Uterine Corpus (Epithelial Lesions)

3.1 MENSTRUAL ENDOMETRIUM VS. ANOVULATION-RELATED ENDOMETRIAL STROMAL BREAKDOWN/DYSFUNCTIONAL UTERINE BLEEDING

	Menstrual Endometrium	Anovulation-Related Endometrial Stromal Breakdown/Dysfunctional Uterine Bleeding
Age	Reproductive-age women	Reproductive-age women; when related to true anovulation, is more common in perimenopause
Location	Endometrium	Endometrium
Symptoms	Cyclical vaginal bleeding	Irregular vaginal bleeding, often mid cycle
Signs	Vaginal bleeding	Vaginal bleeding; mildly increased endometrial thickness/stripe (<10 mm)
Etiology	Normal/physiologic	Anovulatory cycle, failed follicle, absence of progression to luteal phase, PCOS; occasionally coagulopathy
Histology	1. Markedly fragmented endometrium with loss of normal architecture; extensive hemorrhage; diffuse stromal breakdown, aggregates of condensed predecidual cells admixed with blood and inflammatory cells, including numerous neutrophils (Figs. 3.1.1 3.1.2, 3.1.3)	1. Variably fragmented sample with subcapsular stromal condensation (early stromal breakdown) or hyperchromatic stromal balls (Figs. 3.1.5 3.1.6, 3.1.7)
	2. Fragmented endometrial glands with secretory exhaustion forming cords (Fig. 3.1.4)	2. Endometrial glands with features of interval, proliferative (often disordered) or early secretory endometrium (Figs. 3.1.5 3.1.6, 3.1.7)
	3. Sheets of syncytial metaplasia	3. Epithelial metaplastic changes (eosinophilic, papillary, syncytial, tubal metaplasia) can be seen (Fig. 3.1.8)
	4. Extensive fibrin is often present	4. Fibrin thrombi in the stroma in cases of prolonged bleeding (Fig. 3.1.6)
Special studies	None helpful in this differential	None helpful in this differential
Treatment	None indicated	Management of the underlying cause; hormonal therapy with cyclic estrogens/progestins
Prognosis	Unremarkable	Benign, but can affect fertility; resampling should be considered if the symptoms persist

Figure 3.1.1 Menstrual endometrium. Markedly disrupted endometrium with loss of normal architecture and extensive stromal hemorrhage.

Figure 3.1.2 Menstrual endometrium. Stromal hemorrhage and diffuse stromal breakdown.

Figure 3.1.3 Menstrual endometrium. Clusters of predecidualized stromal cells with inflammatory cells including numerous neutrophils.

Figure 3.1.4 Menstrual endometrium. Diffuse stromal breakdown with fragmented late secretory glands.

Figure 3.1.5 Interval endometrium with early stromal breakdown. Inset, higher magnification, some glands with subnuclear vacuoles indicating developing secretory changes.

Figure 3.1.6 Proliferative endometrium with stromal breakdown (stromal balls) and fibrin underneath the endometrial surface epithelium. Inset, higher magnification, background endometrium with proliferative glands with mitoses.

Figure 3.1.7 Disordered proliferative endometrium with early stromal collapse. Condensed subsurface stroma and surface epithelial metaplastic changes (fragment, upper right).

Figure 3.1.8 Endometrial stromal breakdown. Stromal balls surrounded by epithelium with prominent eosinophilic metaplastic changes.

3.2 ARTIFACTUAL GLANDULAR CROWDING VS. ENDOMETRIAL HYPERPLASIA

	Artifactual Glandular Crowding	Endometrial Hyperplasia
Age	Any age, more common in reproductive age	Reproductive age and postmenopausal
Location	Endometrium	Endometrium
Symptoms	Abnormal vaginal bleeding is usually an indication for endometrial biopsy	Abnormal vaginal bleeding
Signs	No specific signs	Constitutional symptoms: obesity, diabetes, PCOS; thickened endometrial stripe on sonography
Etiology	N/A	Unopposed estrogenic stimulation; somatic mutations in PTEN, KRAS, CTNNB1; hereditary syndromes, Lynch and Cowden syndromes
Histology	1. Distorted tissue with “glandular molding,” “telescoping,” and tearing of the stroma around the glands (Figs. 3.2.1 3.2.2, 3.2.3)	1. Glandular crowding in the relatively intact fragments of endometrium; dilated glands of different sizes, complex, irregular glandular outlines (Figs. 3.2.6 and 3.2.7)
	2. Endometrial stromal breakdown and associated tissue fragmentation (Fig. 3.2.4)	2. Endometrial stromal breakdown can be present, but tissue fragmentation should not interfere with the assessment of architecture
	3. Squamous morular metaplasia is very uncommon	3. Squamous metaplasia can be present (Fig. 3.2.8)
	4. Endometrial glands without cytologic atypia, similar to the background noncrowded endometrium (Fig. 3.2.5)	4. Cytologic atypia can be present
	5. Epithelial metaplastic changes can be present	5. Epithelial metaplastic changes can be present
Special studies	Not helpful in this differential	Not helpful in this differential
Treatment	None	Hormonal treatment (progestins) or hysterectomy in cases of atypical hyperplasia (if fertility preservation is not desired)
Prognosis	No prognostic significance; however, endometrial sampling should be repeated, if symptoms persist	Dependent on the presence or absence of cytologic atypia; cases of complex atypical hyperplasia have up to 40% chance of coexisting endometrial carcinoma

Figure 3.2.1 Artifactual glandular crowding. Proliferative endometrium with small tubular glands. Gland-to-stroma ratio appears increased due to stromal disruption.

