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Cancers of the Uterine Corpus. SUNY Downstate Medical Center Division of Gynecologic Oncology Mark Borowsky, MD. American Cancer Society Female Cancers: 2000 Statistics. Cancers of the uterine corpus are the 4 th most common cancer in American women Lifetime incidence ~2-3%. Lifetime risk.

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cancers of the uterine corpus

Cancers of the Uterine Corpus

SUNY Downstate Medical Center

Division of Gynecologic Oncology

Mark Borowsky, MD

american cancer society female cancers 2000 statistics
American Cancer SocietyFemale Cancers: 2000 Statistics
  • Cancers of the uterine corpus are the 4th most common cancer in American women
  • Lifetime incidence ~2-3%
american cancer society female cancers 2000 statistics4
American Cancer SocietyFemale Cancers: 2000 Statistics
  • Median Age 61
  • 25% diagnosed before the menopause
  • 5% diagnosed before age 40
slide5

American Cancer SocietyFemale Cancers: 2000 Statistics

  • 6,500 Deaths per year
  • 8th cause of female cancer death
  • 2% of all female cancer death
  • Uterine corpus cancer cases and deaths have increased 25% and 12% respectively from 1994 to 2004
cancers of the uterine corpus histologic types
Cancers of the Uterine Corpus:Histologic Types
  • Carcinoma (94%)
    • Endometrioid (87%)
    • Adenosquamous (4%)
    • Papillary Serous* (3%)
    • Clear Cell* (2%)
    • Mucinous (1%)
    • Other (3%)
  • Sarcoma (6%)
    • Carcinosarcoma* (60%)
    • Leiomyosarcoma* (30%)
    • Endometrial Stromal Sarcoma (10%)
    • Adenosarcoma (<1%)

*poor prognosis histology

endometrial cancer type i ii concept
Endometrial Cancer:Type I/II Concept
  • Type I
    • Estrogen Related
    • Younger and heavier patients
    • Low grade
    • Background of Hyperplasia
    • Perimenopausal
    • Exogenous estrogen
  • Type II (~10% of total cases)
    • Aggressive
    • High grade
    • Unfavorable Histology
    • Unrelated to estrogen stimulation
    • Occurs in older & thinner women
  • Familial/genetic (~15% of total cases)
      • Lynch II syndrome/HNPCC
      • Familial trend
slide9

Uterine Cancer: Surgical Staging

  • Replaced Clinical Staging 1989
  • Conceptual rationale
    • Better defines extent of disease (metastases, depth of invasion, cervix involvement, etc.)
    • Minimizes over/under treatment
    • Minimally increases perioperative morbidity/mortality
    • Decreases overall Rx risks and costs
    • Better allows comparison of therapeutic results
uterine cancer surgical staging
Uterine Cancer: Surgical Staging
  • Clinical Stage I will be upstaged 30% of the time at laparotomy
    • 5% for positive adnexa (Surgical Stage IIIa)
    • 6% for positive para-aortic lymph nodes (Surgical Stage IIIc)
    • 9% for positive pelvic nodes (Surgical Stage IIIc)
    • 12% for positive cytology on pelvic washings (Surgical Stage IIIa)
    • 6% other {eg. cervical (St II) or abdominal disease (St IV)}
  • Clinical Stage II or III will be upstaged 60% of the time at laparotomy
slide11

Endometrial Cancer: Clinical vs. Surgical Staging

Lanciano et al: Radiother Oncol 28:189,1993

slide13

Endometrial Cancer Prognosis:

  • Overall 5Yr Survival 84%
  • Stage and Grade are the most important prognostic factors
  • Altered oncogene/tumor suppressor gene expression is now being evaluated (molecular staging concept)
slide14

