Uterine Pathology

Why it matters

• Abnormal uterine bleeding is one of the most common reasons women present to outpatient gynecology, and in the postmenopausal patient it is cancer until proven otherwise.
• Endometrial carcinoma is the most common gynecologic malignancy in the United States and its incidence is rising in parallel with obesity; most cases are diagnosed at an early stage because bleeding is an early symptom, which explains the relatively favorable overall prognosis.
• Leiomyomas are the most common indication for hysterectomy in the United States.

Epidemiology worth recalling

• Leiomyoma: clinically or sonographically detectable in the majority of women by age 50; substantially more prevalent, earlier in onset, and more symptomatic in Black women.
• Endometrial cancer: peak incidence in the postmenopausal years (typically sixth to seventh decade); onset before age 50 should raise suspicion for Lynch syndrome.
• Endometriosis: roughly one in ten reproductive-age women; a leading identifiable cause of chronic pelvic pain and subfertility, with a characteristic multi-year delay from symptom onset to diagnosis.
• Endometritis: overwhelmingly postpartum, and far more common after cesarean than vaginal delivery.

Estrogen-excess mechanism (endometrial hyperplasia and Type I endometrioid carcinoma)

• Modifiable: obesity (peripheral aromatization of androstenedione to estrone in adipose tissue — the single most important modifiable driver), unopposed estrogen therapy without a progestin in a woman with a uterus, tamoxifen (partial agonist at the endometrium while antagonist at breast), diabetes and metabolic syndrome.
• Non-modifiable: early menarche, late menopause, nulliparity, chronic anovulation (PCOS), estrogen-secreting tumors (granulosa cell tumor), advancing age.
• Protective: combined oral contraceptives, progestin-containing IUD, multiparity, smoking (a true but non-recommendable association examiners enjoy).

Estrogen-independent mechanism (Type II serous/clear cell carcinoma)

• Serous carcinoma carries TP53 mutation and arises in atrophic endometrium in thin, older women, with early lymphovascular and peritoneal spread.
• Key contrast: p53-abnormal serous tumors are characteristically mismatch-repair proficient, whereas mismatch-repair–deficient/MSI-high tumors are typically endometrioid. MMR deficiency does not equal Type II disease — this is a frequently tested inversion.

Germline/hereditary syndromes

• Lynch syndrome (MLH1, MSH2, MSH6, PMS2): endometrial cancer is often the sentinel malignancy, preceding colorectal cancer. Tumors are usually endometrioid histology and frequently early-onset (<50), which is why NCCN supports universal tumor MMR testing.
• Cowden syndrome (PTEN): endometrial cancer plus breast and thyroid neoplasia.

Leiomyoma

• Non-modifiable: Black race, family history, early menarche, nulliparity; somatic MED12 mutations and HMGA2 rearrangements underlie clonal growth.
• Hormonal: estrogen and progesterone both promote growth — hence growth during pregnancy and regression after menopause.

Endometriosis

• Retrograde menstruation (Sampson) plus impaired immune clearance; also coelomic metaplasia and lymphatic/vascular dissemination theories.
• Risk rises with early menarche, short cycles, heavy prolonged flow, nulliparity, and outflow obstruction (imperforate hymen, transverse vaginal septum) — the stem's tip-off in an adolescent.

Infectious/iatrogenic

• Endometritis: cesarean delivery, prolonged rupture of membranes, prolonged labor, retained products, chorioamnionitis; polymicrobial ascending flora.
• Asherman syndrome: instrumentation of the gravid uterus (repeated D&C), severe endometritis, genital tuberculosis.

Endometrial carcinoma / hyperplasia

• Postmenopausal bleeding — the classic stem: an obese, hypertensive, diabetic, nulliparous woman in her 60s with spotting. Mechanism: fragile hyperplastic or invasive endometrium.
• Premenopausally, intermenstrual or heavy irregular bleeding in a woman with PCOS or on tamoxifen.
• Advanced disease: pelvic pain, enlarged fixed uterus, weight loss; pyometra in the elderly with cervical stenosis.

