Uterine Pathology — Leiomyoma, Endometriosis, Carcinoma

LEIOMYOMA (UTERINE FIBROIDS)

• Clonal myometrial proliferation with chromosomal abnormalities
• Arise from single smooth muscle cell with somatic mutations
• MED12 mutations (50-70% of leiomyomas), HMGA2, FH, PTEN alterations
• Excessive growth factor responsiveness (FGF, TGF-β pathway activation)
• Loss of normal growth inhibition; estrogen and progesterone receptor overexpression

• Aberrant estrogen and progesterone signaling
• Local upregulation of estrogen receptor (ER) and progesterone receptor (PR) expression
• Increased aromatase activity → local estrogen synthesis
• Progesterone resistance in leiomyomas (altered PR isoform ratios)
• Enhanced growth factor signaling (FGF, PDGF, TGF-β) within myoid tissue

• Myometrial remodeling and smooth muscle differentiation
• Dysregulated angiogenesis and aberrant neovascularization
• Extracellular matrix (ECM) accumulation (collagen I, III, fibronectin)
• Enhanced smooth muscle differentiation with altered apoptosis
• Hypoxic microenvironment driving VEGF expression

ENDOMETRIOSIS

• Implantation and tissue remodeling theory
• Retrograde menstruation with viable endometrial cells implanting on peritoneal surfaces
• Altered cellular adhesion and reduced apoptosis of ectopic endometrial cells
• Enhanced angiogenesis and neurogenesis in ectopic lesions
• Defects in endometrial-peritoneal interaction promoting establishment

• Aberrant immune tolerance and inflammation
• Abnormal macrophage infiltration (10-20× higher in peritoneal fluid of endometriosis patients)
• Elevated TNF-α, IL-6, IL-8, RANTES promoting persistent inflammation
• Reduced natural killer (NK) cell cytotoxicity allowing ectopic implant survival
• Impaired regulatory T cell (Treg) function

• Molecular and genetic alterations
• KRAS mutations (~40% of lesions), PTEN deletions, ARID1A mutations
• Aberrant Wnt/β-catenin pathway signaling
• Progesterone resistance (altered PR-B/PR-A ratio in eutopic endometrium)
• Abnormal aromatase expression in ectopic lesions enabling local estrogen production
• Increased angiogenesis (VEGF, FGF overexpression)

ENDOMETRIAL ADENOCARCINOMA

• Estrogen-driven proliferation (Type I, endometrioid pattern)
• Unopposed estrogen stimulation from PCOS, obesity, exogenous HRT
• Chronic endometrial hyperplasia → dysplasia → carcinoma progression
• Activating PIK3CA, PTEN mutations in hyperplasia-carcinoma sequence
• Enhanced ER/PR expression in proliferative states

• Molecular carcinogenesis pathways (Type II, serous/clear cell)
• TP53 mutations (50-80% of serous carcinomas) → malignant transformation
• BRCA1/2 mutations associated with increased risk
• Molecular subgroups: MMR-deficient, POLE-mutant, TP53-mutant, CTNNB1-altered
• High-grade serous carcinomas originating from serous intraepithelial carcinoma (SIEC)

• Disrupted cell cycle regulation and apoptosis
• Loss of functional p53, increased genomic instability
• PTEN/PI3K pathway dysregulation
• Altered Wnt signaling (CTNNB1 mutations)
• High microsatellite instability (MSI-H) or mismatch repair deficiency

LEIOMYOMA

• Reproductive-age women: Peak incidence 40-50 years
• African ancestry: 2-3× higher prevalence and larger, more numerous fibroids
• Nulliparity: Protective factor is multiparity
• Estrogen and progesterone dependency: Grow during reproductive years, regress post-menopause
• Obesity: Associated with increased estrogen exposure
• Early menarche: Prolonged reproductive window exposure
• Genetic predisposition: Higher familial concordance (MED12, HMGA2, PTEN mutations)

