Endometrial Cancer

2. Uterine Anatomy 2 components: -The muscle is called myometrium -proliferative inner lining called the endometrium The top of the uterus is called the fundus, the middle portion the body, and the lower 4 cm. is the cervix. The round ligaments hold the fundus forward, and terminate in the superficial inguinal area. The rectouteruine ligaments hold the cervix back and upward. The cardinal ligaments just the connective tissue around the uterine blood vessels. The broad ligaments are from the lateral uterus and maintain uterine support via their peritoneal continuations. The blood supply to the uterus comes predominantly off of the internal iliac arteries, which gives rise to the paired uterine arteries. Lymphatic drainage from the top of the uterus follows the round ligament to the superficial inguinal nodes, from the middle uterus to the extemal iliac nodes and internal iliac nodes, and from the uterocervical junction to the nodes. The venous drainage follows lymphatics. The ovarian artery comes off of the aorta to supply the ovary and fallopian tube, and this blood supply anastomoses with the uterine arteries.

4. Histology The endometrium consists of a simple columnar epithelium forming numerous tubular glands supported by a thick vascular stroma. �Both glands and stroma undergo extensive changes during the menstrual cycle. The endometrium is functionally subdivided into two layers: -Stratum functionalis: A thick superficial layer that is sloughed off during menstruation and grows anew during each cycle.�The stroma more closely resembles embryonic mesenchyme than typical lamina propria. -Stratum basalis: Permanent stromal tissue. These tissues remain through each cycle and serve as sources for cells during regrowth of the superficial stratum functionalis. When the stratum functionalis is present (i.e, when it has not just be sloughed off), there is no distinct morphological boundary between these two layers.

5. Histology During the proliferative phase, when the stratum functionalis is growing, the endometrial glands have a relatively smooth contour and mitotic figures are common. In contrast, when the endometrial glands have matured in the secretory phase, their contour is more tortuous and the epithelium consists of mature secretory cells. The endometrium is highly vascular, and the blood vessels also participate in the menstrual cycle. �Distal vessels are sloughed off, while the spiral arteries (named for their helical shape) retract into the stratum basalis and constrict to limit blood loss during menstruation. �The spiral arteries then extend again (like springs) as the stratum functionalis regenerates. The myometrium consists of smooth muscle, organized into poorly-defined layers with bundles of fibers interwoven in varying directions. �In response to hormonal changes pregnancy, the myometrium undergoes both hyperplasia (more smooth muscle cells) and hypertrophy (larger smooth muscle cells). http://www.siumed.edu/~dking2/erg/uterus.htm

9. American Cancer SocietyFemale Cancers: 2000 Statistics Cancers of the uterine corpus are the 4th most common cancer in American women Lifetime incidence ~2-3% As you can see there are approximately 36 thousand new cases of uterine cancer each year in the Unites States 1 out of every 44 women in America will eventually get uterine cancer....for a lifetime incidence of 2 to 3 % This compares to a lifetime risk of about 1 of 70 for ovarian cancer and approximately 1 of 9 for breast cancer.As you can see there are approximately 36 thousand new cases of uterine cancer each year in the Unites States 1 out of every 44 women in America will eventually get uterine cancer....for a lifetime incidence of 2 to 3 % This compares to a lifetime risk of about 1 of 70 for ovarian cancer and approximately 1 of 9 for breast cancer.

10. American Cancer SocietyFemale Cancers: 2000 Statistics Although the median age at diagnosis is 61 years, however 25% will be diagnosed before menopause and 5% will be diagnosed before age 40. For this reason it is important to keep a high index of suspicion, and perform endometrial biopsy for abnormal bleeding even in women who are pre-menopausal.Although the median age at diagnosis is 61 years, however 25% will be diagnosed before menopause and 5% will be diagnosed before age 40. For this reason it is important to keep a high index of suspicion, and perform endometrial biopsy for abnormal bleeding even in women who are pre-menopausal.

11. There are approximately 65 hundred deaths per year in the US from uterine cancer making it the eight leading cause of cancer death in American women. There are approximately 65 hundred deaths per year in the US from uterine cancer making it the eight leading cause of cancer death in American women.

13. 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%) -The vast majority of uterine cancers are carcinomas with most of those being endometrioid or adenosquamous histology -These histologies carry a relatively good prognosis. -about 5% of the carcinomas will be poor prognosis histologies like UPSC or clear cell carcinomas which spread in a more aggressively -The sarcomas also tend to carry a poor prognosis, an they comprise about 6% of uterine corpus CA in the US, but are about 2X as common in black women as compared to whites. As a result the prevalence ratio in at Downstate is roughly 85/15 carcinoma to sarcoma. -The vast majority of uterine cancers are carcinomas with most of those being endometrioid or adenosquamous histology -These histologies carry a relatively good prognosis. -about 5% of the carcinomas will be poor prognosis histologies like UPSC or clear cell carcinomas which spread in a more aggressively -The sarcomas also tend to carry a poor prognosis, an they comprise about 6% of uterine corpus CA in the US, but are about 2X as common in black women as compared to whites. As a result the prevalence ratio in at Downstate is roughly 85/15 carcinoma to sarcoma.

15. The endometrial clear cell tumor Solid sheets of clear cells with transparent cytoplasm and prominent nucleiThe endometrial clear cell tumor Solid sheets of clear cells with transparent cytoplasm and prominent nuclei

16. Uterine papillary serous carcinoma, looks like serous ovarian tumor complex papillations, scant or absent stroma; marked cellular atypia; As in ovarian papillary serous tumors, psammoma bodies can sometimes bee seen.Uterine papillary serous carcinoma, looks like serous ovarian tumor complex papillations, scant or absent stroma; marked cellular atypia; As in ovarian papillary serous tumors, psammoma bodies can sometimes bee seen.

