Microscopy of Endometrial Carcinoma

Endometrial carcinoma has two main histologic types with distinct microscopic appearances: endometrioid carcinoma (80-85% of cases) and serous carcinoma (~15%). Their microscopy differs dramatically.

Endometrial Hyperplasia (Precursor Lesion)

Before invasion, the precursor stages are recognizable on H&E:

Endometrial hyperplasia - (A) without atypia showing glandular crowding and cystic dilation, (B) with atypia showing crowded glands and cellular atypia, (C) high magnification of atypical hyperplasia with rounded vesicular nuclei and prominent nucleoli

FIG. 17.11 - Endometrial hyperplasia. (A) Without atypia: mild glandular crowding and cystic dilation. (B) With atypia: glandular crowding + cellular atypia. (C) High magnification of atypical hyperplasia: rounded vesicular nuclei with prominent nucleoli (arrow). - Robbins & Kumar Basic Pathology

Endometrioid Carcinoma - Microscopic Features

Endometrioid and serous carcinoma - gross and microscopy showing (A) grade 1 glandular pattern, (B) grade 2 mixed glandular/solid, (C) grade 3 solid pattern, (D) poor differentiation

FIG. 22.24 - (A) Gross fungating mass. (B) Grade 1 well-differentiated endometrioid adenocarcinoma with preserved glandular architecture, back-to-back glands, no intervening stroma. (C) Grade 2 moderately differentiated with glandular architecture plus solid areas. (D) Grade 3 poorly differentiated with predominantly solid growth. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Key microscopic features of endometrioid carcinoma:

Glandular architecture: The tumor closely mimics proliferative endometrium. Glands are crowded back-to-back with loss of intervening stroma ("gland-to-gland" apposition).

Grading (FIGO 1-3):

Grade 1 (well differentiated): Almost entirely well-formed glands; minimal solid component (<5%). Cells show mild atypia, elongated nuclei.
Grade 2 (moderately differentiated): Well-formed glands mixed with solid sheets that make up 6-50% of the tumor. Moderate cytologic atypia.
Grade 3 (poorly differentiated): Predominantly solid growth pattern (>50% solid). Marked nuclear atypia, prominent nucleoli, frequent mitoses.

Distinguished from hyperplasia by:

Desmoplastic stromal reaction around invading glands
Confluent glandular growth without intervening stroma
Papillary growth patterns
Myometrial invasion

Squamous differentiation: Up to 20% of endometrioid carcinomas contain foci of squamous metaplasia. In low-grade tumors, the squamous elements appear benign (morules); in high-grade tumors they may be frankly malignant.

Tumor-infiltrating lymphocytes (TILs): Tumors with DNA mismatch repair defects (MLH1 loss by promoter methylation) or polymerase-epsilon (POLE) mutations often show abundant infiltrating T cells - an indicator of microsatellite instability.

Serous Endometrial Carcinoma - Microscopic Features

Endometrial carcinoma microscopy showing (A) endometrioid grade 1 infiltrating myometrium, (B) grade 3 solid pattern, (C) serous carcinoma with papillae and marked atypia, (D) p53 immunohistochemistry showing diffuse strong nuclear staining

FIG. 17.12 - (A) Endometrioid type grade 1 with glandular infiltration into myometrium. (B) Grade 3 with solid growth. (C) Serous carcinoma with papilla formation and marked cytologic atypia. (D) Diffuse strong p53 IHC staining (brown nuclei) = TP53 mutation. - Robbins & Kumar Basic Pathology

Key microscopic features of serous carcinoma:

Feature	Detail
Architecture	Papillary tufts and complex branching papillae; can also form glands
Cytologic atypia	Marked - high nuclear-to-cytoplasmic ratio, hyperchromasia, prominent nucleoli
Mitoses	Numerous, often atypical
Grade	Always high-grade by definition, regardless of architectural pattern
Precursor (SEIC)	Serous endometrial intraepithelial carcinoma - malignant cells confined to epithelial surface only, identical morphology
p53 IHC	Diffuse, strong nuclear positivity (mutant p53 accumulates) - key distinguishing feature

Serous vs. endometrioid distinction: Both can form glands, but serous carcinoma shows far greater nuclear atypia. When architecture alone is ambiguous, p53 IHC helps - diffuse block positivity (or complete absence/"null pattern") indicates TP53 mutation.

Comparison Summary

Feature	Endometrioid	Serous
Frequency	80-85%	~15%
Architecture	Glandular (back-to-back glands)	Papillary tufts, complex papillae
Cytologic atypia	Mild to moderate (G1-G2); severe (G3)	Always severe/high-grade
p53 IHC	Focal/weak (wild-type pattern)	Diffuse strong or null (mutant pattern)
Precursor	Atypical hyperplasia	Serous endometrial intraepithelial carcinoma (SEIC)
Molecular hallmark	PTEN, PIK3CA, KRAS mutations; MMR defects	TP53 mutations (>90%)
Associated setting	Estrogen excess (obesity, perimenopausal)	Endometrial atrophy (older postmenopausal)
Prognosis	Good (stage I: ~90% 5-year survival)	Poor (5-year survival 18-27%)

Sources: Robbins & Kumar Basic Pathology (9780323790185); Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528)

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