Figure 3.2.2 Artifactual glandular crowding. Focus of “molded” glands beneath the endometrial surface (center) due to stromal disruption, note extravasated blood.

Figure 3.2.3 Artifactual glandular crowding. Proliferative endometrium. Stromal disruption creates a few foci with increased gland-to-stroma ratio. Glands are small and retain tubular shapes.

Figure 3.2.4 Artifactual glandular crowding. Extensive endometrial stromal breakdown; stromal balls and prominent epithelial metaplastic changes. A few glands appear back to back due to stromal collapse.

Figure 3.2.5 Artifactual glandular crowding. “Telescoping” and crush, common artifacts seen in endometrial biopsies with tissue distortion.

Figure 3.2.6 Complex endometrial hyperplasia. Increased gland-to-stroma ratio. Endometrial glands of different shapes and sizes.

Figure 3.2.7 Simple hyperplasia. Despite some stromal disruption, most of the stroma is intact. Glands are crowded and irregularly shaped; some are cystically dilated.

Figure 3.2.8 Foci of complex hyperplasia with squamous metaplasia.

3.3 COMPLEX ATYPICAL HYPERPLASIA VS. COMPLEX HYPERPLASIA WITHOUT ATYPIA (+/- METAPLASTIC CHANGES)

	Complex Atypical Hyperplasia	Complex Hyperplasia without Atypia (+/- Metaplastic Changes)
Age	Wide age range; mean age is 53 years	Wide age range, most commonly in perimenopause
Location	Endometrium	Endometrium
Symptoms	Abnormal vaginal bleeding	Abnormal vaginal bleeding
Signs	Noncyclical vaginal bleeding, constitutional symptoms: obesity, diabetes, PCOS; thickened endometrial stripe on sonography	Noncyclical vaginal bleeding, constitutional symptoms: obesity, diabetes, PCOS; thickened endometrial stripe on sonography
Etiology	Unopposed estrogenic stimulation; somatic mutations in PTEN, KRAS, CTNNB1; hereditary syndromes, Lynch and Cowden syndromes	Unopposed estrogenic stimulation
Histology	1. Glands of atypical hyperplasia appear pale compared to the nonhyperplastic/nonatypical endometrial glands (if present) (Fig. 3.3.1)	1. Basophilic-appearing endometrial glands at low magnification (Fig. 3.3.1)
	2. Enlarged rounded vesicular nuclei; stratification and loss of polarity (Fig. 3.3.2)	2. Hyperchromatic elongated nuclei, oriented perpendicular to the basement membrane (Fig. 3.3.2)
	3. Nucleoli often inconspicuous (Fig. 3.3.3) but occasionally may be evident	3. Nucleoli are not seen (unless superimposed metaplastic changes are present)
	4. In presence of metaplastic change (particularly tubal/ciliated), may see nuclear rounding, nuclear enlargement, stratification, vesicular nuclei with nucleoli (Fig. 3.3.4)	4. In presence of metaplastic changes (particularly tubal/ciliated), evaluation of atypia can be difficult; nuclear rounding, some enlargement, and occasional nucleoli are often seen; however, chromatin is evenly distributed (Figs. 3.3.5 and 3.3.6)
Special studies	Not helpful in this differential diagnosis	Not helpful in this differential diagnosis
Treatment	Hysterectomy or progestins therapy if fertility preservation is desired	Progestins therapy to control bleeding; additional endometrial sampling in follow-up to exclude atypical hyperplasia
Prognosis	Significant percent (20%-40%) of uteri with complex atypical hyperplasia diagnosed on preoperative biopsy, demonstrate carcinoma in the hysterectomy specimen	Very small chance (1%-3%) of progression to carcinoma; however, repeat endometrial sampling is recommended for follow-up, particularly if symptoms persist

Figure 3.3.1 Focal complex atypical hyperplasia (top) in a background of complex hyperplasia without atypia. Atypical glands appear pale compared to darker more basophilic glands without atypia.

Figure 3.3.2 Focal complex atypical hyperplasia (top) in a background of complex hyperplasia without atypia. Same case as in Figure 3.3.1, higher magnification. Atypical glands (top) with nuclear enlargement, rounding, stratification, vesicular chromatin, and nucleoli. Compare with more elongated basophilic nuclei, aligned perpendicular to the basement membrane in glands without atypia (bottom).

Figure 3.3.3 Complex atypical hyperplasia. Back-to-back glands with enlarged round nuclei with stratification and occasional nucleoli.

Figure 3.3.4 Complex atypical hyperplasia with superimposed tubal metaplastic changes. Nuclear enlargement and inconspicuous, often multiple nucleoli. Compare to normal proliferative endometrial gland from the background endometrium (inset).