Endometrial Cancer: Poor Prognostic Factors

  • Aggressive Histologic Subtypes (Clear-cell, Serous)
  • Increasing age (over 65)
  • Vascular invasion
  • Aneuploidy
  • Altered oncogene/tumor suppressor gene expression ( “molecular staging” concept- p53, PTEN, microsatellite instability, MDR-1, HER2/neu, ER/PR, Ki 67, PCNA, CD 31,EGF-R, MMR genes)
  • Race?
molecular genetics
Molecular Genetics
  • PTEN mutations: 32%
    • Tumor suppressor gene (chrom 10)
      • Phosphatase
    • Early event in carcinogenesis
  • Associated with:
    • endometrioid histology
    • early stage
    • favorable survival
molecular genetics16
Molecular Genetics
  • p53 tumor suppressor gene
    • Cell cycle and apoptosis regulation
    • Most commonly mutated gene in human cancers
    • Overexpression (marker for mutation)
    • Associated with poor prognosis
    • early stage: 10% have p53 mutation
    • advanced stage: 50% have p53 mutation
    • not found in hyperplasias
    • late event in carcinogenesis
genetic syndromes hnpcc hereditary non polyposis colon cancer
Genetic Syndromes: HNPCCHereditary Non-Polyposis Colon Cancer

Lynch II Syndrome

  • Autosomal dominant inheritance
    • MMR (mismatch repair) mutations
      • Genetic instability leads to error-prone DNA replication
    • hMSH2 (chrom 2)
    • hMLH1 (chrom 3)
  • Early age of colon Ca: mean 45.2 years
  • Endometrial Ca: second most common malignancy
    • 20% cumulative incidence by age 70
    • Earlier age of onset than sporadic cases
  • Other: ovary (3.5-8 fold), stomach, small bowel, pancreas, biliary tract
slide19

Five Year Survival by Race:

Matthews RP, Hutchinson-Colas J, Maiman M, et al.: Papillary Serous and Clear Cell Type Lead to Poor Prognosis of Endometrial Carcinoma in Black Women. Gynecol Oncol. 65: 206-212, 1997.

  • Retrospective review 401 patients (60% black)
  • 5 yr Survival
    • Black women: 56% Other races: 71%
  • Black women were more likely to have clear cell or UPSC histology.
  • After controlling for stage only clear cell and UPSC histology independently predicted poor outcome.
  • Race not predictive of survival when stage and histology controlled for.
diagnosis of disease patient awareness
Diagnosis of disease: Patient Awareness*
  • More than 95% of patients with Endometrial Cancer report having symptoms
    • Postmenapausal bleeding
    • Menorrhagia
    • Metrorrhagia
    • Bloody Discharge
  • Endometrial biopsy is the main diagnostic tool
    • performed either in the office or via D&C in OR
uterine cancer diagnosis screening
Uterine Cancer:Diagnosis/Screening
  • Patient Symptoms/Awareness*
  • Cytology – Not a satisfactory screening test
  • Sonography – Not Cost effective
  • Hysteroscopy – Not Cost effective
  • Histology – Secondary to symptoms (not as a screening test)
cytology not sensitive nor specific
Cytology – Not sensitive, nor specific
  • Less than 50% of patients with endometrial Ca have endometrial cells on Pap smear
  • Endometrial cells and/or AGCUS on a pap are frequently a sign of endometrial pathology and deserve further investigation
slide26

Endometrial Cancer:Transvaginal Ultrasound Screening

Fleischer AC, Wheeler JE, Lindsay I, et al.: An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. American Journal of Obstetrics and Gynecology 184(2): 70-75, 2001.

  • Study of 1,926 asymptomatic postmenopausal women on idoxifene for transvaginal u/s screening
  • All patients agree to biopsy after u/s (1,792 biopsies)
  • Using 6 mm cutoff for “Abnormal” the sensitivity of the test was 33% (missed 67% of atypical hyperplasia and cancer)
  • 45% of women were > or = 6mm
  • PPV was only 2%
  • NPV>99%
slide27

Endometrial Cancer:Transvaginal Ultrasound Screening

Langer RD, Pierce JJ, O'Hanlan KA, et al.: Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. New England Journal of Medicine 337(25): 1792-1798, 1997.

