Cancers of the Uterine Corpus

1
Cancers of the Uterine Corpus

• SUNY Downstate Medical Center
• Division of Gynecologic Oncology
• Mark Borowsky, MD

2
American Cancer SocietyFemale Cancers 2000
Statistics

• Cancers of the uterine corpus are the 4th most
  common cancer in American women
• Lifetime incidence 2-3

3
Lifetime risk
4
American Cancer SocietyFemale Cancers 2000
Statistics

• Median Age 61
• 25 diagnosed before the menopause
• 5 diagnosed before age 40

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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

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Cancers of the Uterine CorpusHistologic 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 (lt1)

poor prognosis histology
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Endometrial CancerType 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

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Endometrial Cancer Type I Risk Factors
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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

10
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

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Endometrial Cancer Clinical vs. Surgical Staging
Lanciano et al Radiother Oncol 28189,1993
12
Endometrial Cancer FIGO Surgical Stage
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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)

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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?

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Molecular Genetics

• PTEN mutations 32
• Tumor suppressor gene (chrom 10)
• Phosphatase
• Early event in carcinogenesis
• Associated with
• endometrioid histology
• early stage
• favorable survival

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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

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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

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Five Year Survival by Race
19
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.
Five Year Survival by Race

• 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.

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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 DC in OR

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Post menopausal bleeding
22
Postmenopausal Bleeding
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Uterine CancerDiagnosis/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)

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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

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Endometrial CancerTransvaginal Ultrasound
Screening
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Endometrial CancerTransvaginal 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 gt or 6mm
• PPV was only 2
• NPVgt99

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Endometrial CancerTransvaginal 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 gt50 of women had endometrial thickness of
  5mm or more

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Endometrial CancerTransvaginal Ultrasound
Screening
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Endometrial CancerTransvaginal 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.
19982801510-1517

• 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

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Endometrial CancerTransvaginal Ultrasound
Screening
31
Endometrial CancerTransvaginal Ultrasound
Screening
32
Summary Endometrial CancerTransvaginal
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

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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 DC obtained at the same time
• Specificity 50-99

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Normal Endometrium
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Endometrial Polyp
36
Polyp and Atypical Hyperplasia
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Focal Simple Hyperplasia
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Grade 3 Endometrial cancer
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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 DC

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Positive Studies

• Bradley WH, Boente MP, Brooker, D, et al.
  Hysteroscopy and Cytology in Endometrial Cancer.
  Obstet Gynecol 20041041030-3
• Zerbe M, Zhang J, Bristow RE, et al. Retrograde
  seeding of malignant cells during hysteroscopy in
  presumed early endometrial cancer. Gynecol Oncol
  20007955-8
• Obermair A, Geramou M, Gucer F, et al. Does
  hysteroscopy facilitate tumor cell dissemination.
  Cancer 200088139-43
• Increase in positive cytology from 2-3 to 10
• (RR 3-4)

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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 2000903143-7
• 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 200313223-7

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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.

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Endometrial CancerWho 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

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Sampling of the Endometrium

• Office biopsy procedures (Pipelle, Vabra
  aspirator, Karman cannula) will agree with a DC
  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. 199540553
• Patients with persistent PMB after negative
  office biopsy should have DC (/- hysteroscopy)
• DC is the gold standard sampling method
• preoperative DC will agree with diagnosis at
  hysterectomy 94 of the time

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Endometrial cyclic changesProliferative phase
46
Endometrial cyclic changesProliferative phase

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Endometrial cyclic changesEarly secretory
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Endometrial cyclic changesmid-secretory
49
Endometrium Post-menopausal atrophy
50
Endometrial Simple Hyperlasia
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Endometrial Hyperlasia - Complex

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Endometrial Hyperplasia - Atypical
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Endometrial Atypical Hyperplasia

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Endometrial Hyperplasia Classification and Risk
of Progression to Cancer
Combined No Atypia (n122) 1.6 Combined
with Atypia (n48) 23
(P0.001) Mean age at study entry 40y/o Mean
study F/U13.4yrs
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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

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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)

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Treatment for Atypical Endometrial Hyperplasia

• Conservative medical therapy can be attempted in
  younger patients who request preservation of
  fertility.
• DC 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

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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 Sep90(3)434-40.

