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Year : 2022  |  Volume : 15  |  Issue : 5  |  Page : 776-778  

Endometrial hyperplasia with secretory changes

Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission06-Apr-2021
Date of Decision21-Jun-2021
Date of Acceptance24-Jun-2021
Date of Web Publication22-Jan-2022

Correspondence Address:
Dr. Dheeraj J Nandagawe
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_252_21

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Endometrial hyperplasia has crucial clinical significance for its obvious association as a precursor lesion to endometrial adenocarcinoma. It almost always occurs in a setting of prolonged estrogen exposure unopposed by progesterone, and hence, the endometrium is mostly, if not always, proliferative in morphology, but rarely, the hyperplastic glands show secretory changes. Endometrial hyperplasia with secretory changes has diagnostic difficulties due to its benign and malignant mimickers. Benign mimickers such as Arias-Stella reaction can be ruled out by clinical signs of gestation, while malignant lesions can be ruled out by histological evidence of stromal or myometrial invasion. Diagnostic difficulty is more pronounced in cases with late secretory endometrium, endometrial polyps with secretory changes, mucinous metaplasia, and hormone-induced changes. In these cases, clinical history with histological workup will be of most value to establish the diagnosis.

Keywords: Endometrial hyperplasia, mimickers of secretory endometrial intraepithelial neoplasia, secretory endometrial intraepithelial neoplasia

How to cite this article:
Nandagawe DJ, Sunita B S. Endometrial hyperplasia with secretory changes. Med J DY Patil Vidyapeeth 2022;15:776-8

How to cite this URL:
Nandagawe DJ, Sunita B S. Endometrial hyperplasia with secretory changes. Med J DY Patil Vidyapeeth [serial online] 2022 [cited 2022 Dec 10];15:776-8. Available from: https://www.mjdrdypv.org/text.asp?2022/15/5/0/336320

  Introduction Top

Endometrial hyperplasia is characterized by increased glandular component in comparison to the stroma. Endometrial hyperplasia mainly encompasses a wide range of proliferative disorders. The WHO 2014 classification of endometrial precancerous lesions[1],[2] uses simple two-tiered system comprising non-atypical endometrial hyperplasia (non-AH) and AH or endometrial intraepithelial neoplasia (EIN). EIN is the most frequent disorder of proliferative endometrium with cytological atypia, but rarely, the hyperplastic glands show secretory changes. We discuss a case of endometrial hyperplasia with secretory changes and differentiate it from benign and malignant mimickers. Recognizing preneoplastic endometrial lesions with secretory features can be vexing and an emerging topic of discussion.

  Case Report Top

A 48-year-old female, P2 L2, both FTND, last live birth 22 years back, posttubectomy, presented with complaints of heavy menstrual bleeding. She had no complaints of dysmenorrhagia and dyspareunia. No history of weight loss or mass descending per vagina was noted. She gave a history of medication at the previous gynecological center, details of which are not available. On radiology, uterus was normal in size with endometrial thickness of 16 mm. Endometrial biopsy was predominantly hemorrhagic and nondiagnostic. The patient was treated as a case of abnormal uterine bleeding with symptomatic management (tranexamic acid 500 mg TDS and mefenamic acid 500 mg TID for 3 days) and planned for radical treatment with hysterectomy. No hormonal therapy was given at our center.

We received a specimen of the uterus with unremarkable external surface. On gross examination, cut surface showed asymmetrical endometrial thickness with irregular surface varying in thickness from 0.7 to 1.7 cm [Figure 1]. Grossly, no endometrial extension into the myometrium was noted. Histological examination of the endometrium through the areas of interest showed round-to-dilated serpiginous glands [Figure 2]. Focal glandular budding and architectural atypia were noted. Some of the tortuous glands were filled with intraluminal secretions. The glands also showed mild-to-moderate cytological atypia and focal nuclear pseudostratification. Intervening stroma was loose and edematous with spiral arterioles. No myometrial/stromal invasion was noted.
Figure 1: Gross appearance of the cut surface of uterus

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Figure 2: H and E sections from area of interest

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Immunohistochemistry (IHC) [Figure 3] revealed loss of PAX2 expression with positive external control and loss of estrogen receptor (ER) and progesterone receptor (PR) expression with stromal elements showing positive internal control. Ki-67 index was 5%–6%.
Figure 3: Immunohistochemical profile of the case

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Based on the histological and IHC findings, diagnosis of atypical hyperplasia with secretory changes was given.

  Discussion Top

Endometrial hyperplasia has crucial clinical significance for its obvious association as a precursor lesion to endometrial adenocarcinoma. Endometrial hyperplasia almost always occurs in a setting of prolonged estrogen exposure unopposed by progesterone, and hence, the endometrium is mostly if not always proliferative in morphology.