Figure 3.3.5 Complex hyperplasia with tubal metaplastic changes. Evaluation of atypia is difficult in this setting. No definite atypia identified.

Figure 3.3.6 Complex hyperplasia with prominent tubal metaplastic changes. Evaluation of atypia is difficult in this setting. No definite atypia identified.

3.4 ENDOMETRIAL HYPERPLASIA/CARCINOMA WITH SECRETORY DIFFERENTIATION VS. SECRETORY ENDOMETRIUM

	Endometrial Hyperplasia/Carcinoma with Secretory Differentiation	Secretory Endometrium
Age	Broad age range, from third decade to postmenopause	Reproductive-age women
Location	Endometrium	Endometrium
Symptoms	Abnormal vaginal bleeding	Abnormal vaginal bleeding
Signs	Constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors	Menometrorrhagia is usually an indication for an endometrial biopsy
Etiology	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, and KRAS. Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)	Physiologic change; menometrorrhagia can be caused by ovarian cycle disturbances, submucosal leiomyomas, etc.
Histology	1. Distinct areas of crowded glands with divergent appearance compared to background endometrium	1. Diffusely crowded endometrial glands with relatively uniform glandular and stromal changes of secretory phase (Fig. 3.4.5)
	2. Architectural disorder: the long axes of the glands pointing in different directions; budding, branching glands and staghorn-shaped (Figs. 3.4.1 and 3.4.2) glands	2. Crowded irregular glands with long axis parallel to each other (Fig. 3.4.6)
	3. Crowded hyperplastic glands without secretory changes can be present (Fig. 3.4.3); cribriform or confluent glands in cases of carcinoma	3. Occasional noncrowded inactive glands without secretory changes (basalis) can be seen
	4. Nuclear features divergent from the background endometrial glands; cytologic atypia in cases of atypical hyperplasia and carcinoma (Fig. 3.4.4)	4. Small, uniform, bland-appearing nuclei (Fig. 3.4.7)
	5. Mitotic figures can be seen but often rare	5. Mitotic figures are rare (usually absent)
Special studies	• None helpful in this differential	• None helpful in this differential
	• Ki 67 has been suggested by some; increased proliferative activity in glands	• Ki 67 has been suggested by some; low proliferative activity in glands (Fig. 3.4.5, inset)
Treatment	Repeat sampling during the first part of the menstrual cycle can be recommended for further evaluation and determination of presence of cytologic atypia	In cases with concern for underlying endometrial hyperplasia, repeat biopsy during the first part of the menstrual cycle should be recommended; treatment of an underlying condition
Prognosis	Increased risk of concurrent endometrial carcinoma, if cytologic atypia is present	Unremarkable; related to an underlying condition

Figure 3.4.1 Complex hyperplasia with secretory changes. Haphazardly arranged irregularly shaped glands of varying sizes.

Figure 3.4.2 Complex hyperplasia with extensive secretory changes. Markedly crowded endometrial glands with irregular shapes.

Figure 3.4.3 Endometrioid carcinoma with extensive secretory changes. Confluent endometrial glands. Range of early (sub- and supranuclear vacuoles) to midsecretory changes.

Figure 3.4.4 Complex atypical hyperplasia with extensive secretory changes. Same case as in Figure 3.4.2, higher magnification. Nuclei with vesicular chromatin and some stratification. Occasional nucleoli are seen.

Figure 3.4.5 Secretory endometrium. Crowded endometrial glands without significant variation in size and shape. Ki 67 proliferative activity is essentially zero (inset).

Figure 3.4.6 Early secretory endometrium. Irregular crowded endometrial glands with long axis parallel to each other. Note uniform subnuclear vacuoles reflecting early secretory phase.

Figure 3.4.7 Secretory endometrium. Higher magnification, irregularly shaped glands in predecidualized stroma with small round basally placed nuclei.