Leiomyoma

• Heavy menstrual bleeding with clots and iron-deficiency anemia (submucosal), producing fatigue, pica, and koilonychia.
• Bulk symptoms: pelvic pressure, urinary frequency (bladder compression), constipation, hydronephrosis if the ureter is compressed.
• Exam: enlarged, firm, irregular, mobile, nontender uterus. Tenderness suggests degeneration or torsion.
• Pregnancy: acute focal pain with low-grade fever and mild leukocytosis = red (carneous) degeneration.

Endometriosis

• The triad of cyclic dysmenorrhea beginning before flow, deep dyspareunia, and dyschezia, plus infertility.
• Exam: uterosacral nodularity, a fixed retroverted uterus, and adnexal tenderness or a mass (endometrioma).
• Cyclic hematuria, hemoptysis, or a bleeding umbilical nodule if implants are extrapelvic.

Leiomyoma (per ACOG)

• First-line medical: levonorgestrel-releasing IUD for bleeding with a non-distorted cavity; NSAIDs and tranexamic acid as cycle-limited options; combined hormonal contraceptives.
• Escalation: GnRH agonist (leuprolide) or oral GnRH antagonist with hormonal add-back (elagolix, relugolix combination) to shrink fibroids and correct anemia preoperatively — limited duration because of hypoestrogenic bone loss.
• Procedural: uterine artery embolization, radiofrequency ablation, or hysteroscopic myomectomy for submucosal lesions; abdominal/laparoscopic myomectomy preserves fertility; hysterectomy is definitive.
• Contraindicated/cautioned: the FDA warns against laparoscopic power morcellation without containment because of the risk of disseminating an occult leiomyosarcoma; UAE is generally avoided in women actively seeking pregnancy.

Of the disease

• Iron-deficiency anemia from chronic menorrhagia — the most common complication of fibroids and adenomyosis; high-output failure in extreme cases.
• Hydronephrosis and renal impairment from ureteral compression by a large fibroid or by deep infiltrating endometriosis — silent until creatinine rises. Obtain imaging in any woman with a large mass and abnormal renal function.
• Acute pelvic pain emergencies: torsion of a pedunculated subserosal fibroid, red (carneous) degeneration in pregnancy, and rupture of an endometrioma with chemical peritonitis — all surgical or near-surgical considerations.
• Infertility and pregnancy complications: submucosal fibroids impair implantation; fibroids and adenomyosis increase malpresentation, preterm birth, cesarean delivery, and postpartum hemorrhage from atony (the fibroid uterus contracts poorly) — an obstetric emergency.
• Endometriosis: adhesive bowel obstruction, ureteral obstruction, and a modestly increased risk of clear cell and endometrioid ovarian carcinoma.
• Endometritis progressing to pelvic abscess, septic pelvic thrombophlebitis (persistent fever despite appropriate antibiotics), or sepsis — emergencies requiring imaging and escalation.
• Carcinoma: myometrial and lymphovascular invasion, nodal and peritoneal spread; pyometra signals obstructed infected cavity.
• Asherman syndrome: amenorrhea, recurrent pregnancy loss, and abnormal placentation (accreta spectrum).

Of the treatment

• GnRH agonists/antagonists: hypoestrogenic vasomotor symptoms and bone mineral density loss — the reason for add-back therapy and limited duration.
• Tranexamic acid: theoretical thrombotic risk; avoid with active thromboembolic disease.
• Uterine artery embolization: post-embolization syndrome (pain, low-grade fever, malaise), fibroid expulsion, and premature ovarian insufficiency.
• Myomectomy: adhesions, recurrence, and uterine rupture in a subsequent labor after transmural entry — an obstetric emergency.
• Hysterectomy: ureteral and bladder injury, vaginal cuff dehiscence, and surgical menopause if oophorectomy is performed.
• Unopposed estrogen given to a woman with a uterus: iatrogenic hyperplasia and carcinoma.