  • 448 Women, all asymptomatic and all on HRT
  • All agree to TV u/s and biopsy
  • Threshold of 5mm used
  • 4% incidence of cancer
  • Test Sensitivity was 90% at threshold of 5mm
  • But >50% of women had endometrial thickness of 5mm or more
slide29

Endometrial Cancer:Transvaginal Ultrasound Screening

Rebecca Smith-Bindman, MD; Karla Kerlikowske, MD; Vickie A. Feldstein, MD, etal: Endovaginal Ultrasound to Exclude Endometrial Cancer and Other Endometrial Abnormalities. JAMA. 1998;280:1510-1517

  • Meta-analysis 35 studies, 5,892 women
  • All with PMB, HRT use varied
  • 5mm threshold used
  • Sensitivity 92%
  • Specificity 92% for non HRT users
  • Specificity 77% for HRT users
slide32

Summary: Endometrial Cancer:Transvaginal Ultrasound Screening

  • Normal endometrial stripe:
    • Postmenopausal 4- 8 mm
    • Postmenopausal on HRT 4- 10 mm
  • U/S for Detection of any uterine pathology
    • Sensitivity: 85-95%
    • Specificity: 60-80%
    • PPV 2-10%
    • NPV 99%
slide33

Hysteroscopy – Not satisfactory for screening test

  • Studies of the efficacy of hysteroscopy as a diagnostic tool vary widely
  • Sensitivity reported ranging from 60-95% compared to D&C obtained at the same time
  • Specificity 50-99%
hysteroscopy and positive cytology
Hysteroscopy and Positive Cytology?
  • Studies have been mixed:
    • Some studies suggest an increase in positive peritoneal cytology seen at staging laparotomy in patients who have had hysteroscopy
    • Other studies have failed to find a difference in positive cytology in patients diagnosed via hysteroscopy as compared to office biopsy or D&C
positive studies
Positive Studies:

Bradley WH, Boente MP, Brooker, D, et al.: Hysteroscopy and Cytology in Endometrial Cancer. Obstet Gynecol 2004;104:1030-3

Zerbe M, Zhang J, Bristow RE, et al.: Retrograde seeding of malignant cells during hysteroscopy in presumed early endometrial cancer. Gynecol Oncol 2000;79:55-8

Obermair A, Geramou M, Gucer F, et al.: Does hysteroscopy facilitate tumor cell dissemination. Cancer 2000;88:139-43

Increase in positive cytology from ~2-3% to ~10%

(RR 3-4)

negative studies
Negative Studies:

Gu M, Shi W, Huang J, et al.: Association between initial diagnostic procedure and hysteroscopy and abnormal peritoneal wahisngs in patients with endometrial carcinoma. Cancer 2000;90:3:143-7

Selvaggi L Cormio G, Ceci O, et al.: Hysteroscopy does not increase the risk of microscopic extrauterine spread in endometrial carcinoma. Int J Gynecol Cancer 2003;13:223-7

hysteroscopy not satisfactory
Hysteroscopy – Not satisfactory
  • Too much cost and risk to be used as a screening test.
  • Useful for evaluation of abnormal uterine bleeding where office biopsy is unrevealing.
  • Use in conjunction with uterine curettage
  • Useful to see and resect polyps and small submucous fibroids
  • Useful to perform directed biopsy of small lesions.
endometrial cancer who needs an endometrial biopsy
Endometrial Cancer:Who Needs an Endometrial Biopsy?
  • Postmenopausal bleeding
  • Perimenopausal intermenstrual bleeding
  • Abnormal bleeding with history of anovulation
  • Postmenopausal women with endometrial cells on Pap
  • Thickened endometrial stripe via sonography
sampling of the endometrium
Sampling of the Endometrium
  • Office biopsy procedures (Pipelle, Vabra aspirator, Karman cannula) will agree with a D&C performed in the OR ~95% of the time
  • Office biopsy has a 16% false negative rate when the lesion is in a polyp or the cancer covers less than 50% of the endometrium
    • Guido et al. J Reprod Med. 1995;40:553
  • Patients with persistent PMB after negative office biopsy should have D&C (+/- hysteroscopy)
  • D&C is the gold standard sampling method
    • preoperative D&C will agree with diagnosis at hysterectomy 94% of the time
endometrial hyperplasia classification and risk of progression to cancer
Endometrial Hyperplasia Classification and Risk of Progression to Cancer:

Combined No Atypia (n=122) 1.6%

Combined with Atypia (n=48) 23% (P=0.001)

Mean age at study entry= 40y/o Mean study F/U=13.4yrs

treatment for endometrial hyperplasia without atypia
Treatment for Endometrial Hyperplasia without atypia:
  • Progestin therapy continuous or cyclical
    • Childbearing age:
      • Progestin dominant OCPs or
      • Depo-Provera 150mg IM q3 months or
      • Provera 10mg po 10 days/month and
      • May follow with ovulation induction after normal biopsy if pregnancy desired
    • Peri or Postmenopausal:
      • Provera 20mg po 10 days/month or
      • Depo-Provera 200mg IM q2 months
  • Repeat biopsy in 3-4 months
slide56

Treatment for Atypical Endometrial Hyperplasia:

  • 23% risk of progression to carcinoma (over 10 years) if untreated.
  • Standard treatment when childbearing is complete is total hysterectomy (abdominal or vaginal)
  • Frozen section to rule out carcinoma (up to 20% have coexisting endometrial cancer)
treatment for atypical endometrial hyperplasia
Treatment for Atypical Endometrial Hyperplasia:
  • Conservative medical therapy can be attempted in younger patients who request preservation of fertility.
  • D&C prior to initiation of medical therapy to rule out carcinoma
    • Megace 40-80mg/day, Norethindrone acetate 5mg/day
  • Conservative therapy may also be attempted in young patients with early, well differentiated endometrial carcinomas.
    • Megace 120-200mg/day, Norethindrone acetate 5-10mg/day
conservative medical therapy
Conservative/Medical Therapy:

Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol. 1997 Sep;90(3):434-40.

  • Objective
    • Determine efficacy of conservative treatment of AH/ECA in patients <40 yrs. of age
  • Methods
    • Retrospective Study of pathology records of women age < 40 diagnosed with AH or ECA at Johns Hopkins Jan/90 - Jan/96
conservative medical therapy59
Conservative/Medical Therapy:
  • Results
    • Among 29 pts treated with progestins

16/17 (94%) w/ AH regressed

9/12 (75%) w/ ECA regressed

    • Median length of treatment required for regression was 9 mos.

T.C.Randall, R.J.Kurman.

Obstet Gynecol 1997;90:434-440

conservative medical therapy60
Conservative/Medical Therapy:
  • Results
    • At a mean f/u of 40 mos all pts were alive w/o evidence of progressive dz.
    • 5 of 25 women attempting pregnancies delivered healthy full term infants.

T.C.Randall, R.J.Kurman.

Obstet Gynecol 1997;90:434-440

slide61

Conservative/Medical Therapy:

Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Report of seven cases and review of the literature. Cancer. 1997 Jan 15;79(2):320-7.

  • 13 of 20 patients (62%) with well differentiated endometrial carcinoma regressed with progestins (3 later recurred).

Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, Koupolovic J, Ben-Baruch G. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol. 2003 Oct;102(4):718-25.

  • 13 of 13 patients regressed with progestin therapy, 6 later recurred
slide62

Conservative/Medical Therapy:

  • Conclusion
    • Treatment of AH/ECA with progestins appears to be a safe alternative to hysterectomy in women < 40 yrs of age in whom fertility is desired.
    • Perform hysterectomy after childbearing is completed.
endometroid carcinoma grading
Endometroid carcinoma, Grading
  • FIGO - Gr 1 - < 5% solid tumor

- Gr 2 - 6 % - 50% solid

- Gr 3 - > 50% solid tumor

  • NUCLEAR GRADE
    • Size, shape , staining and chromatin, variability, prominent nucleoli.
    • High nuclear grade adds one point to FIGO grade
slide66

Endometrial carcinoma:

Poor Prognosis Cell Types - Papillary Serous

slide68

Uterine Cancer: Pre-op Evaluation

  • CA125
  • Chest X-ray
  • Mammograms
  • Colon Evaluation
  • Others as indicated
slide69