ENDOMETRIOSIS

• Retrograde menstruation: Heavy/prolonged menses increase risk
• Early menarche and long menstrual cycles: Extended menstrual exposure
• Nulliparity/reduced parity: Protective effect from pregnancy (menstrual suppression)
• Delayed childbearing: Older age at first pregnancy
• Müllerian anomalies: Obstructive malformations facilitating reflux
• Family history: 10% concordance in first-degree relatives
• Environmental toxins: PCB/dioxin exposure (animal models)
• Immune dysfunction: Reduced NK cell activity, macrophage infiltration

ENDOMETRIAL ADENOCARCINOMA (Type I, Endometrioid - 80%)

• Obesity: 2-4× increased risk; increased aromatase, insulinemia, chronic inflammation
• Diabetes mellitus and metabolic syndrome: Hyperinsulinemia → endometrial proliferation
• Unopposed estrogen exposure:
• Exogenous HRT (estrogen without progestin)
• PCOS with anovulation and persistent estrogen
• Nulliparity (no progestin-protective months)
• Hypertension: Associated with metabolic syndrome
• Tamoxifen use: Partial agonist effects on endometrium
• Age: Peak incidence 60-70 years
• Lynch syndrome (mismatch repair mutations): 40-60% lifetime risk of endometrial cancer

ENDOMETRIAL ADENOCARCINOMA (Type II, Serous/Clear Cell - 20%)

• Age: Elderly women (70+ years typically)
• Atrophic endometrium: Not estrogen-dependent
• Prior pelvic radiation: High-grade malignancies
• BRCA1/2 mutations: Increased serous adenocarcinoma risk
• TP53 germline mutations: Li-Fraumeni syndrome

LEIOMYOMA

• Abnormal uterine bleeding (AUB)
• Menorrhagia (heavy menstrual bleeding) most common symptom (30-60%)
• Submucosal fibroids distort endometrial cavity → increased surface area and abnormal vasculature
• Mechanical stretching of myometrium → impaired contractility
• Dysmenorrhea from uterine contractions attempting to expel fibroids
• Metrorrhagia (irregular bleeding) with cavity-distorting lesions

• Pelvic pain and pressure
• Dysmenorrhea and dyspareunia
• Chronic pelvic pain from mass effect and inflammation
• Feeling of pelvic fullness/heaviness; abdominal distension
• Pain severity correlates with fibroid size and subtype (submucosal/intramural > subserosal)

• Reproductive dysfunction
• Infertility: 2-3% of cases; cavity distortion impairs embryo implantation
• Recurrent pregnancy loss: Submucosal fibroids disrupt decidualization
• Obstructed labor with large intramural/intracavitary lesions

• Mass effect symptoms
• Urinary frequency/urgency (anterior fibroids compress bladder)
• Constipation/rectal symptoms (posterior/lateral fibroids)
• Lower extremity edema (venous/lymphatic compression)

• Physical examination findings
• Irregularly enlarged, firm, nodular uterus on bimanual exam
• Abdominal mass palpable with large subserosal fibroids
• Absence of fever or acute peritoneal signs (unless degeneration occurs)

• Laboratory/imaging correlates
• Normal serum β-hCG, normal CA-125 (though may be mildly elevated)
• Ultrasound: Hypoechoic or heterogeneous intramural/intracavitary masses with calipers
• MRI: T2 hypointense (fibrotic) masses; superior for mapping multiple fibroids and myometrial junctional zone assessment
• Elevated hemoglobin A1c (chronic menorrhagia → iron-deficiency anemia)

ENDOMETRIOSIS

• Dysmenorrhea (50-70% of patients)
• Severe, progressive pain during menses
• Mediated by prostaglandin E2 and leukotriene production by ectopic lesions
• Onset typically in 2nd-3rd decade
• Classic description: "Worst pain with heaviest bleeding"

• Chronic pelvic pain
• Cyclic or acyclic lower abdominal/pelvic pain
• Deep dyspareunia (pain with deep penetration); lesions on uterosacral ligaments/pouch of Douglas
• Dysphoria and reduced quality of life in severe cases

• Infertility (30-50% association)
• Reduced fertility rates even with minimal disease
• Mechanism: abnormal oocyte quality, impaired implantation, anti-sperm antibodies
• Peritoneal inflammation and adhesion formation obstruct oviducts

