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A. Overview of Benign and Malignant Conditions

  1. Glandular Tumors ±> Polyps and/or Hyperplasia ±> Endometrial Adenocarcinoma
  2. Stromal Tumors ±> Stromal Nodule ±> Stromal Sarcoma
  3. Mesodermal Tumor ±> Adenofibroma ±> Malignant Mixed Mesodermal Tumor (MMMT)
  4. Smooth Muscle ±> Leiomyoma ±> Leiomyosarcoma

B. Endometrial Adenocarcinoma [1]

  1. Most frequent cancer of female genital tract
    1. 7% of all female cancers in USA
    2. 36,000 cases in USA in 1998; 142,000 worldwide 2004
    3. 6,300 deaths per year in USA in 1998; 42,000 deaths worldwide 2004
    4. Median age 63 years (75% of patients are post-menopausal)
    5. Two main types of endometrial adenocarcinoma (Types I and II)
  2. Type I Versus Type II
    1. Type I occurs in younger persons, type II (atrophic) in older
    2. Type I diploid, type II aneuploid
    3. Loss of heterozygosity: type I has low and type II high levels
    4. Type I has K-ras mutations, type II p53 mutations
    5. Type I has microsatellite instability, type II has erbB2 (Her2/neu) amplification
    6. PTEN mutations in Type I is most common genetic change
    7. Type I is typically hormonally driven, type II is not
    8. Type I has much better prognosis than type II
  3. Risks
    1. Risk of development of adenoCa increases with increasing endometrial hyperplasia
    2. Unopposed estrogen replacement therapy (ERT): ~1.4X overall [2]
    3. Unopposed low dose estrogen (Premarin® 0.325mg/d) probably does not increase risk
    4. Combined estrogen/progestin probably reduces overall risk ~30% [2]
    5. Use of sequential contraceptives: 7X risk
    6. Use of combination oral contraceptives: 0.2-0.5X risk (20-50% risk reduction) [4]
    7. Tamoxifen: 1.5-4X risk [5,6]
    8. Obesity: 3-10X risk
    9. Late menopause (>52 years): ~2.4X risk
    10. Smaller number of children: 2-5X risk
  4. Tamoxifen and Risk of Uterine Cancer [5,6]
    1. Overall, ~1.5-4X increased risk of endometrial cancer with use of tamoxifen
    2. Prior to treatment, Pap smear, pelvic exam, and careful history should be obtained
    3. Transvaginal ultrasonographyh should be considered
    4. Any uterine bleeding or discharge should be evaluated very seriously
    5. Endometrial biopsy should be considered in persons with >5mm endometrial thickness
  5. Associated signs
    1. Obesity
    2. Diabetes
    3. Hypertension
    4. Infertility
  6. Pathogenesis
    1. Increased estrogen production: functional granulosa cell tumor, obesity, infertility
    2. Nulliparity and late menopause increase risk of uterine cancers
    3. PTEN (tumor suppressor gene) mutations commonly found in Type I tumors dc. Overexpression of the Her-2/neu gene (10% of uterine cancers)
    4. Mutations of p53 tumor suppressor gene associated with advanced stage, poor prognosis
    5. Uterine cancer is most common extracolonic cancer in familial Lynch Syndrome
  7. Histologic Types
    1. Endometrioid adenocarcinoma in ~80% of endometrial malignancies
    2. Variants on endometrioid: with squamous differentiation, villoglandular, secretory, with ciliated cells
    3. Other types (20%): mucinous, serous, clear cell, papillary serous, adenoacanthoma, adenosquamous, mixed, transitional cell, squamous, undifferentiated
    4. Adenoacanthomas represent <5% of uterine cancers
    5. Adenosquamous (1-2%) has squamous cells in addition to glandular element
    6. Adenosquamous carcinoma may have well or poorly differentiated squamous element
    7. Uncommon variants include papillary serous and clear cell (glycogen) carcinomas
    8. Papillary serous, clear cell, and adenosquamous CAs have poor prognosis
    9. Tamoxifen use increases the risk of variant tumor types [5]
  8. Clinical Features
    1. Usually occurs in peri- or postmenopausal women
