63
Mucinous metaplasia (Mod Pathol 2012;25:1496):
- Simple: p16, PTEN, beta catenin
- Complex (papillary): PAX2, PR, PTEN, beta catenin
- Low Ki67 proliferative index
Hobnail metaplasia:
- HNF1β
- Low Ki67 proliferative index
Secretory changes:
- Low Ki67 proliferative index
Papillary syncytial metaplasia (Int J Gynecol Pathol 2012;31:206):
- HMGA2
- Low Ki67 proliferative index

Videos

Benign and premalignant lesions of the endometrium - Dr. Parra-Herran, from pathCast

Sample pathology report

Endometrium, biopsy:
- Complex atypical hyperplasia (endometrial intraepithelial neoplasia) with metaplastic changes (see comment)
- Comment: There are foci with cytologic atypia that exceed the allowable spectrum of atypical changes seen in endometrial metaplasia. Therefore, the findings are most consistent with atypical endometrial hyperplasia.

Differential diagnosis

For squamous metaplasia:
- Squamous cell carcinoma:
  - Cytologic malignancy with invasion
  - Mitoses
  - Show immunophenotype typical of squamous differentiation
  - Diffuse p16 expression may suggest cervical origin of a squamous carcinoma
- Reactive / reparative
- Atypical polypoid adenomyoma:
  - Polypoid lesion with prominent myofibroblastic stroma and endometrial intraepithelial neoplasia
For mucinous metaplasia:
- Benign endocervical proliferations:
  - Presence of reserve cells
- Endometrial neoplasia with progestin effect
For tubal metaplasia:
- Atypical endometrial hyperplasia / endometrial intraepithelial neoplasia
- Serous carcinoma:
  - Nucleomegaly and atypia with robust mitoses
  - Immunohistochemistry: diffuse p16+, aberrant p53 expression (diffuse expression or null phenotype), high Ki67 proliferative index
For eosinophilic metaplasia:
- Eosinophilic / oxyphilic variant of endometrioid carcinoma
For papillary metaplasia:
- Surface repair
- Serous carcinoma:
  - Nucleomegaly and marked atypia
  - Immunohistochemistry: p16+ diffuse, aberrant p53 expression (diffuse expression or null phenotype), high Ki67 proliferative index
For secretory metaplasia:
- Clear cell carcinoma:
  - Malignant nuclear features
  - Clinically, may describe a mass lesion
- Arias-Stella reaction:
  - Pregnancy, trophoblastic disease, progestin therapy
  - Decidualization of the stroma
  - Low nuclear to cytoplasmic ratio without stromal invasion
For hobnail metaplasia:
- Serous carcinoma
- Clear cell carcinoma (Histopathology 2014;64:585):
  - Malignant nuclear features
  - Abundant clear cytoplasm with high nuclear to cytoplasmic ratio
  - Immunohistochemistry: ER / PR-, HNF1β+, high Ki67 proliferative index
- Arias-Stella reaction (Int J Gynecol Pathol 2004;23:223):
  - Nucleomegaly with exaggerated hyperplastic appearance and centronuclear vacuolization with hormone effect
  - Pregnancy, trophoblastic disease, progestin therapy
  - Decidualization of the stroma
  - Low nuclear to cytoplasmic ratio without stromal invasion
For stromal metaplasias:
- Retained fetal parts
- Heterologous elements in carcinosarcoma or adenosarcoma
- If adipose stromal metaplasia → consider uterine perforation

Additional references

Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019, Nucci: Gynecologic Pathology - A Volume in Foundations in Diagnostic Pathology Series, 2nd edition, 2020 J Clin Pathol 2011;64:97, Surg Pathol Clin 2019;12:315, Diagn Histopathol 2017;23:303

Board review style question #1

A 53 year old woman presents to the gynecologist with chief complaint of vaginal bleeding. An endometrial biopsy is performed and shows fragments of ciliated inactive endometrial tissue with foci of cytologic atypia. Immunohistochemical studies show a wild type pattern of p53 expression, patchy expression of p16 and low Ki67 proliferative index. What is the most likely diagnosis?

Atypical endometrial hyperplasia
Endometrioid adenocarcinoma
Hobnail metaplasia
Serous endometrial intraepithelial carcinoma (SEIC)
Tubal metaplasia

Board review style answer #1

E. Tubal metaplasia

Comment Here

Reference: Endometrial metaplasia

Board review style question #2

What subtype of carcinoma is most commonly associated with squamous metaplasia?

Endometrioid adenocarcinoma
Invasive squamous cell carcinoma of the cervix
Ovarian high grade serous carcinoma
Uterine carcinosarcoma
Uterine serous carcinoma

Board review style answer #2

A. Endometrioid adenocarcinoma

Comment Here

Reference: Endometrial metaplasia

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