• Bowel/urinary symptoms
• Dysmenorrheal diarrhea or constipation (anterior peritoneal/bowel involvement)
• Hematochezia or gross hematuria if rectosigmoid or bladder involved
• Urinary frequency, dysuria with bladder endometriosis

• Physical examination findings
• Nodular, tender uterosacral ligaments or pouch of Douglas on rectovaginal exam
• Fixed, retroverted uterus (adhesions from chronic inflammation)
• Adnexal masses (endometriomas, ovarian involvement)
• Absence of systemic findings; normal vitals (unless ruptured endometrioma)

• Laboratory/imaging correlates
• CA-125 mildly elevated (>30 U/mL) in moderate-severe disease; not diagnostic
• Transvaginal ultrasound: Hypoechoic ovarian cysts with "ground-glass" echogenicity (endometriomas)
• MRI: Multilocular ovarian cysts with hyperintense T1 signal (hemorrhage); fat-suppressed images confirm blood)
• Diagnostic laparoscopy with biopsy: Gold standard; reveals petechial lesions, purple/reddish implants, adhesions

ENDOMETRIAL ADENOCARCINOMA

• Postmenopausal bleeding (90% of cases)
• Vaginal bleeding/bloody spotting after 12+ months of amenorrhea
• Even small volume warrants investigation
• Most common presenting complaint; excellent prognosis if early stage at diagnosis

• Abnormal uterine bleeding in reproductive years
• Heavy, prolonged menses or intermenstrual bleeding
• Often attributed to benign causes, delaying diagnosis

• Vaginal discharge
• Serosanguinous, blood-stained, or watery discharge
• May precede visible bleeding in some cases

• Pelvic pain and pressure (advanced disease)
• Dysmenorrhea or chronic pelvic pain with advanced local invasion
• Abdominal distension, bowel symptoms with peritoneal involvement

• Systemic symptoms (advanced/metastatic)
• Unintentional weight loss, fatigue, night sweats
• Signs of metastatic disease (lymph node enlargement, hepatomegaly)

• Physical examination findings
• Often unremarkable in early-stage disease
• Enlarged, boggy uterus on bimanual exam (endometrial thickening)
• Vaginal/cervical masses visible on speculum exam (gross tumor extension)
• Lymphadenopathy, hepatosplenomegaly with advanced disease
• Ascites (peritoneal carcinomatosis)

• Laboratory/imaging correlates
• Elevated CA-125 (especially Type II serous cancers); not diagnostic
• Transvaginal ultrasound: Endometrial thickness >4 mm postmenopausal warrants evaluation
• Endometrial biopsy: Gold standard diagnostic test (>90% sensitivity)
• MRI: T2 hyperintense endometrial thickening; T1 signal invasion into myometrium (staging)
• CBC: Normocytic or iron-deficiency anemia from chronic bleeding
• Comprehensive metabolic panel, LFTs for metastatic workup

LEIOMYOMA

• Histological findings
• Smooth muscle bundles arranged in whorled, fascicular pattern (pathognomonic appearance)
• Benign spindle cells with blunt-ended nuclei, uniform chromatin, minimal mitotic activity (<5 mitoses/10 hpf)
• Interlacing fascicles of smooth muscle separated by fibrous tissue
• Surrounding compressed myometrium ("pseudocapsule")
• Variants: mitotically active leiomyoma (≥10 mitoses/10 hpf but benign behavior), cellular leiomyoma (hypercellular but benign), atypical leiomyoma (atypia but low mitotic activity—controversial malignant potential)
• Immunohistochemistry: Positive for smooth muscle markers (desmin, α-smooth muscle actin); negative for epithelial markers

• Gross pathology appearance
• Firm, whorled, tan-white masses with characteristic "fish-flesh" or "cut-to-white" appearance
• Sharply demarcated from surrounding myometrium
• Size range: <1 cm to >20 cm (documented fibroids >100 lbs rarely)
• Intramural fibroids distort myometrial contour; submucosal indent endometrial cavity; subserosal pedunculated on serosal surface
• Areas of degeneration: hyalinization (yellowing, cystic spaces), fatty replacement (lipid-rich), red degeneration (hemorrhagic infarction during pregnancy)