    2. Chief complaint is abnormal uterine bleeding (especially early stages)
    3. Fractional curettage is required for early detection (PAP smear ineffective)
    4. Endometrial cancer, unlike cervical Ca, may spread directly to para-aortic lymph nodes
    5. CA-125 levels may be increased and, if so, can be used to follow therapy
  9. Detection [7]
    1. Endovaginal ultrasound to assess for thickened endometrium
    2. In 92% of abnormal endometrial biopsies, ultrasound showed >5mm endometrium
    3. In 96% of endometrial cancer by biopsy result, ultrasound showed >5mm endometrium
    4. Therefore, ultrasound measured endometrium <5mm is likely benign uterine condition
    5. Endometrial biopsy should follow any abnormal ultrasound
    6. CT Scan required for initial staging
  10. Prognostic Features
    1. Tumor Stage
    2. Histological type and grade
    3. Depth of myometrial invasion
    4. Less important: age, peritenal cytology, progesterone receptor status, menopausal stage
  11. Staging
    1. Stage 1A - tumor limited to endometrium
    2. Stage 1B - invasion of less than half the myometrium
    3. Stage 1C - invasion of more than half the myometrium
    4. Stage 2A - endocervical glandular involvement only
    5. Stage 2B - cervical stromal invasion
    6. Stage 3A - tumor invading serosa or adnexa, or malignant peritoneal cytology
    7. Stage 3B - vaginal metastasis
    8. Stage 3C - metastasis to pelvic or para-aortic lymph nodes only
    9. Stage 4A - tumor invasion of the bladder or bowel mucosa
    10. Stage 4B - distant metastasis (including lymph nodes)
  12. Grade
    1. Diffuse or polypoid growth patterns occur
    2. Grade 1: Completely glandular tumor (~60% of cases)
    3. Grade 2: Moderately differentiated: glandular tumor and some solid tumor (<50%)
    4. Grade 3: Poorly differentiated, large areas of solid tumor (>51%), few glands
    5. Grading within a stage provides most important prognostic information
    6. Higher grade tumors have poorer outcomes
    7. Type I versus type 2 (see above) is probably as accurate as histologic grading
  13. Treatment of Stages 1 and 2 Disease [1]
    1. Surgery is used whenever possible and may be curative (histerectomy)
    2. Pelvic lymphadenectomy can be done to reduce recurrence, stage disease
    3. Negative pelvic lymph nodes with Stage 1A or 1B obviates need for radiation therapy
    4. Radiotherapy should be offered to patients with positive lymph nodes or stage 1C [3]
    5. Adjuvant radiation significantly improved overall survival in Stage 1C regardless of lymph node status (40-55% reduction in mortality over time) [3]
    6. Pre-operative radiotherapy is not done due to increased surgical risk
    7. Post-operative therapy for stage 1A or 1B reduces local recurrence but not overall survival and substantially increases morbidty [6]
    8. If at least 2 of the 3 risk factors (Stage 1C, Grade 3, Age >60 years) present, then pelvic external beam radiotherapy should be offerred
    9. Intracavitary (intravaginal) radiotherapy may be used at time of local recurrence or for vaginal extension
  14. Treatment of Stages 3 and 4 Disease [1]
    1. Surgery to achieve minimal residual disease remains cornerstone
    2. Systemic chemotherapy improves relapse-free and overall survival
    3. Doxorubicin is a relatively active agent
    4. Carboplatin may be added to doxorubicin
    5. Paclitaxel (Taxol®) is active in some subtypes of uterine cancer
    6. Combination carboplatin + paclitaxel is often used in Stage 4 or recurrent uterine cancers
    7. After surgery for Stage 3 or 4 uterine cancer, doxorubicin+cisplatin showed superior mortality and progression free survival compared with radiotherapy
  15. Prognosis: 5 Year Survival
    1. Stage 1: 85%
    2. Stage 2: 75%
    3. Stage 3: 52%
    4. Stage 4: 27%
    5. Grade of tumor also differentiates survival within a Stage

