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Summary Table

Category	Detail
Risk Factors	Prolonged unopposed estrogen exposure: obesity, nulliparity, early menarche, late menopause, anovulation (PCOS), tamoxifen use, estrogen-only HRT, Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome)
Etiology	Type I: estrogen-dependent endometrioid adenocarcinoma arising from endometrial hyperplasia. Type II: estrogen-independent (serous, clear cell) arising from atrophic endometrium
Patient Presentation	Postmenopausal vaginal bleeding (most classic). In premenopausal women: abnormal uterine bleeding, menorrhagia, or intermenstrual bleeding
Classic Physical Exam	Often unremarkable in early disease. May have enlarged, boggy uterus. Advanced disease: pelvic mass, ascites
Key Diagnostic Results	Endometrial biopsy showing adenocarcinoma. Endometrial thickness >4 mm on transvaginal ultrasound in a postmenopausal woman prompts biopsy
Management	Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) + surgical staging. Adjuvant radiation or chemotherapy based on stage and histologic grade
Keywords	"Postmenopausal bleeding," "unopposed estrogen," "endometrial thickness >4 mm," "obesity + anovulation," "tamoxifen use," "Lynch syndrome"

1. Pathophysiology

Endometrial cancer is fundamentally a disease of estrogen-progesterone imbalance. The endometrium is an estrogen-responsive tissue. Under normal physiology, estrogen stimulates endometrial proliferation during the follicular phase, and progesterone secreted after ovulation counteracts this by inducing secretory differentiation and stabilizing the endometrium. When progesterone is absent or insufficient, estrogen drives continuous, unchecked proliferation, which over time leads to endometrial hyperplasia and eventually malignant transformation.

This is the mechanistic basis for understanding why every major risk factor converges on the same theme: excess estrogen without progesterone opposition. Obesity is the most important modifiable risk factor because adipose tissue contains aromatase, which converts adrenal androgens into estrone (a peripheral estrogen source). The more adipose tissue, the higher the circulating estrogen. Anovulatory states such as PCOS remove the progesterone counterbalance entirely because no corpus luteum forms. Tamoxifen, while acting as an estrogen antagonist in breast tissue, behaves as a partial estrogen agonist in the endometrium, which is why breast cancer patients on tamoxifen carry increased endometrial cancer risk and require monitoring for abnormal bleeding.

Type I endometrial cancer (endometrioid adenocarcinoma) accounts for roughly 80% of cases. It follows the estrogen-driven pathway described above, tends to be low grade, is preceded by hyperplasia, and generally carries a favorable prognosis because it presents early with bleeding.

Type II endometrial cancer (serous papillary and clear cell carcinoma) is fundamentally different. It is not estrogen-dependent, arises from atrophic endometrium in older, thinner women, behaves aggressively, and is often diagnosed at an advanced stage. Type II tumors frequently harbor p53 mutations and carry a significantly worse prognosis. The test-writer uses this distinction to assess whether students understand that not all endometrial cancers are driven by estrogen excess.

Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer) deserves special mention. It is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). After colorectal cancer, endometrial cancer is the second most common malignancy in Lynch syndrome, with a lifetime risk of 40-60%. A young woman presenting with endometrial cancer and a family history of colon, ovarian, or endometrial cancer should raise suspicion for this syndrome.

2. Classification and Clinical Manifestation

Histologic Classification

Feature	Type I (Endometrioid)	Type II (Serous / Clear Cell)
Frequency	~80% of cases	~10-20% of cases
Estrogen dependence	Yes	No
Precursor lesion	Endometrial hyperplasia (especially atypical)	Endometrial intraepithelial carcinoma / atrophic endometrium
Typical patient	Younger, obese, premenopausal or perimenopausal	Older, thin, postmenopausal
Molecular profile	PTEN loss, microsatellite instability, KRAS mutations	p53 mutations, HER2 overexpression
Grade	Usually low grade (grade 1-2)	High grade by definition
Prognosis	Favorable	Poor
Behavior	Confined to uterus at diagnosis in most cases	Early extrauterine spread, peritoneal dissemination

FIGO Staging

Stage	Description
I	Confined to the uterine corpus
IA	Invasion limited to less than half of the myometrium
IB	Invasion into half or more of the myometrium
II	Invasion into the cervical stroma (but not beyond the uterus)
III	Local or regional spread
IIIA	Invasion of the serosa and/or adnexa
IIIB	Vaginal or parametrial involvement
IIIC1	Pelvic lymph node metastasis
IIIC2	Para-aortic lymph node metastasis
IV	Distant metastasis
IVA	Invasion of bladder or bowel mucosa
IVB	Distant metastasis (including intra-abdominal or inguinal lymph nodes)

Endometrial Hyperplasia Classification

Type	Progression Risk to Cancer	Management
Hyperplasia without atypia	~1-3%	Progestin therapy (oral medroxyprogesterone acetate or levonorgestrel IUD), surveillance
Atypical hyperplasia	~30% (some sources up to 40%)	Hysterectomy is recommended. Progestin therapy only if fertility preservation is desired, with close surveillance

The presence of cytologic atypia is the single most important histologic feature that determines cancer risk. This distinction is heavily tested.

