Differential Diagnosis: Uterine/Endometrial Pathology

Quick Orientation Map

1. Endometriosis

Clinical Features

• Affects ~10% of reproductive-age females; peak in 3rd-4th decade
• Classic triad: dysmenorrhea + dyspareunia + infertility (30-40% present with infertility)
• Pelvic pain worse cyclically (because ectopic tissue bleeds with the menstrual cycle)
• Three forms: superficial peritoneal, ovarian ("chocolate cysts"), and deep infiltrating endometriosis
• Menstrual irregularities are common
• On exam: fixed retroverted uterus, uterosacral nodularity, adnexal masses (endometriomas)
• Sites (descending frequency): ovaries > uterine ligaments > rectovaginal septum > cul-de-sac > pelvic peritoneum > bowel serosa

Histological Features

• Diagnostic triad: ectopic endometrial glands + endometrial stroma + hemosiderin-laden macrophages (evidence of cyclical bleeding)
• In some cases, only stroma is present (without glands) - still diagnostic
• "Chocolate cysts" on ovary = endometriomas lined by endometrial epithelium filled with old hemorrhagic material
• Peritoneal deposits show hemosiderin deposits and fibrosis
• Superficial/ovarian forms can be precursors to endometrioid and clear cell carcinoma (ARID1A mutations overlap)

2. Adenomyosis

Clinical Features

• Defined as endometrial tissue within the myometrium (unlike endometriosis, it stays connected to the endometrium - "downgrowth")
• Occurs in up to 20% of uteri
• Symptoms: menometrorrhagia + colicky dysmenorrhea + dyspareunia - particularly worse in the premenstrual period
• Uterus is diffusely, symmetrically enlarged (boggy uterus on exam) - contrast with the asymmetric nodular enlargement of fibroids
• Can co-exist with endometriosis
• No malignant potential on its own

Histological Features

• Irregular nests/islands of endometrial stroma with or without glands embedded within myometrial smooth muscle fascicles
• These islands remain in continuity with the basal endometrium (hallmark distinction from endometriosis)
• Surrounding myometrium shows hypertrophy/hyperplasia (reactive)
• No hemosiderin deposits typically (unlike ectopic endometriosis)

Key Distinction from Endometriosis

• Adenomyosis = within myometrium, continuous with endometrium, no distant sites
• Endometriosis = outside uterus, not in continuity with endometrium, can spread to ovaries/peritoneum/distant sites

3. Endometrial Hyperplasia

Clinical Features

• Results from unopposed estrogen stimulation (endogenous or exogenous)
• Risk factors: anovulatory cycles, PCOS, estrogen-secreting ovarian tumors (granulosa cell tumor), obesity, estrogen-only HRT, tamoxifen use
• Presentation: irregular/heavy uterine bleeding in perimenopausal women; occasionally postmenopausal bleeding
• Uterine size usually normal
• WHO Classification determines prognosis and management:
  • Hyperplasia without atypia: ~1-3% risk of progression to carcinoma
  • Atypical hyperplasia (EIN): up to 40% already have concurrent carcinoma on hysterectomy - managed by hysterectomy or progestin therapy if fertility desired

Histological Features

• Hyperplasia without atypia: increased gland-to-stroma ratio; glands vary in size and shape; may be dilated (cystic); back-to-back glands focally but stroma retained; no nuclear atypia
• Atypical hyperplasia (EIN): complex, back-to-back glands with branching; nuclear atypia - rounded nuclei, vesicular (open) chromatin, conspicuous nucleoli; cells lose perpendicular orientation to basement membrane
• Molecular: PTEN mutations in >20% of hyperplasias (both with and without atypia)
• Considerable morphologic/genetic overlap with well-differentiated endometrioid carcinoma - accurate distinction may require hysterectomy

4. Endometrial Carcinoma

Clinical Features

• Postmenopausal women, typically younger (55-65 years)
• Associated with estrogen excess: obesity, nulliparity, late menopause, diabetes, hypertension, PCOS
• Classic presentation: postmenopausal vaginal bleeding (key red flag symptom)
• Arises on a background of endometrial hyperplasia
• Generally well-differentiated, better prognosis; 5-year survival ~85% if stage I

• Older, postmenopausal women, often African descent (2x higher mortality)
• Not estrogen-related; arises from endometrial atrophy
• More aggressive; propensity for extrauterine spread (lymphatic, transtubal)
• 5-year survival only 18-27%, even uterus-confined tumors have 80% recurrence rate

Histological Features

• Well-differentiated (Grade 1): glandular pattern mimicking proliferative endometrium, invades myometrium
• Grade 3: predominantly solid growth, loss of gland formation
• Desmoplastic stromal response at invasion front
• Key mutations: PTEN (30-80%), PIK3CA (~40%), KRAS (~25%), ARID1A (~33%), MLH1 silencing (~20%)
• Lynch syndrome association (mismatch repair deficiency)