3.5 ENDOMETRIAL HYPERPLASIA/CARCINOMA WITH PROGESTIN TREATMENT EFFECT VS. SECRETORY/GESTATIONAL ENDOMETRIUM

	Endometrial Hyperplasia/Carcinoma with Progestin Treatment Effect	Secretory/Gestational Endometrium
Age	Premenopausal women, occasional postmenopausal	Reproductive-age women
Location	Endometrium	Endometrium
Symptoms	N/A, follow-up endometrial sampling	Abnormal vaginal bleeding
Signs	History of prior endometrial hyperplasia/carcinoma, ongoing treatment with progestins; constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors	Menometrorrhagia is usually an indication for an endometrial biopsy; spontaneous (or rarely elective) abortion, positive urine/serum β-hCG
Etiology	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, and KRAS. Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)	Physiologic change; menometrorrhagia can be caused by ovarian cycle disturbances, submucosal leiomyomas, etc.; gestation, spontaneous abortion
Histology	1. Areas of extensively decidualized endometrial stroma with rare inactive glands are usually seen (resembling decidua/gestational endometrium) (Fig. 3.5.1)	1. Diffusely crowded endometrial glands with relatively uniform glandular and stromal changes of secretory phase; occasional noncrowded inactive glands without secretory changes (basalis) can be seen (Fig. 3.5.6); areas of decidua (if gestational endometrium)
	2. Varying amount of glandular proliferation; glands of varying sizes, dilated irregular glands as well as small glands (Fig. 3.5.2)	2. Relatively uniformly sized glands
	3. Glandular proliferation with cribriform, papillary, and solid growth; squamous differentiation is often prominent (Figs. 3.5.2 3.5.3, 3.5.4, 3.5.5)	3. Crowded irregular glands with long axis parallel to each other (Fig. 3.5.7); or hypersecretory glands (if gestational endometrium); solid growth, papillary architecture and squamous differentiation are not seen
	4. Small round nuclei with smudged chromatin or persistent cytologic atypia	4. Small, uniform, bland-appearing nuclei
	5. Mitotic figures are rare	5. Mitotic figures are rare (usually absent) Also see Figs. 3.4.5 3.4.6, 3.4.7
Special studies	None helpful in this differential	None helpful in this differential
Treatment	Continued progestin therapy or hysterectomy	In cases with negative urine/serum β-hCG and with concern for underlying endometrial hyperplasia, repeat biopsy during the first part of the menstrual cycle should be recommended; treatment of an underlying condition
Prognosis	Complete resolution of carcinoma/hyperplasia is seen in a proportion of patients (40%)	Unremarkable; related to an underlying condition

Figure 3.5.1 Inactive decidualized endometrium, consistent with exogenous progestin therapy effect with focal residual glandular proliferation.

Figure 3.5.2 Same case as in Figure 3.5.1, different area. Residual endometrial hyperplasia. Complex back-to-back glands of different sizes and shapes.

Figure 3.5.3 Endometrial hyperplasia with progestin treatment effect. Irregular, merging glands with luminal secretions.

Figure 3.5.4 Focus of residual endometrioid carcinoma with progestin treatment effect. Glandular proliferation appears solid, but nuclei are bland and small. Such solid growth associated with therapy does not warrant elevation of FIGO grade.

Figure 3.5.5 Endometrial hyperplasia with progestin treatment effect. Crowded glands with secretory changes and foci of squamous differentiation. Note small basally placed nuclei in the glandular epithelium.

Figure 3.5.6 Secretory endometrium. Crowded endometrial glands without significant variation in size and shape. A few small inactive glands are present for comparison (upper right).

Figure 3.5.7 Secretory endometrium. Irregular crowded endometrial glands with long axis parallel to each other. Predecidualized stroma synchronous with the glandular changes of mid to late secretory phase.

3.6 COMPLEX ATYPICAL HYPERPLASIA VS. FIGO GRADE 1 ENDOMETRIOID CARCINOMA

	Complex Atypical Hyperplasia	FIGO Grade 1 Endometrioid Carcinoma
Age	Wide age range; mean age is 53 years	Wide age range; mean age is 63 years
Location	Endometrium	Endometrium
Symptoms	Abnormal vaginal bleeding	Abnormal vaginal bleeding; pelvic pain or pressure and abdominal distension in advanced cases
Signs	Noncyclical vaginal bleeding, constitutional symptoms: obesity, diabetes, PCOS; thickened endometrial stripe on sonography	Noncyclical vaginal bleeding, constitutional symptoms: obesity, diabetes, PCOS; thickened endometrial stripe or endometrial mass on MRI or sonography; abnormal Pap smear
Etiology	Unopposed estrogenic stimulation; somatic mutations in PTEN, KRAS, CTNNB1; hereditary syndromes, Lynch and Cowden syndromes	Unopposed estrogenic stimulation; somatic mutations in PTEN, PIK3CA, KRAS, CTNNB1, ARID1A; hereditary syndromes, Lynch and Cowden syndromes
Histology	1. Crowded back-to-back glands surrounded by stroma (Fig. 3.6.1)	1. Confluent glands without intervening stroma (Fig. 3.6.3)
	2. Small foci of cribriforming (<2 mm) can be seen (Fig. 3.6.2)	2. Cribriform growth >2 mm (Fig. 3.6.4)
	3. Normal-appearing endometrial stroma, can appear compressed between crowded glands	3. Altered desmoplastic inflamed stroma (this criterion cannot be used in a polyp) (Fig. 3.6.5)
	4. No extensive papillary architecture with true fibrovascular cores; intraglandular infoldings can be present	4. Complex papillary architecture
	5. Fragments of crowded glands with rounded outlines	5. Long folded strips of epithelium without intervening stroma (in biopsy/curettage) (Fig. 3.6.6)
Special studies	Not helpful in this differential diagnosis	Not helpful in this differential diagnosis
Treatment	Hysterectomy or progestin therapy if fertility preservation is desired	Hysterectomy with bilateral salpingo-oophorectomy, +/- pelvic and periaortic lymphadenectomy. Progestin therapy can be considered for fertility preservation (tumors limited to endometrium on MRI or transvaginal ultrasound and in the absence of suspicious/metastatic disease on imaging)
Prognosis	Significant percent (20%-40%) of uteri with complex atypical hyperplasia (diagnosed on preoperative biopsy) demonstrate carcinoma in the hysterectomy specimen	Stage dependent; 5-year survival for stage IA tumors is 95%

Figure 3.6.1 Complex atypical hyperplasia. Focus of nearly back-to-back glands with some shape irregularity, surrounded by nearly normal endometrial stroma.