• Laboratory values
• No specific serum markers (CA-125, β-hCG normal)
• CBC may show iron-deficiency anemia if chronic menorrhagia
• Ferritin/serum iron assessment for heavy menstrual bleeding

• Diagnostic imaging
• Transvaginal ultrasound: First-line modality
• Hypoechoic or heterogeneous myometrial masses
• Submucosal fibroids: protrusion into endometrial cavity (distort echo pattern)
• Acoustic shadowing with posterior attenuation (fibrosis produces acoustic impedance)
• Transabdominal ultrasound: Better for large, subserosal fibroids
• MRI: Superior for detailed anatomic mapping
• T2 hypointense signal (fibrous/smooth muscle tissue with low water content)
• T1 iso- to hypointense
• Gadolinium enhancement variable (depends on cellular vs. fibrotic

Leiomyoma — stepwise per ACOG

• Expectant management: asymptomatic fibroids need no therapy; they are estrogen/progesterone-dependent and regress after menopause.
• Acute heavy bleeding: stabilize with IV fluids/transfusion, then high-dose estrogen or an antifibrinolytic (tranexamic acid); iron repletion for chronic menorrhagia.
• First-line medical: NSAIDs and hormonal suppression — levonorgestrel-releasing IUD (best bleeding control when the cavity is undistorted), combined hormonal contraceptives, or oral progestins. These control bleeding but do not appreciably shrink fibroids.
• Second-line: GnRH agonists (leuprolide) induce a hypoestrogenic state and shrink fibroids — used short-term preoperatively to correct anemia and reduce volume; GnRH antagonist combinations (relugolix or elagolix with estradiol/norethindrone add-back) are FDA-approved for fibroid-associated heavy bleeding. Add-back therapy limits bone mineral density loss.
• Procedural/definitive: hysteroscopic myomectomy for submucosal lesions; abdominal/laparoscopic myomectomy when fertility is desired; uterine artery embolization for women declining surgery; hysterectomy is definitive.
• Contraindicated/cautioned: unopposed estrogen; laparoscopic power morcellation in peri-/postmenopausal women (FDA safety warning — risk of upstaging occult leiomyosarcoma); prolonged GnRH agonist use without add-back.

Endometriosis — per ACOG/ASRM

• First-line: NSAIDs plus continuous combined hormonal contraceptives; empiric therapy is acceptable without laparoscopic confirmation.
• Second-line: progestins (norethindrone acetate, depot medroxyprogesterone, levonorgestrel IUD), then GnRH agonist/antagonist with add-back; aromatase inhibitors for refractory disease. Danazol is largely abandoned for androgenic effects.
• Surgical: laparoscopic excision/ablation of implants and adhesiolysis; hysterectomy with bilateral salpingo-oophorectomy is definitive.
• Key caveat: hormonal suppression does not treat infertility — ovulation is suppressed. Infertile patients need surgery or IVF.

Endometrial carcinoma — per NCCN/SGO

• Atypical hyperplasia/EIN: hysterectomy; progestin therapy (levonorgestrel IUD or megestrol) only if fertility-sparing is required, with serial sampling.
• Definitive: surgical staging — total hysterectomy, bilateral salpingo-oophorectomy, peritoneal assessment, with sentinel lymph node mapping.
• Adjuvant: vaginal brachytherapy or external-beam radiation by risk group; carboplatin–paclitaxel for advanced/high-risk or serous histology; immune checkpoint inhibitors (pembrolizumab, dostarlimab) for mismatch-repair-deficient advanced disease.

Leiomyoma — disease complications

• Iron-deficiency anemia: chronic menorrhagia from increased endometrial surface area; microcytosis with low ferritin. Severe symptomatic hemorrhage is an emergency.
• Torsion of a pedunculated subserosal fibroid: vascular pedicle twists → infarction; sudden severe pain with peritoneal signs — surgical emergency.
• Red (carneous) degeneration: rapid pregnancy-associated growth outstrips blood supply → hemorrhagic infarction; acute localized pain, low-grade fever, leukocytosis. Managed conservatively with analgesia, not surgery.
• Obstetric complications: malpresentation, obstructed labor, postpartum hemorrhage from impaired myometrial contraction.
• Hydronephrosis: bulky lateral fibroids compress the ureters; rising creatinine with pelvic mass.
• Leiomyosarcoma: not a degeneration product of a fibroid — suspicion is raised by rapid growth or any growth after menopause, when estrogen withdrawal should cause regression.