Clinical Manifestation by Stage

Presentation	Associated Stage
Postmenopausal bleeding (painless)	Early (Stage I in >70% of cases)
Abnormal premenopausal bleeding (menorrhagia, intermenstrual)	Early, but often diagnosed later due to delayed workup
Pelvic pain, pressure, enlarged uterus	Locally advanced (Stage II-III)
Bowel or bladder symptoms	Stage IV
Weight loss, abdominal distension, ascites	Metastatic disease

3. Diagnostic Workup

Summary Table

Test	Role	Key Finding
Transvaginal ultrasound (TVUS)	Best initial test	Endometrial thickness >4 mm in a postmenopausal woman is abnormal and warrants biopsy
Endometrial biopsy (Pipelle)	Most accurate initial tissue sampling	Histologic confirmation of hyperplasia or carcinoma
Dilation and curettage (D&C)	Confirmatory if biopsy is nondiagnostic or insufficient	More comprehensive tissue sampling under anesthesia
Hysteroscopy with directed biopsy	Gold standard for direct visualization and sampling	Allows visualization of focal lesions that blind biopsy may miss
Pelvic MRI	Preoperative staging	Best imaging for assessing depth of myometrial invasion and cervical stromal involvement
CT chest/abdomen/pelvis	Metastatic workup	Lymphadenopathy, distant metastasis
CA-125	Adjunctive in advanced or serous histology	May be elevated in extrauterine disease; useful for monitoring treatment response

The diagnostic sequence on the exam almost always begins with a postmenopausal woman presenting with vaginal bleeding. The best initial step is transvaginal ultrasound to measure endometrial stripe thickness. The threshold of >4 mm in a postmenopausal woman is the number to remember. If the stripe is thickened or the patient has persistent bleeding regardless of stripe thickness, the next step is tissue sampling.

Endometrial biopsy (Pipelle sampling) is the standard office-based procedure and is the best initial tissue diagnostic test. It has a sensitivity of approximately 90-95% for detecting endometrial cancer. However, it is a blind sampling technique, meaning it can miss focal lesions. If the Pipelle biopsy returns as insufficient tissue, nondiagnostic, or discordant with clinical suspicion, the next step is dilation and curettage, ideally with hysteroscopy for direct visualization.

A common exam scenario involves a postmenopausal woman on tamoxifen who develops vaginal bleeding. The workup is the same: TVUS first, then biopsy. Do not simply attribute the bleeding to tamoxifen without ruling out malignancy.

Preoperative staging with pelvic MRI is used to evaluate the depth of myometrial invasion, which directly impacts surgical planning and the decision to perform lymph node dissection. CT imaging is reserved for evaluating distant spread in advanced-stage disease or aggressive histologic subtypes like serous carcinoma.

One important caveat: endometrial cancer is surgically staged, not clinically staged. The final FIGO stage is determined at the time of surgery, not by imaging alone. This is a testable concept.

4. Management and Treatment

Summary Table

Stage / Scenario	Primary Treatment	Adjuvant Therapy
Stage IA, Grade 1-2	TAH-BSO + surgical staging	Observation (no adjuvant therapy needed)
Stage IA, Grade 3 or Stage IB	TAH-BSO + pelvic and para-aortic lymph node dissection	Vaginal cuff brachytherapy +/- pelvic external beam radiation
Stage II	Radical hysterectomy + BSO + lymph node dissection	Pelvic radiation +/- brachytherapy
Stage III	Surgical debulking + staging	Chemotherapy (carboplatin + paclitaxel) + radiation
Stage IV	Maximal surgical cytoreduction if feasible	Systemic chemotherapy (carboplatin + paclitaxel), hormonal therapy for selected cases
Type II (serous/clear cell), any stage	TAH-BSO + comprehensive staging (omentectomy, peritoneal biopsies)	Chemotherapy (carboplatin + paclitaxel) +/- radiation, even in early stage
Atypical hyperplasia, fertility desired	Progestin therapy: medroxyprogesterone acetate 10-20 mg/day or megestrol acetate 40-160 mg/day, or levonorgestrel IUD	Repeat endometrial biopsy every 3-6 months; hysterectomy after childbearing is complete
Advanced/recurrent, MSI-high or dMMR	Immune checkpoint inhibitor: pembrolizumab	Based on molecular profiling

Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) is the cornerstone of treatment for endometrial cancer. The ovaries are removed because they are a source of estrogen, and occult metastasis to the adnexa may be present. Surgical staging includes peritoneal washings, pelvic and para-aortic lymph node assessment, and inspection of all peritoneal surfaces.

For early-stage, low-grade disease (Stage IA, Grade 1-2), surgery alone is curative in the vast majority of patients, and adjuvant therapy is not indicated. This is a testable point because examinees may reflexively add radiation.

For higher-risk early-stage disease (Stage IA Grade 3, Stage IB, or Stage II), adjuvant vaginal cuff brachytherapy reduces local recurrence at the vaginal cuff, which is the most common site of recurrence. External beam pelvic radiation is added when lymph node involvement is present or suspected.