Figure 3.6.2 Complex atypical hyperplasia. Focus of intraglandular cribriforming (<1 mm).

Figure 3.6.3 Endometrioid carcinoma, FIGO grade 1. Glandular confluence without intervening stroma.

Figure 3.6.4 Endometrioid carcinoma, FIGO grade 1. Areas of cribriform growth (>2 mm).

Figure 3.6.5 Endometrioid carcinoma, FIGO grade 1. Altered, fibroblastic stroma with inflammation; small glands with some confluence.

Figure 3.6.6 Endometrioid carcinoma, FIGO grade 1; endometrial curettage specimen, long interconnected fragments of glandular epithelium devoid of stroma.

3.7 FRAGMENTS OF FIGO GRADE 1 ENDOMETRIOID CARCINOMA WITH METAPLASTIC-LIKE DIFFERENTIATION IN BIOPSY/CURETTAGE VS. METAPLASIA

	Fragments of FIGO Grade 1 Endometrioid Carcinoma with Metaplastic-like Differentiation in Biopsy/Curettage	Metaplasia
Age	Wide age range; mean age is 63 years	Usually in reproductive-age women, occasionally, in postmenopausal
Location	Endometrium	Endometrium
Symptoms	Abnormal vaginal bleeding; pelvic pain or pressure and abdominal distension in advanced cases	Abnormal vaginal bleeding
Signs	Noncyclical vaginal bleeding, constitutional symptoms: obesity, diabetes, PCOS; thickened endometrial stripe or endometrial mass on MRI or sonography; abnormal Pap smear	Abnormal vaginal bleeding
Etiology	Unopposed estrogenic stimulation; somatic mutations in PTEN, PIK3CA, KRAS, CTNNB1, ARID1A; hereditary syndromes, Lynch and Cowden syndromes	Related to relative excess of estrogens; often associated with endometrial stromal breakdown; can be related to IUD
Histology	1. Confluent glands without intervening stroma (Figs. 3.7.1 and 3.7.2); cribriform growth	1. Often involves surface endometrium (Fig. 3.7.6); no true glandular confluence; tangentially oriented sheets of metaplastic epithelium can mimic cribriform growth, but usually not very extensive (Figs. 3.7.7 and 3.7.8)
	2. Altered desmoplastic inflamed stroma (this criterion cannot be used in a polyp)	2. Stromal breakdown is often seen; no stromal desmoplasia (Figs. 3.7.6 and 3.7.9)
	3. Complex papillary architecture (Figs. 3.7.3 and 3.7.4)	3. Small areas with papillary-like growths lacking well-developed fibrovascular cores (Fig. 3.7.10)
	4. Cytologic atypia, usually mild (Fig. 3.7.5)	4. Mild cytologic atypia can be seen (Fig. 3.7.10)
	5. Mitotic figures can be seen, but not a constant feature	5. Mitotic figures are rare
Special studies	Not helpful in this differential diagnosis	Not helpful in this differential diagnosis
Treatment	Hysterectomy with bilateral salpingo-oophorectomy, +/- pelvic and periaortic lymphadenectomy. Progestin therapy can be considered for fertility preservation (tumors limited to endometrium on MRI or transvaginal ultrasound and in the absence of suspicious/metastatic disease on imaging)	None required; treatment of underlying causes if needed
Prognosis	Stage dependent; 5-year survival for stage IA tumors is 95%	Benign; however, if symptoms persist, repeat endometrial sampling is recommended to exclude underlying neoplastic process

Figure 3.7.1 Endometrioid carcinoma with extensive metaplastic changes. Confluent epithelial proliferation with some cribriform formations. Associated inflammation is commonly seen.

Figure 3.7.2 Endometrioid carcinoma with extensive metaplastic changes and secretory changes.

Figure 3.7.3 Endometrioid carcinoma with metaplastic changes. Long papillary structures with well-developed fibrovascular cores.

Figure 3.7.4 Endometrioid carcinoma with metaplastic changes. Same case as in Figure 3.7.3, higher magnification. Papillae are lined by epithelium with abundant eosinophilic and vacuolated cytoplasm. The nuclei are small and bland.

Figure 3.7.5 Endometrioid carcinoma with metaplastic changes. Prominent papillary architecture with mucinous differentiation. Detached cell clusters. Mildly atypical vesicular nuclei.

Figure 3.7.6 Proliferative endometrium with focal endometrial stromal breakdown. Surface epithelium overlying collapsed subepithelial stroma displays prominent eosinophilic and papillary metaplastic change. Detached papillary clusters can be seen.

Figure 3.7.7 Fragmented endometrial tissue with prominent epithelial metaplastic changes.

Figure 3.7.8 Fragmented endometrial tissue with prominent epithelial metaplastic changes. Same case as in Figure 3.7.7, higher magnification. Surface epithelium uniformly thickened and eosinophilic.