Endometrial hyperplasia is an exaggerated glandular proliferation with increased G: S ratio (>1), without significant cytological atypia. These cases may progress to EIN/AH with evident cytological atypia and architectural changes in the form of glandular crowding, with exclusion of benign mimickers and carcinoma.[3]

A study by Ip[4] has explained various benign and malignant mimickers of hyperplastic endometrium. The endometrial hyperplasia can mimic Arias-Stella reaction of gestational endometrium and late secretory endometrium. Also metaplastic glands with mucinous metaplasia and endometrial polyps may coexist with premalignant conditions. In the present context, secretory hyperplasia has to be differentiated from these conditions to establish the diagnosis.

Secretory change in hyperplastic lesions may be induced by spontaneous ovulation after prolonged anovulatory cycles or in response to exogenous hormones in patients being treated for endometrial hyperplasia. Secretory changes in the index case can be due to hormonal therapy at previous center which is routinely used as a part of therapy in cases with heavy menstrual bleeding (details cannot be confirmed due to nonavailability of documents).

Truskinovsky et al.[5] described the secretory pattern in normal secretory endometrium and endometrial hyperplasia with secretory changes. In the late secretory phase, the regular serrated glands are with their long axes parallel to each other and perpendicular to the endometrial surface. In our case, the secretory glands were neither perpendicular to the endometrial surface nor long axis parallel to each other. Instead, it showed irregular glands with budding. Cytologically, the glandular cells were uniform with predominantly round nuclei showing mild nuclear atypia.

The IHC in establishing the diagnosis of endometrial hyperplasia is of importance. Various IHC markers used were ER, PR, PAX2, and Ki-67. A study by Enora Laas et al. demonstrated the use of ER and PR in the epithelium of endometrial glands.[6] The study comprehended progressive loss of hormonal markers in the spectrum from normal to malignant epithelium. Our case also shows loss of expression for ER and PR with the stromal components being positive (internal control). Quick et al. showed the utility of PAX2 in the diagnosis of the premalignant and malignant condition of the endometrium.[7] Loss of PAX2 expression is being associated with premalignant and malignant conditions of the endometrium. Our case showed loss of PAX2 with positive external control.

According to Gurda et al., Ki-67 index does not assist in distinguishing nonatypical from atypical hyperplasia or from well-differentiated carcinoma; in these settings, a combination of conventional histologic features is required to establish a diagnosis.[8] We also performed Ki-67 study which shows hot spots with high Ki-67 index, but rest of the secretory endometrium was with low activity.

Further, along with the histological and IHC studies, grossing of these specimens is also important to find the extent of hyperplasia for focal hyperplastic changes in secretory or proliferative endometrium by taking extra sections through the uterine isthmus and bilateral cornual sections.[9]

  Conclusion Top

The diagnostic approach starts with the clinical history as always, history of drugs, gestation, and duration of cycles. The radiological correlation will be of help, and if any, endometrial biopsy is performed preoperatively. Proper grossing of the specimen is required to look for the extent of hyperplasia. Careful application of current knowledge about secretory EIN to suspect the case and application of IHC for confirming the diagnosis are of great importance for the diagnosis of the premalignant condition.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Giannella L, Delli Carpini G, Sopracordevole F, Papiccio M, Serri M, Giorda G, et al. Atypical Endometrial Hyperplasia and Unexpected Cancers at Final Histology: A Study on Endometrial Sampling Methods and Risk Factors. Diagnostics (Basel) 2020;13:10-474.  Back to cited text no. 1
Emons G, Beckmann MW, Schmidt D, Mallmann P; Uterus Commission of the Gynecological Oncology Working Group (AGO). New WHO Classification of Endometrial Hyperplasias. Geburtshilfe Frauenheilkd 2015;75:135-6.  Back to cited text no. 2
Parra-Herran CE, Monte NM, Mutter GL. Endometrial intraepithelial neoplasia with secretory differentiation: Diagnostic features and underlying mechanisms. Mod Pathol 2013;26:868-73.  Back to cited text no. 3
Ip PP. Benign endometrial proliferations mimicking malignancies: A review of problematic entities in small biopsy specimens. Virchows Arch 2018;472:907-17.  Back to cited text no. 4
Truskinovsky AM, Lifschitz-Mercer B, Czernobilsky B. Hyperplasia and carcinoma in secretory endometrium: A diagnostic challenge. Int J Gynecol Pathol 2014;33:107-13.  Back to cited text no. 5
Laas E, Ballester M, Cortez A, Gonin J, Daraï E, Graesslin O. Supervised clustering of immunohistochemical markers to distinguish atypical endometrial hyperplasia from grade 1 endometrial cancer. Gynecol Oncol 2014;133:205-10.  Back to cited text no. 6
Quick CM, Laury AR, Monte NM, Mutter GL. Utility of PAX2 as a marker for diagnosis of endometrial intraepithelial neoplasia. Am J Clin Pathol 2012;138:678-84.  Back to cited text no. 7
Gurda GT, Baras AS, Kurman RJ. Ki-67 index as an ancillary tool in the differential diagnosis of proliferative endometrial lesions with secretory change. Int J Gynecol Pathol 2014;33:114-9.  Back to cited text no. 8
Malpica A, Wong KK. The molecular pathology of ovarian serous borderline tumors. Ann Oncol 2016;27 Suppl 1:i16-9.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3]


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