Residency · Residency · Pathology

Endometrial Biopsy Interpretation and Carcinoma Classification

Introduction

Endometrial biopsy and curettage are among the most common specimens in gynecologic pathology. The pathologist must accurately interpret the endometrial cycle, recognize hyperplasia, and classify carcinomas using the current WHO system. Molecular classification is increasingly integrated into prognostication and treatment planning.

Normal Endometrial Histology

Proliferative Phase

The proliferative phase corresponds to the follicular phase (days 5-14) and features straight, narrow glands lined by pseudostratified columnar epithelium with mitotic activity. The stroma is compact with scattered mitoses.

Secretory Phase

The earliest reliable dating feature is the appearance of subnuclear vacuoles on days 16-17. Supranuclear secretions develop by days 19-20, with luminal secretions appearing by days 21-22. Stromal predecidual change begins periarterially around day 23, and spiral arterioles become prominent in the late secretory phase.

Menstrual Endometrium

Menstrual endometrium is characterized by stromal breakdown, hemorrhage, neutrophilic infiltrate, and glandular collapse. Fibrin thrombi are typically found in stromal vessels.

Endometrial Hyperplasia

Hyperplasia Without Atypia

This form of hyperplasia shows architectural crowding with an increased gland-to-stroma ratio but no cytologic atypia. The risk of progression to carcinoma is low, approximately 1-3%. It is often related to unopposed estrogen exposure from conditions such as anovulation, obesity, or tamoxifen use.

Atypical Hyperplasia / Endometrioid Intraepithelial Neoplasia (AH/EIN)

AH/EIN features crowded glands with cytologic atypia including nuclear rounding, prominent nucleoli, and loss of polarity. The volume of altered glands exceeds the stroma. This lesion carries a risk of concurrent carcinoma of 25-40% at hysterectomy. PAX2 loss and PTEN loss on immunohistochemistry support the diagnosis.

Classification of Endometrial Carcinoma

Endometrioid Carcinoma (Type I)

Endometrioid carcinoma is the most common type, accounting for approximately 80% of cases, and typically arises in a background of hyperplasia. FIGO grading is based on the solid component: Grade 1 (5% or less solid), Grade 2 (6-50% solid), and Grade 3 (more than 50% solid). Notable nuclear atypia raises the grade by one. Common molecular alterations include PTEN loss, PIK3CA, ARID1A, KRAS, and microsatellite instability. Squamous, mucinous, and secretory differentiation are frequently encountered.

Serous Carcinoma (Type II)

Serous carcinoma is high-grade by definition and displays papillary and glandular architecture. It is p53 aberrant, showing either overexpression or a null staining pattern, with a high Ki-67 index. This subtype arises from serous endometrial intraepithelial carcinoma (SEIC) in atrophic endometrium and behaves aggressively with early peritoneal and omental spread. Molecularly, it shows wild-type PTEN but frequent TP53 mutations and HER2 amplification.

Clear Cell Carcinoma

Clear cell carcinoma features hobnail cells, clear or eosinophilic cytoplasm, and hyalinized papillae. It has a variable p53 staining pattern and is typically Napsin A positive and HNF1-beta positive. Its aggressive behavior is similar to that of serous carcinoma.

Molecular Classification (The Cancer Genome Atlas / ProMisE)

MMR immunohistochemistry (MLH1, PMS2, MSH2, MSH6) should be performed on all endometrial carcinomas. When MLH1/PMS2 loss is identified, MLH1 promoter methylation testing is needed to distinguish sporadic tumors from Lynch syndrome. POLE mutation testing identifies a favorable prognostic subgroup even among high-grade tumors.

Practical Biopsy Interpretation Tips

When tissue is scanty, the report should state "insufficient for diagnosis" if no endometrial glands or stroma are present. Lower uterine segment tissue should be distinguished from true endometrial tissue, as it lacks functional glands. Artifacts such as telescoping, crush, and cautery can mimic atypia and must not be over-interpreted. In reproductive-age women, pregnancy-related changes should always be considered in the differential.

Clinical Pearls

MMR testing on all endometrial carcinomas is recommended by NCCN for Lynch syndrome screening. Molecular classification increasingly guides adjuvant therapy decisions beyond histologic type and grade alone. AH/EIN on biopsy carries a significant risk of concurrent carcinoma, and hysterectomy is recommended when fertility is not desired. Serous carcinoma can arise in atrophic endometrium with minimal tissue on biopsy, making p53 immunohistochemistry essential for detection.

References

1. WHO Classification of Tumours Editorial Board. Female Genital Tumours. WHO Classification of Tumours, 5th ed. Lyon: IARC Press; 2020.
2. Soslow RA, et al. Endometrial carcinoma diagnosis: use of FIGO grading and genomic subcategories in clinical practice. Int J Gynecol Pathol. 2019;38(Suppl 1):S64-S74.
3. Talhouk A, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 2015;113(2):299-310.
4. Emons G, et al. New WHO classification of endometrial hyperplasia. Geburtshilfe Frauenheilkd. 2015;75(2):135-136.

For the intern

At 3 a.m., your priority is distinguishing hyperplasia from carcinoma and recognizing high-grade histology. If you see crowded glands with significant cytologic atypia (enlarged, rounded nuclei with prominent nucleoli), call it atypical hyperplasia/endometrioid intraepithelial neoplasia (EIN) and flag for attending review in the morning—this carries a 25-40% risk of concurrent carcinoma. If you see papillary architecture with marked nuclear atypia, consider serous carcinoma and order p53 immunohistochemistry (IHC) urgently if staging is imminent. For straightforward endometrioid carcinomas, FIGO grading based on solid component percentage can wait until morning with your attending. Always check if sufficient endometrial tissue is present—if you only see blood, mucus, or lower uterine segment, label it "insufficient for diagnosis." Dating the endometrial cycle and distinguishing benign secretory changes from hyperplasia are daytime tasks best done with your attending.

Common pitfalls

• Over-interpreting crush artifact or telescoping as atypia—look for well-preserved areas before diagnosing atypia;真 cytologic atypia shows nuclear enlargement, rounding, and loss of polarity in intact cells
• Forgetting to order mismatch repair (MMR) IHC on all carcinomas—this is now standard for Lynch syndrome screening per National Comprehensive Cancer Network (NCCN) guidelines and should be reflexed
• Missing serous endometrial intraepithelial carcinoma (SEIC) in scant atrophic endometrium—even small foci with marked atypia warrant p53 IHC
• Confusing lower uterine segment with true endometrium—lower segment lacks functional changes and shouldn't be dated or used to diagnose hyperplasia

Make it stick

Imagine you're on call, and a stat endometrial biopsy comes in. Your task is to quickly assess for any life-threatening or immediately impactful findings. You scan the slides: Are the glands overtly malignant, or is there significant atypia that suggests a high-risk precursor? If you see clear-cut carcinoma (e.g., complex papillary structures with marked nuclear atypia) or atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN) with significant cytologic changes, you prioritize flagging this for immediate attending review. Don't spend precious overnight hours precisely grading an endometrioid carcinoma; focus on identifying the presence of cancer or a high-risk pre-cancer. Confirming adequate tissue is also crucial—if it's just blood and mucus, an "insufficient for diagnosis" call is key to prevent treatment delays.

If you remember one thing

Prioritize identifying overt carcinoma or atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN) on an endometrial biopsy, as these warrant urgent clinical attention. Don't over-interpret artifact, but don't miss high-grade disease or insufficient material—those are the critical overnight calls.

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