Figure 3.7.9 Endometrial stromal breakdown and associated surface epithelial metaplastic changes. The nuclei can appear stratified. Note cilia on the surface.

Figure 3.7.10 Fragmented endometrial tissue with prominent epithelial metaplastic changes. Same case as in Figure 3.7.7, higher magnification. Detached tangentially oriented fragment of eosinophilic epithelium may mimic papillary structure. Note lack of fibrovascular core. The nuclei are relatively uniform and mildly atypical.

3.8 FIGO GRADE 1 ENDOMETRIOID CARCINOMA WITH PROMINENT SQUAMOUS DIFFERENTIATION VS. FIGO GRADE 2 ENDOMETRIOID CARCINOMA

	FIGO Grade 1 Endometrioid Carcinoma with Prominent Squamous Differentiation	FIGO Grade 2 Endometrioid Carcinoma
Age	Wide age span from third decade to late postmenopause; most cases are between 55 and 65 years	Wide age span from third decade to late postmenopause; most cases are between 55 and 65 years
Location	Endometrium	Endometrium
Symptoms	Vaginal bleeding	Vaginal bleeding
Signs	Abnormal uterine or postmenopausal bleeding; constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors	Abnormal uterine or postmenopausal bleeding; constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors
Etiology	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, and KRAS	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, and KRAS
	Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)	Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)
Histology	1. Solid (squamous) appearing areas are tinctorially different from the glandular areas, usually more eosinophilic or pale (Figs. 3.8.1 and 3.8.2)	1. No difference in staining between solid and glandular areas (Fig. 3.8.5)
	2. Squamous areas are usually surrounded by glandular areas	2. Solid areas variably distributed, often at the edges of the tumor nests
	3. Cells in the squamous areas have moderate to abundant eosinophilic cytoplasm; well-defined cell membranes can be seen (Fig. 3.8.3)	3. The amount and quality of the cytoplasm is similar between solid and glandular areas; cell borders are indiscernible (Fig. 3.8.6)
	4. N:C ratio is not increased	4. N:C ratio can be increased
	5. Nuclei in squamous areas are bland and uniform, often smaller and less atypical than those in glandular areas (Fig. 3.8.4)	5. Nuclear features are similar in solid and glandular areas (Fig. 3.8.7)
	6. Keratinization (Fig. 3.8.3) can be seen	6. Keratinization is absent in nonsquamous solid areas
Special studies	Positive p63 staining in squamous areas (suggested by some experts)	Negative p63 staining in solid nonsquamous areas (suggested by some experts)
Treatment	Hysterectomy with bilateral salpingo-oophorectomy, +/- pelvic and periaortic lymphadenectomy. Conservative management with progestins can be considered for fertility preservation (tumors limited to endometrium on MRI or transvaginal ultrasound and in the absence of suspicious/metastatic disease on imaging); otherwise stage dependent (see FIGO grade 2 endometrioid carcinoma)	Hysterectomy with bilateral salpingo-oophorectomy, +/- pelvic and periaortic lymphadenectomy Stage IA tumors are generally cured by surgery alone; adjuvant vaginal brachytherapy for stage IB, +/- pelvic RT for cases with adverse risk factors; stage III and IV, chemotherapy +/- RT and vaginal brachytherapy
Prognosis	Stage dependent; 5-year survival is 90% for stage I tumors, 30%-50% stage II tumors, and 20% for stage III-IV tumors	Stage dependent; 5-year survival is 90% for stage I tumors, 30%-50% stage II tumors, and 20% for stage III-IV tumors

Figure 3.8.1 Endometrioid carcinoma, FIGO grade 1 with squamous differentiation. Squamous areas (center) appear pale compared to more basophilic glandular areas at the periphery.

Figure 3.8.2 Endometrioid carcinoma, FIGO grade 1 with squamous differentiation. Squamous areas occupying centers of the tumor nests are eosinophilic compared to more basophilic glands at the periphery.

Figure 3.8.3 Endometrioid carcinoma, FIGO grade 1 with squamous differentiation. Pale squamous area (top) has eosinophilic focus of keratinization. The cells in squamous areas have abundant cytoplasm and defined cell borders.

Figure 3.8.4 Endometrioid carcinoma, FIGO grade 1 with squamous differentiation. Higher magnification, squamous cells in the center with abundant pale pink cytoplasm and elongated nuclei with occasional grooves. Glandular cells forming glands are columnar with rounded vesicular nuclei.

Figure 3.8.5 Endometrioid carcinoma, FIGO grade 2. Solid and glandular areas have similar tinctorial properties at low power.

Figure 3.8.6 Endometrioid carcinoma, FIGO grade 2. Predominantly solid growth in this area with occasional glands with round lumina. The cells occupying solid areas and lining glandular spaces are identical.

Figure 3.8.7 Endometrioid carcinoma, FIGO grade 2. Same case as in Figure 3.8.5, higher magnification. Tumor cell nuclei are similar in solid and gland-forming areas.