Uterine Cancer: Pre-op Evaluation

  • Transvaginal U/S?
  • CT Scan?
  • MRI?
slide71

Uterine Cancer: Surgical Staging

  • Preoperative preparation
  • Antimicrobial prophylaxis
  • DVT prophylaxis
  • Steep Trendelenburg
  • Long instruments available
slide72

Endometrial Cancer: Intra-operative Surgical Principals

  • Availability of frozen section to determine the extent of staging procedure.
  • Capability of complete surgical staging
  • Capability of tumor reduction if indicated
slide74

Endometrial Cancer: Surgical Approach

  • TAH-BSO/washings only
    • Endometrioid*
    • Grades 1 and < 50% myometrial invasion*
    • or Grade 2 and no or minimal invasion and < 2 cm tumor diameter*

*Verified via frozen section

slide75

Endometrial Cancer: Surgical Approach

  • Complete Surgical Staging*
    • All Grade 3
    • Any > 50% myometrial invasion
    • Any >2 cm tumor diameter
    • All Serous/clear cell subtype**
    • Pre operative assessment of advanced disease (gross cervical or vaginal dz, etc)

*TAH-BSO, washings, lymphadenectomy **omental/peritoneal biopsy

laparoscopic staging
Laparoscopic Staging:

Magrina JF, Weaver AL. Laparoscopic treatment of endometrial cancer: five-year recurrence and survival rates. Eur J Gynaecol Oncol. 2004;25(4):439-41.

Holub Z, Jabor A, Bartos P, Eim J, Urbanek S, Pivovarnikova R. Laparoscopic surgery for endometrial cancer: long-term results of a multicentric study. Eur J Gynaecol Oncol. 2002;23(4):305-10.

GOG LAP2 Protocol: Randomized study of Total Hysterectomy, BSO and Staging via Laparotomy vs. Laparoscopy- study still open

  • Previous studies show:
    • Similar blood loss
    • Same incidence of complications
    • Low incidence of conversion of laparoscopy to laparotomy
    • Longer operative times for laparoscopy (160 min vs. 115min)
    • Shorter hospital stay (4 vs 7 days) for laparoscopy
    • No difference in recurrence risk.
slide77

Endometrial Cancer: Adjuvant Therapy

  • Brachytherapy
  • External beam radiotherapy
  • Hormonal therapy
  • Cytotoxic chemotherapy
  • Combination therapy
slide78

Endometrial Cancer: Adjuvant Radiation

  • Stratify patients into risk for recurrence based on Grade and Stage
    • Low Risk (<5% recurrence): Stage IA or superficial IB, Grade 1 or 2, no LVSI -these patients require no further treatment after surgery
    • Intermediate Risk (5-10% recurrence): Grade 1 with at least middle third invasion or Stage IB Grade 2 and no LVSI. No consensus exists for this group.
    • High Risk (>10% recurrence): Any Grade 3, Any Stage IC or greater, Grade 2 with middle third invasion or LVSI- these patients should get adjuvant radiation with either WPR 4,500-5,000 cGy and/or vaginal brachy therapy.
slide79

Endometrial Cancer: Adjuvant Radiation

  • GOG 99
  • 390 patients, Stage IB, IC, IIA or IIB, all grades (UPSC and clear cell excluded)
  • Patients randomized to 5,040 cGy WPR (no brachy therapy) vs. no RT
  • 3yr survival 96% vs 89% for RT vs control group (p=0.009)
  • Among patients with Grade 2 or 3, or > middle third invasion or + LVSI the 5yr recurrence free percentage was 87% for the RT group vs 73% for the control group
slide80

Endometrial Cancer: Adjuvant Postop Radiotherapy

  • Estimated cost 5,040 cGy PRT: $20,000
  • Treatment duration: 25 to 30 days
  • Morbidity compounded by recent surgery
slide81

Endometrial Cancer: Adjuvant Hormonal Therapy

Vergote et al: Cancer 64:1011, 1989

slide84

Endometrial Cancer: ERT/HRT

  • 3 small published studies prior to GOG 137
  • GOG 137- closed after WHI study results
  • Preliminary results (April 2004: 32 mos F/U) of GOG 137 agree with prior studies: No evidence that ERT/HRT adversely influences the disease-free survival of women treated for endometrial cancer
slide85