• Papillary growth pattern with fronds lined by highly atypical cells
• High nuclear-to-cytoplasmic ratio, hyperchromasia, atypical mitoses
• TP53 mutation is the hallmark (present in precursor "serous EIC" and invasive carcinoma)
• Strong, diffuse p53 immunostaining (IHC marker)
• Precursor: Serous endometrial intraepithelial carcinoma (EIC) - noninvasive, lining gland surfaces

Fig A: Endometrioid Grade 1 - glandular pattern invading myometrium. Fig B: Endometrioid Grade 3 - predominantly solid. Fig C: Serous carcinoma - papillary pattern, marked atypia. Fig D: IHC p53 accumulation (brown) - hallmark of TP53 mutation in serous type.

Fig A: Serous EIC (arrow) - malignant cells lining gland surfaces without stromal invasion. Fig B: p53 IHC on EIC. Fig C: Invasive serous carcinoma - papillary pattern with severe atypia. Fig D: Strong diffuse p53 positivity.

5. Endometrial Stromal Tumor (ESS)

Clinical Features

• Primarily perimenopausal women (age 45-50); ~1/3 postmenopausal
• Most frequent symptom: abnormal uterine bleeding
• Abdominal pain and pressure from enlarging uterus (less common)
• Pelvic exam: uterine enlargement (regular or irregular); rubbery parametrial induration
• Pre-operative diagnosis is usually mistaken for leiomyoma - diagnosis often made on endometrial biopsy or at surgery
• No apparent relationship to parity or associated conditions; rare in African American women

Histological Features

• Cells resemble normal proliferative-phase endometrial stroma - small, uniform, ovoid cells with scant cytoplasm
• Characteristic "tongue-like" myometrial invasion with permeation of lymphovascular channels (worm-like plugs in vessels)
• Low-grade: minimal atypia, low mitotic rate, ER/PR positive
• High-grade: marked atypia, high mitotic rate, necrosis
• IHC: CD10 positive (stromal marker); ER/PR positive in low-grade; WT1 and SMARCA4 loss in some high-grade

6. Leiomyoma (Uterine Fibroid)

Clinical Features

• Most common tumor in women; more common in African-Caribbean women
• Estrogen and progesterone dependent - shrink after menopause
• Multiple in most cases (contrast with leiomyosarcoma which is almost always solitary)
• Location determines symptoms:
  • Submucosal: heavy menorrhagia, infertility, recurrent pregnancy loss; may prolapse through cervical os
  • Intramural: heavy periods, endometrial distortion, infertility
  • Subserosal: pressure symptoms (urinary frequency/retention, constipation, backache); pedunculated forms mimic ovarian tumor
• Enlarged irregular, nodular uterus on bimanual exam (vs. diffusely boggy in adenomyosis)
• Malignant transformation (<1%) to leiomyosarcoma - extremely rare
• Complications: red degeneration (in pregnancy), torsion of pedunculated fibroid

Histological Features

• Sharply circumscribed, well-defined borders (unlike leiomyosarcoma which is infiltrative)
• Bundles of smooth muscle cells arranged in whorled/intersecting fascicles
• Cells morphologically identical to normal myometrium - bland spindle cells, abundant eosinophilic cytoplasm, cigar-shaped nuclei, no atypia
• No significant mitotic activity (contrast with leiomyosarcoma: >10 MF/10 HPF)
• May show secondary changes: hyaline degeneration (most common), cystic, red/carneous (pregnancy), calcific, fatty degeneration
• Gross: gray-white, firm, whorled cut surface
• Molecular: MED12 mutations in ~70%; chromosomal rearrangements of 6 and 12

Critical Histological Distinctions for Case Questions

Clinical Clue Summary for MCQs

• Postmenopausal bleeding → always think endometrial carcinoma first; work up with endometrial biopsy
• Severe dysmenorrhea + infertility + normal uterus → endometriosis (look for adnexal mass/chocolate cyst)
• Diffusely enlarged boggy uterus + dysmenorrhea + heavy menses → adenomyosis
• Irregular nodular uterus + heavy menses, asymptomatic → leiomyoma
• Irregular heavy bleeding + risk factors (obesity, PCOS, anovulation) → endometrial hyperplasia
• Uterine enlargement mistaken for fibroids on exam, abnormal bleeding in 45-50 yo → think endometrial stromal sarcoma (CD10+, JAZF1-SUZ12 fusion)
• Tamoxifen use → risk for endometrial hyperplasia AND endometrial polyps
• Lynch syndrome (MMR defect) → increased risk of endometrioid carcinoma (MLH1 silencing)
• Obese + hypertensive + diabetic + postmenopausal bleeding → classic Type I (endometrioid) carcinoma triad