3.9 ENDOMETRIOID CARCINOMA WITH PAPILLARY ARCHITECTURE VS. SEROUS CARCINOMA

	Endometrioid Carcinoma with Papillary Architecture	Serous Carcinoma
Age	Wide age range, from third decade into late postmenopause; mean age 63 years	Postmenopausal; mean age in late 60s
Location	Endometrium	Endometrium
Symptoms	Vaginal bleeding, discharge	Postmenopausal bleeding
Signs	Constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors	Often present with subclinical advanced-stage disease
Etiology	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, and KRAS	Somatic TP53 mutation is nearly ubiquitous
	Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)	PIK3CA, FBXW7, PPP2R1A mutations in a subset of cases
		May be associated with BRCA1/2 mutations
Histology	1. Background of endometrial hyperplasia	1. Background of atrophic endometrium, serous intraepithelial carcinoma; often involves endometrial polyp
	2. Papillary structures with smooth apical epithelial surfaces (Figs. 3.9.1 and 3.9.2)	2. Irregular scalloped outlines of the papillae (Figs. 3.9.5 and 3.9.6)
	3. Squamous differentiation and/or metaplastic features (mucinous, tubal, etc.) can be present (Fig. 3.9.3)	3. Squamous, mucinous differentiation is typically absent
	4. Low to intermediate cytologic grade (Fig. 3.9.4); vesicular chromatin; uniform small nucleoli; mitotic figures are infrequent	4. High cytologic grade; brisk mitotic activity (Fig. 3.9.7)
	5. Relatively clean background	5. Debris in the background can be seen (Fig. 3.9.5)
Special studies	• Weak focal expression of p53	• Strong, diffuse, or completely absent expression of p53
	• Patchy expression of p16	• Strong, diffuse expression of p16
	• Positive ER and PR	• Often diminished or lost expression of ER and PR
	• Loss of PTEN can be seen in some cases	• PTEN retained
Treatment	Hysterectomy and bilateral salpingo-oophorectomy +/- lymphadenectomy; adjuvant chemotherapy +/- radiotherapy depending on tumor stage	Hysterectomy and bilateral salpingo-oophorectomy, lymphadenectomy, peritoneal sampling; +/- adjuvant chemotherapy, +/- radiotherapy
Prognosis	Prognosis is dependent on tumor stage, grade, and patients’ age. Survival is not compromised in low-grade tumors with <50% depth of myometrial invasion	Significantly worse prognosis compared to endometrioid carcinoma; reported 5-year survival for all stages 38%; 5-year survival for stage I carcinoma is 53%-57%

Figure 3.9.1 Endometrioid carcinoma, FIGO grade 1 with papillary/villoglandular architecture. Papillary structures have smooth outlines.

Figure 3.9.2 Endometrioid carcinoma, FIGO grade 1 with papillary architecture. Papillary structures with slightly irregular contours. The luminal borders are relatively smooth.

Figure 3.9.3 Endometrioid carcinoma, FIGO grade 1 with papillary architecture and extensive surface metaplastic-like differentiation (squamous and eosinophilic).

Figure 3.9.4 Endometrioid carcinoma, FIGO grade 1 with papillary/villoglandular architecture. Same case as in Figure 3.9.1, higher magnification. Papillae are lined by columnar cells with basally placed elongated nuclei arranged perpendicular to the basement membrane. Cytologic atypia is mild.

Figure 3.9.5 Serous carcinoma. Markedly irregular luminal borders with detached cell clusters. Note debris in the background.

Figure 3.9.6 Serous carcinoma. Irregular, scalloped luminal borders; occasional detached cell clusters.

Figure 3.9.7 Serous carcinoma. Higher magnification, papillary structure with irregular border lined by atypical cells with pleomorphic nuclei and occasional prominent nucleoli. Mitoses are frequent.

3.10 ENDOMETRIOID CARCINOMA WITH SMALL NONVILLOUS PAPILLAE VS. SEROUS CARCINOMA

	Endometrioid Carcinoma with Small Nonvillous Papillae	Serous Carcinoma
Age	Wide age range; mean age 63 years (same as for typical endometrial endometrioid carcinoma)	Postmenopausal; mean age in late 60s
Location	Endometrium	Endometrium
Symptoms	Vaginal bleeding, discharge	Postmenopausal bleeding; pelvic pain, distension in advanced cases
Signs	Constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors	Often present with subclinical advanced-stage disease
Etiology	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, and KRAS	Somatic TP53 mutation is nearly ubiquitous
	Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)	PIK3CA, FBXW7, PPP2R1A mutations in a subset of cases
		May be associated with BRCA1/2 mutations
Histology	1. Background of endometrial hyperplasia and areas of typical endometrioid carcinoma can be present	1. Background of atrophic endometrium, serous intraepithelial carcinoma; often involves endometrial polyp; other patterns of serous carcinoma (papillary, glandular) can be present
	2. Often no glandular confluence	2. Often no glandular confluence
	3. Small intraglandular or surface papillae consist of buds of cells with metaplastic-like changes (Figs. 3.10.1 3.10.2, 3.10.3)	3. Prominent intraglandular papillary infoldings (Fig. 3.10.6)
	4. Low cytologic grade, mildly enlarged round nuclei with small nucleoli; low nucleocytoplasmic ratio (Fig. 3.10.4)	4. High cytologic grade, enlarged hyperchromatic or vesicular nuclei, high nucleocytoplasmic ratio (Fig. 3.10.7)
	5. Mitotic figures are infrequent	5. Brisk mitotic activity
	6. Relatively clean background, mucin can be seen	6. Debris in the background
Special studies	• Weak focal expression of p53 (Fig. 3.10.5, left)	• Strong, diffuse, or completely absent expression of p53 (Fig. 3.10.8, left)
	• Patchy expression of p16 (Fig. 3.10.5, right)	• Strong, diffuse expression of p16 (Fig. 3.10.8, right)
	• Positive ER and PR, although can be diminished in metaplastic-appearing papillae	• Often diminished or lost expression of ER and PR
	• Loss of PTEN	• PTEN retained
Treatment	Same as typical endometrioid carcinoma. See Section 3.9	See Section 3.9
Prognosis	Same as typical endometrioid carcinoma. See Section 3.9	See Section 3.9