• Postmenopausal bleeding = endometrial cancer until excluded. The single best next step is transvaginal ultrasound with endometrial biopsy; ACOG treats a stripe of 4 mm or less as reassuring, but persistent bleeding still requires tissue. Never accept "atrophy" without sampling if bleeding recurs.
• Obesity is the dominant risk factor because adipose aromatase converts androstenedione to estrone. The exam stem's obese, diabetic, hypertensive, nulliparous woman is signaling Type I endometrioid carcinoma.
• Endometrial cancer under 50, or a family history of colorectal/ovarian cancer, means Lynch syndrome — NCCN supports universal mismatch-repair testing on the tumor, and risk-reducing hysterectomy with BSO after childbearing in known carriers.
• HPV 16/18 causes cervical cancer, not endometrial cancer. This is the classic distractor. Cervical screening follows USPSTF/ASCCP intervals and is entirely separate from the workup of postmenopausal bleeding.
• Fibroid versus adenomyosis on exam: fibroid = firm, irregular, mobile, nontender; adenomyosis = boggy, symmetrically enlarged, tender.
• Rapid uterine growth after menopause — when estrogen withdrawal should be shrinking fibroids — is the buzz for leiomyosarcoma, and it is why the FDA warns against uncontained power morcellation.
• Endometriosis buzzwords: uterosacral nodularity, fixed retroverted uterus, chocolate cyst, powder-burn lesions. Laparoscopy is the gold standard, but ACOG endorses empiric NSAIDs plus a combined hormonal contraceptive before surgery. CA-125 is not a diagnostic test for endometriosis.
• Amenorrhea after a D&C with cyclic pain and no withdrawal bleed after estrogen–progestin = Asherman syndrome; the lesion is the endometrium, not the hypothalamic–pituitary–ovarian axis.

• Endometrial cancer is the most common gynecologic malignancy; majority are Type I (endometrioid) related to estrogen excess
• Leiomyomas (fibroids) are benign smooth muscle tumors; most common pelvic tumor in women
• Asherman syndrome = intrauterine adhesions causing amenorrhea/infertility (post-curettage, infection)
• Endometritis presents with fever, vaginal discharge, and uterine tenderness in the postpartum period
• Leiomyosarcoma is rare but aggressive; diagnosed by rapid growth or mitotic activity >10/10 hpf

• Endometrial cancer: Postmenopausal vaginal bleeding (80% present early) OR abnormal uterine bleeding in obese/hypertensive women
• Fibroids: Heavy menstrual bleeding, pelvic pressure/mass effect, infertility; may be asymptomatic
• Asherman syndrome: Amenorrhea or hypomenorrhea after D&C/miscarriage; secondary infertility
• Endometritis: Fever + lower abdominal pain + vaginal discharge within 24-48 hours postpartum

• Confusing benign fibroids with leiomyosarcoma: Clinical suspicion based on rapid growth, imaging findings (heterogeneity, necrosis), and histologic features (mitotic activity) is key—routine fibroids don't require removal unless symptomatic
• Missing Lynch syndrome in "young" endometrial cancer: Suspect in patients <50 years or with strong family history of colon/ovarian cancer; requires genetic testing and surveillance
• Attributing all postmenopausal bleeding to cancer: While 10-15% of postmenopausal bleeding is cancer, atrophy and polyps are more common; always biopsy if persistent

• Endometrial cancer: Total abdominal/laparoscopic hysterectomy + BSO with surgical staging; adjuvant radiation/chemo for advanced disease
• Fibroids (symptomatic): NSAIDs for bleeding; GnRH agonists (leuprolide) for preoperative shrinkage; myomectomy (preserve uterus) or hysterectomy (definitive)
• Endometritis: Broad-spectrum IV antibiotics (e.g., cephalosporin + gentamicin ± clindamycin); evaluate for RPOC
• Asherman syndrome: Hysteroscopic lysis of adhesions + estrogen therapy to prevent recurrence
• Hyperplasia: Simple hyperplasia → progestin therapy; complex atypical → hysterectomy or close surveillance with progestin