C. Endometrial Stromal Tumors

  1. Benign tumors are called endometrial stromal nodules
  2. Malignant tumors are stromal sarcomas, low or high grade
  3. Low grade tumors
    1. May be polypoid (exophytic) and fill uterine cavity
    2. May diffusely invade the uterus (endophytic)
    3. Cells look like proliferative phase stroma, with few or no mitoses
  4. High grade sarcomas
    1. May be difficult to distinguish from undifferentiated sarcomas
    2. May represent progression from low grade
  5. Recurrence
    1. Possible, even following surgical resection
    2. Better cure if low grade

D. Heterologous Stromal Tumors

  1. Uterine Adenosarcoma
    1. Combination of benign glandular epithelium and malignant stroma
    2. Contrast with carcinosarcoma (malignant mixed mesodermal tumor)
  2. Carcinosarcoma and Malignant Mixed Mesodermal Tumor (MMMT)
    1. Epithelial and stromal components both highly malignant
    2. Derived from multipotential stromal cells
    3. Mixed Mesodermal tumor: mesenchymal elements normally absent from uterus
    4. Increased risk of development of MMMT with tamoxifen use [8]
    5. These tissues include striated muscle, bone, osteoid, cartilage and fat
    6. Carcinosarcoma has only epithelial and stromal components, both malignant
    7. Generally poor prognosis, overall 5 year survival 25%

E. Smooth Muscle Tumors

  1. Leiomyoma
    1. Benign tumor of smooth muscle origin
    2. Most common tumor arising from female genital tract, with 25% women >30years
    3. Often multiple, each leiomyoma is clonal
    4. Estrogens enhance growth of these tumors. Slow growing, very few or no mitosis
    5. Firm, pale gray, whorled, pseudo-encapsulated (real space between tumor and normal myometrium)
    6. May cause bleeding, usually due to ulceration
    7. Large tumors may interfere with bowel or bladder function.
    8. Treatment: myomectomy, hysterectomy
  2. Leiomyosarcoma
    1. Very rare tumors, usually occur in older women (>50)
    2. Diagnosis by Mitotic count and nuclear atypia
    3. Aggressive tumor, often fatal
    4. Total abdominal hysterectomy (TAH) OR
    5. Bilateral salpingoopherectomy (BSO) with hysterectomy

F. HNPCC (Lynch) Syndrome Type II [9]

  1. Called hereditary non-polyposis colon cancer syndrome (HNPCC)
  2. Due to Mutations in DNA mismatch repair proteins
    1. Most patients have hMSH2 (chr 2p16; ~45%) or hMLH1 (chr 3p; ~45%) mutations
    2. Remaining patients have hPMS1 (chr 2q), hPMS2 (chr 7p), or MSH6 mutations (<5% each)
    3. Inactivation of these genes leads to "microsatellite" instability
    4. Mutations in these genes confer ~80% lifetime risk of colon cancer (versus ~4% normal)
  3. Many patients with HNPCC have extracolonic tumors (Type II Lynch Syndrome)
  4. Highest risk of extracolonic cancers with Type II NHPCC was endometrial cancer (~50%)
  5. Ovarian and gastric cancers also increased in HNPCC patients
  6. Therefore, all patients with endometrial cancer should be asked about colon cancer

References

  1. Amant F, moerman P, Neven P, et al. 2005. Lancet. 366(9484):491 abstract
  2. Million Women Study Collaborators. 2005. Lancet. 365(9470):1543 abstract
  3. Lee CM, Szabo A, Shrieve DC, et al. 2006. JAMA. 295(4):389 abstract
  4. Vessey M, Painter R, Yeates D, et al. 2003. Lancet. 362(9379):185 abstract
  5. Bergman L, Beelen MLR, Gallee MPW, et al. 2000. Lancet. 356(9233):881 abstract
  6. Suh-Burgmann EJ and Goodman A. 1999. Ann Intern Med. 131(2):127 abstract
  7. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. 1998. JAMA. 280(17):1510 abstract
  8. Creutzberg CL, van Putten WLJ, Koper PCM, et al. 2000. Lancet. 355(9213):1404 abstract
  9. Seiden MV, Patel D, O'Neill MJ, Oliva E. 2007. NEJM. 356(17):1760 (Case Record) abstract