For advanced-stage disease (Stage III-IV), the standard systemic chemotherapy regimen is carboplatin (AUC 5-6) + paclitaxel (175 mg/m$^2$), administered every 3 weeks for 6 cycles. This is the same backbone regimen used for ovarian cancer and is high-yield to know.

Type II tumors (serous and clear cell) are managed aggressively regardless of stage. Even Stage IA serous carcinoma requires comprehensive surgical staging including omentectomy and peritoneal biopsies, followed by adjuvant chemotherapy, because of the high propensity for peritoneal spread (similar to ovarian cancer behavior).

For the young patient with atypical hyperplasia or early Grade 1 endometrioid cancer who desires fertility preservation, continuous progestin therapy is an acceptable temporizing approach. Options include oral medroxyprogesterone acetate, megestrol acetate, or a levonorgestrel-releasing intrauterine device. These patients must undergo repeat endometrial sampling every 3 to 6 months to confirm regression, and definitive hysterectomy is strongly recommended once childbearing is complete.

Molecular profiling has become increasingly relevant. Tumors with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status respond to immune checkpoint inhibitors such as pembrolizumab, particularly in the recurrent or advanced setting. The combination of pembrolizumab + lenvatinib is used for advanced endometrial cancer that is microsatellite stable (MSS) and has progressed on prior chemotherapy.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Endometrial hyperplasia without atypia	Also causes abnormal uterine bleeding and thickened endometrial stripe	Biopsy shows proliferative glands without cytologic atypia; low risk of progression (~1-3%). Cancer shows invasion through the basement membrane
Cervical cancer	Also causes vaginal bleeding in postmenopausal women	Cervical cancer presents with postcoital bleeding, visible cervical lesion on speculum exam. Endometrial cancer has a normal-appearing cervix with bleeding from the os
Endometrial polyp	Causes postmenopausal bleeding and thickened endometrial stripe on TVUS	Polyps appear as a focal, well-defined echogenic mass within the endometrial cavity, often with a feeding vessel on Doppler. Benign on biopsy
Atrophic vaginitis	Very common cause of postmenopausal bleeding	Thin, pale, friable vaginal mucosa on exam. Endometrial stripe is thin (<4 mm). Source of bleeding is vaginal, not uterine
Uterine sarcoma (leiomyosarcoma)	Rapidly enlarging uterine mass with bleeding	Sarcomas arise from the myometrium, not the endometrium. Presents with a rapidly growing "fibroid" especially in a postmenopausal woman. Endometrial biopsy may be negative because the tumor is submucosal/intramural
Ovarian cancer (serous)	Type II endometrial serous carcinoma behaves similarly; both cause elevated CA-125	Ovarian cancer typically presents with adnexal mass, ascites, and omental caking. Endometrial cancer presents with uterine bleeding. However, advanced serous endometrial cancer can mimic ovarian cancer on imaging
Tamoxifen-induced changes	Tamoxifen causes endometrial thickening on TVUS	Tamoxifen produces subendometrial cystic changes that give a falsely thickened appearance on TVUS. Any bleeding on tamoxifen still requires biopsy to rule out malignancy

6. Traps and High-Yield Pearls

The single most common trap on this topic is the student who sees postmenopausal bleeding and jumps directly to endometrial biopsy without first ordering a transvaginal ultrasound. While biopsy is the tissue diagnostic test, the best initial step in a stable postmenopausal patient with vaginal bleeding is TVUS. The ultrasound serves as a triage tool: if the endometrial stripe is less than or equal to 4 mm, the negative predictive value for cancer is greater than 99%, and biopsy can be deferred with clinical follow-up. If the stripe is thickened, biopsy follows.

Another frequently tested trap is the tamoxifen patient. Students see a thickened endometrial stripe on routine imaging and want to biopsy. The key principle is: do not biopsy an asymptomatic tamoxifen patient based on ultrasound findings alone, because tamoxifen causes subendometrial cystic changes that artificially inflate the measured thickness. Biopsy is indicated only when there is abnormal bleeding.

Students also confuse atypical hyperplasia with cancer. The distinction matters enormously for management: atypical hyperplasia can be treated with progestins in a young patient desiring fertility, whereas invasive cancer generally requires hysterectomy. However, up to 40% of patients with atypical hyperplasia on biopsy are found to have concurrent invasive carcinoma in the hysterectomy specimen, which is why hysterectomy remains the definitive recommendation when fertility is not a concern.

The Type I vs. Type II distinction is another area where students lose points. A thin, elderly postmenopausal woman with aggressive-appearing endometrial cancer does not fit the "classic" estrogen-excess profile, and that mismatch itself is a clue that you are dealing with a Type II (serous or clear cell) tumor, which requires more aggressive staging and treatment.

Finally, remember that endometrial cancer is surgically staged. A question stem that provides imaging results and asks for the "stage" is testing whether you know that final staging requires pathologic evaluation of the surgical specimen, not imaging alone. The correct answer in such a scenario is to proceed with surgery, not to assign a clinical stage based on MRI or CT findings.

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