• Objective
• Determine efficacy of conservative treatment of
  AH/ECA in patients lt40 yrs. of age
• Methods
• Retrospective Study of pathology records of women
  age lt 40 diagnosed with AH or ECA at Johns
  Hopkins Jan/90 - Jan/96

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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
199790434-440
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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
199790434-440
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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 1579(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 Oct102(4)718-25.

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

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Conservative/Medical Therapy

• Conclusion
• Treatment of AH/ECA with progestins appears to be
  a safe alternative to hysterectomy in women lt 40
  yrs of age in whom fertility is desired.
• Perform hysterectomy after childbearing is
  completed.

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Endometroid carcinoma, Grading

• FIGO - Gr 1 - lt 5 solid tumor
• - Gr 2 - 6 - 50 solid
• - Gr 3 - gt 50 solid tumor
• NUCLEAR GRADE
• Size, shape , staining and chromatin,
  variability, prominent nucleoli.
• High nuclear grade adds one point to FIGO grade

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Grade 1 Endometroid Carcinoma
65
Grade 3 Endometroid Carcinoma
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Endometrial carcinoma Poor Prognosis Cell Types
- Papillary Serous
67
Endometrial Carcinoma - Poor Prognosis Cell Types
Clear Cell
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Uterine Cancer Pre-op Evaluation

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

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Uterine Cancer Pre-op Evaluation

• Transvaginal U/S?
• CT Scan?
• MRI?

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Uterine Cancer Pre-op Evaluation
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Uterine Cancer Surgical Staging

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

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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

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Endometrial Cancer Nodal Involvement
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Endometrial Cancer Surgical Approach

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

Verified via frozen section
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Endometrial Cancer Surgical Approach

• Complete Surgical Staging
• All Grade 3
• Any gt 50 myometrial invasion
• Any gt2 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
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Laparoscopic Staging

• Magrina JF, Weaver AL. Laparoscopic treatment of
  endometrial cancer five-year recurrence and
  survival rates. Eur J Gynaecol Oncol.
  200425(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.
  200223(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.

77
Endometrial Cancer Adjuvant Therapy

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

78
Endometrial Cancer Adjuvant Radiation

• Stratify patients into risk for recurrence based
  on Grade and Stage
• Low Risk (lt5 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 (gt10 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.

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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
  (p0.009)
• Among patients with Grade 2 or 3, or gt middle
  third invasion or LVSI the 5yr recurrence free
  percentage was 87 for the RT group vs 73 for
  the control group

80
Endometrial Cancer Adjuvant Postop Radiotherapy

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

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Endometrial Cancer Adjuvant Hormonal Therapy
Vergote et al Cancer 641011, 1989
82
Endometrial Cancer Single Agent Chemotherapy
Response Rates

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Endometrial Cancer Chemotherapy Response Rates
84
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

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Endometrial Cancer Recurrence

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

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Endometrial Cancer Site of RecurrenceIn
Radiated Patients
87
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

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(No Transcript)
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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)

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Uterine Sarcomas

• Order of incidence Carcinosarcoma (60),
  leiomyosarcoma (30), endometrial stromal sarcoma
  (10), and adenosarcoma (lt1)
• 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

91
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)

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Carcinosarcoma (MMMT) Homologous
93
Carcinosarcoma (MMMT) Heterologous
94
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

95
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)

96
Leiomyosarcoma
97
Leiomyosarcoma

• Tumors usually show high cellularity, marked
  pleomorphism, and atypical mitotic figures.
• Two thirds of LMS are intramural and 10
  submucosal
• Need gt10 mitoses/ 10hpf for diagnosis

98
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

99
Endometrial Stromal Sarcoma
100
Endometrial Stromal Sarcoma
101
Endometrial stromal sarcoma
102
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

103
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

104
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

105
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

106
Management of Uterine Sarcomas

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