Figure 3.10.1 Endometrioid carcinoma with small nonvillous papillae. Endometrial curettage, glandular proliferation with busy papillary architecture.

Figure 3.10.2 Endometrioid carcinoma with small nonvillous papillae. Same case as in Figure 3.10.1, higher magnification, tightly packed intraglandular epithelial infoldings.

Figure 3.10.3 Endometrioid carcinoma with small nonvillous papillae. Associated endometrial hyperplasia displays dilated glands with intraglandular papillary tufts and detached cell clusters.

Figure 3.10.4 Endometrioid carcinoma with small nonvillous papillae. Same case as in Figure 3.10.2, higher magnification, intraglandular papillary infoldings composed of cells with abundant eosinophilic cytoplasm and round bland nuclei. Cells have metaplastic-like appearance.

Figure 3.10.5 Endometrioid carcinoma with small nonvillous papillae. Weak and focal expression of p53 (left) and focally strong, but patchy expression of p16 (right).

Figure 3.10.6 Serous carcinoma. Prominent intraglandular papillary infoldings; round and elongated detached intraluminal cell clusters.

Figure 3.10.7 Serous carcinoma. Higher magnification, markedly atypical cells with vesicular pleomorphic nuclei with nucleoli. Numerous mitoses.

Figure 3.10.8 Serous carcinoma. Strong and diffuse expression of both p53 (left) and p16 (right).

3.11 ENDOMETRIOID CARCINOMA VS. SEROUS CARCINOMA WITH GLANDULAR ARCHITECTURE

	Endometrioid Carcinoma	Serous Carcinoma with Glandular Architecture
Age	Wide age range, from third decade into late postmenopause; mean age 63 years	Postmenopausal; mean age in late 60s
Location	Endometrium	Endometrium
Symptoms	Vaginal bleeding, discharge	Postmenopausal bleeding
Signs	Constitutional symptoms, obesity, diabetes mellitus, polycystic ovarian syndrome, estrogen-producing ovarian tumors	Often presents with subclinical advanced-stage disease
Etiology	Unopposed estrogenic stimulation. Somatic mutations in PTEN, PIK3CA, ARID1A, KRAS, and TP53	Somatic TP53 mutation is nearly ubiquitous
	Lynch syndrome (germline mutations in mismatch repair genes) and Cowden syndrome (germline mutation in PTEN)	PIK3CA, FBXW7, PPP2R1A mutations seen in a subset of cases
		May be associated with BRCA1/2 mutations
Histology	1. Background of endometrial hyperplasia	1. Background of atrophic endometrium, serous intraepithelial carcinoma; often involves endometrial polyp
	2. Squamous differentiation or metaplastic features (mucinous, tubal, etc.) can be present	2. Squamous, mucinous differentiation is typically absent
	3. Smooth luminal borders; small round glands present in some areas; solid growth can be seen in higher-grade tumors (Figs. 3.11.1 and 3.11.2)	3. Elongated glands with irregular scalloped luminal borders; or small slit-like spaces; solid growth is not common but can be seen (Figs. 3.11.4 3.11.5, 3.11.6, 3.11.7)
	4. Low to intermediate cytologic grade; rare cases with high-grade cytologic features; vesicular chromatin; uniform small nucleoli (Fig. 3.11.3)	4. High cytologic grade; vesicular or smudged chromatin; multiple red nucleoli can be seen (Fig. 3.11.8)
	5. Mitotic figures are infrequent	5. Brisk mitotic activity
	6. Relatively clean background	6. Debris in the background
Special studies	• Weak focal expression of p53	• Strong, diffuse, or completely absent expression of p53 (Fig. 3.11.9, left)
	• Patchy expression of p16 (Fig. 3.11.2, inset)	• Strong, diffuse expression of p16 (Fig. 3.11.9, right)
	• Positive ER and PR	• Often diminished or lost expression of ER and PR
	• Loss of PTEN can be seen in some cases	• PTEN retained
Treatment	Same as typical endometrioid carcinoma. See Section 3.9	See Section 3.9
Prognosis	Same as typical endometrioid carcinoma; dependent on grade, stage, and presence of risk factors. See Section 3.9	See Section 3.9