Leiomyoma — treatment complications

• GnRH agonist hypoestrogenism: vasomotor symptoms and bone mineral density loss; mitigated by add-back therapy.
• Post-embolization syndrome after uterine artery embolization: pain, fever, nausea from infarcted tissue; must be distinguished from infection/pyomyoma. Rarely, ovarian failure or fibroid expulsion.
• Asherman syndrome: intrauterine adhesions after aggressive hysteroscopic resection; secondary amenorrhea and infertility.

Endometriosis

• Adhesive disease: cyclic bleeding and inflammation → dense adhesions, frozen pelvis, tubal occlusion and infertility.
• Ruptured endometrioma: acute abdomen with chemical peritonitis — emergency.
• Ureteral or bowel obstruction: deep infiltrating disease; silent hydronephrosis or obstructive symptoms.
• Malignant transformation: rare progression of an endometrioma to clear cell or endometrioid ovarian carcinoma (ARID1A-associated).
• Surgical/medical: premature surgical menopause after bilateral oophorectomy; bone loss with prolonged GnRH suppression.

Endometrial carcinoma

• Myometrial invasion and lymphatic spread: depth of invasion and grade drive nodal risk; pelvic/para-aortic nodes are the first station.
• Serous histology disseminates transtubally to the peritoneum even with minimal invasion.
• Treatment-related: lymphedema and lymphocyst after lymphadenectomy, radiation cystitis/proctitis and vaginal stenosis, chemotherapy neuropathy, and perioperative venous thromboembolism (a leading cause of postoperative death in gynecologic oncology).

• Whorled, firm, tan-white mass with interlacing smooth-muscle fascicles = leiomyoma; MED12 is the classic recurrent mutation. Desmin and smooth muscle actin positive.
• The single most tested association: postmenopausal bleeding is endometrial carcinoma until proven otherwise. Best next step = endometrial biopsy (transvaginal ultrasound showing an endometrial stripe >4 mm mandates sampling; a negative or insufficient biopsy with persistent bleeding requires hysteroscopy with dilation and curettage).
• Growth after menopause is the red flag. Fibroids are hormone-dependent and shrink with estrogen withdrawal; an enlarging uterine mass in a postmenopausal woman suggests leiomyosarcoma — which arises de novo, not from malignant transformation of a leiomyoma. This is the most common distractor in the question bank.
• Red (carneous) degeneration in pregnancy: acute pain, low-grade fever, and leukocytosis in a gravid patient with known fibroids — treat with analgesia and observation, not laparotomy.
• ***Powder-burn* or gunpowder peritoneal lesions and a chocolate cyst (endometrioma) with ground-glass echogenicity = endometriosis. Exam findings: nodular, tender uterosacral ligaments** and a fixed, retroverted uterus. Laparoscopy with biopsy is the gold standard, but ACOG endorses empiric hormonal therapy first.
• Hormonal suppression does not treat endometriosis-associated infertility — it prevents conception. Surgical ablation/excision or IVF is required. A classic trap answer is "start a GnRH agonist" in a woman trying to conceive.
• Unopposed estrogen is the unifying risk factor for type I endometrioid carcinoma: obesity (peripheral aromatization), PCOS with chronic anovulation, nulliparity, estrogen-only hormone therapy, and tamoxifen (endometrial agonist, breast antagonist). Lynch syndrome carries a very high lifetime endometrial cancer risk — endometrial cancer is often the sentinel malignancy, preceding colorectal cancer.
• Serous carcinoma is TP53-mutant, arises in atrophic endometrium of older women, and is not estrogen-driven — high grade, psammoma bodies, early peritoneal spread despite minimal myometrial invasion.
• Distractor to avoid: adenomyosis gives a symmetrically enlarged, boggy, tender uterus with dysmenorrhea; leiomyomas give an irregular, firm, nontender, nodular uterus.