Endometrial Cancer: Recurrence

  • Pelvic examination
  • Pap smears
  • CA125 (high-risk)
  • Chest X-ray (high-risk)
slide87

Endometrial Cancer: Follow-Up

  • 75-95% of recurrences are in first 36 months
  • 60% of patients have symptoms (pain, wgt loss, vaginal bleeding)
  • Rare to cure distant recurrences
  • 50% vaginal recurrences cured
slide89

Uterine Sarcomas

  • Account for fewer than 10% of all corpus cancers
  • Abnormal vaginal bleeding most frequent presenting symptom for all histologic types
  • No specific staging system (commonly use staging of endometrial carcinoma)
slide90

Uterine Sarcomas

  • Order of incidence: Carcinosarcoma (60%), leiomyosarcoma (30%), endometrial stromal sarcoma (10%), and adenosarcoma (<1%)
  • Higher rates of MMMT and LMS seen in Black women (2X greater than whites)
  • Exposure to radiation may enhance the development of pelvic sarcomas (seen mainly in mixed sarcomas)
  • Mean age between 65-75 for carcinosarcoma but earlier for LMS and ESS
slide91

Carcinosarcoma

  • Contains both carcinomatous and sarcomatous elements
  • In homologous MMMT, sarcomatous element is stromal sarcoma in 60% and LMS in the remainder.
  • In heterologous MMMT rhabdomyosarcoma most common element (others: chondrosarcoma, osteosarcoma and liposarcoma).
  • Carcinomatous element usually adenocarcinoma (endometrioid,clear cell, PSA)
slide94

Carcinosarcoma

  • Overall 5 year survival poor (25%) and strongly associated with degree of myometrial invasion.
  • ~60% have spread outside the uterus at time of diagnosis
  • ~35% regional lymph node spread in clinical stage 1 patients
  • Early hematogenous spread to liver and lung is common
  • In pts without extrauterine disease, 40% chance of distant recurrence
slide95

Leiomyosarcoma

  • LMS represent ~30% of uterine sarcomas
  • LMS rarely arises from benign leiomyomata
  • Arises in the myometrium, unlike all the other uterine sarcomas (less likely to be detected on EMC)
slide97

Leiomyosarcoma

  • Tumors usually show high cellularity, marked pleomorphism, and atypical mitotic figures.
  • Two thirds of LMS are intramural and 10% submucosal
  • Need >10 mitoses/ 10hpf for diagnosis
slide98

Endometrial Stromal Sarcoma

  • Accounts for ~10% of uterine sarcomas
  • Tumor group divided into benign stromal nodule , low-grade ESS and high grade ESS
  • Areas of hemorrhage, necrosis, and deep myometrial invasion common in high grade ESS and 40% extend beyond the uterus at the time of diagnosis
slide102

Adenosarcoma

  • First described in 1974
  • Rare
  • Composed of a benign epithelial and a malignant non-epithelial component
  • Mean age between 55 and 60 years
  • Tend to be solitary masses in uterine fundus
slide103

Adenosarcoma

  • Disease usually limited to endometrium, but myometrial invasion is possible
  • Sarcomatous element usually homologous and of lower grade compared to MMMT
  • Adenosarcoma with Sarcomatous Overgrowth is a poor prognostic feature
slide104

Management of Uterine Sarcomas

  • Surgery is the hallmark of treatment with TAH/BSO being the standard procedure
  • For patients with advanced or recurrent disease, aggressive surgical intervention is unlikely to influence outcome.
  • Bilateral oopherectomy is strongly recommended for patients with Low grade ESS
slide105

Management of Uterine Sarcomas

  • Indications for adjunctive RT or primary RT parallels the indications for endometrial CA
  • Adjuvant RT has been shown to improve local control, effect on overall survival unknown
slide106

Management of Uterine Sarcomas

  • MMMT- Ifosfamide (25% response), cisplatinum(18% response).
  • LMS- only adriamycin appears to have significant activity (25% response rate)