17. 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 Among the endometrial carcinomas, it has become more common to distinguish between the type I vs type II tumors. -The majority will fall into Type I- the classic Estrogen related cancer. E, younger, low grade, endometroid -Type II refers to those tumors which appear unrelated to estrogen- generally the high grade tumors and poor prognosis histologies in women without classic risk factors. -A third category of tumors are being recognized the genetic/familial cases like HNPCC (a defect in MSH mismatch repair genes) 40X risk of EM ca (5X Ov) pts as young as 16y/o Among the endometrial carcinomas, it has become more common to distinguish between the type I vs type II tumors. -The majority will fall into Type I- the classic Estrogen related cancer. E, younger, low grade, endometroid -Type II refers to those tumors which appear unrelated to estrogen- generally the high grade tumors and poor prognosis histologies in women without classic risk factors. -A third category of tumors are being recognized the genetic/familial cases like HNPCC (a defect in MSH mismatch repair genes) 40X risk of EM ca (5X Ov) pts as young as 16y/o

18. Endometrial Cancer: Type I Risk Factors -Classic risk factors that relate to the Type I Estrogen dependent Em Ca & are shown here -Obesity causes peripherial Estrone production and also may cause an anovulatory state in the pre-menopausal patient who develops endometrial cancer -Note the effect of exogenous estrogen which increases the relative risk of endometrial cancer from 5 to 14 fold depending on the number of years of use. It is worth mentioning that these cases tend to be well differentiated and as a result they have a better prognosis than matched cases in which no exogenous estrogen was used. -Atypical hyperplasia is clearly a precursor lesion for EM Ca and it is the cellular Atypia which is the key as we will discuss shortly -Note the protective effect of OCP which are felt to prevent about 2000 cases of Em Ca in the US each year -Classic risk factors that relate to the Type I Estrogen dependent Em Ca & are shown here -Obesity causes peripherial Estrone production and also may cause an anovulatory state in the pre-menopausal patient who develops endometrial cancer -Note the effect of exogenous estrogen which increases the relative risk of endometrial cancer from 5 to 14 fold depending on the number of years of use. It is worth mentioning that these cases tend to be well differentiated and as a result they have a better prognosis than matched cases in which no exogenous estrogen was used. -Atypical hyperplasia is clearly a precursor lesion for EM Ca and it is the cellular Atypia which is the key as we will discuss shortly -Note the protective effect of OCP which are felt to prevent about 2000 cases of Em Ca in the US each year

20. Molecular Genetics PTEN mutations: 32% Tumor suppressor gene (chrom 10) Phosphatase Early event in carcinogenesis Associated with: endometrioid histology early stage favorable survival PTEN mutations are a common genetic alteration in the Type I tumors- those of endometrioid histology and low grade. The mutation may be seen in premalignant disease like atypical hyperplasia. As a result of its association with low grade disease it is also correlated favorably with survival.PTEN mutations are a common genetic alteration in the Type I tumors- those of endometrioid histology and low grade. The mutation may be seen in premalignant disease like atypical hyperplasia. As a result of its association with low grade disease it is also correlated favorably with survival.

21. 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 p53 tumor suppressor gene Cell cycle and apoptosis regulation Most commonly mutated gene in human cancers Overexpression (marker for mutation) Associated with poor prognosis not found in hyperplasias late event in carcinogenesis early stage: 10% have p53 mutation advanced stage: 50% have p53 mutation It is associated more strongly with high risk histologies (UPSC, clear cell carcinoma and grade 3 tumors) p53 tumor suppressor gene Cell cycle and apoptosis regulation Most commonly mutated gene in human cancers Overexpression (marker for mutation) Associated with poor prognosis not found in hyperplasias late event in carcinogenesis early stage: 10% have p53 mutation advanced stage: 50% have p53 mutation It is associated more strongly with high risk histologies (UPSC, clear cell carcinoma and grade 3 tumors)

22. 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 Other genetic mutations of interest in endometrial carcinoma are the mutations in mismatch repair genes- In these patients genetic instability leads to error-prone DNA replication. This leads to a cancer syndrome known as Lynch II which is characterized by the following: Early age of colon Ca with an average age of 45. Endometrial Ca is the second most common malignancy with a 20% cumulative incidence by age 70 Earlier age of onset than sporadic cases Other adenocarcinomas are common as well: ovary (3.5-8 fold), stomach, small bowel, pancreas, biliary tract. Other genetic mutations of interest in endometrial carcinoma are the mutations in mismatch repair genes- In these patients genetic instability leads to error-prone DNA replication. This leads to a cancer syndrome known as Lynch II which is characterized by the following: Early age of colon Ca with an average age of 45. Endometrial Ca is the second most common malignancy with a 20% cumulative incidence by age 70 Earlier age of onset than sporadic cases Other adenocarcinomas are common as well: ovary (3.5-8 fold), stomach, small bowel, pancreas, biliary tract.

23. Epidemiology CRC is the 3rd most common cancer in the US, and the 2nd most common cause of cancer death in the US. 10% of CRC is hereditary Lynch syndrome accounts for 2%-7% of all CRC cases. Women with Lynch syndrome have: 40-60% lifetime risk of developing colon cancer 40-60% lifetime risk for endometrial cancer 10-12% lifetime risk for ovarian cancer.

24. Diagnosis Lynch syndrome lacks overt phenotypic markers, therefore, accurate family history is crucial. If the clinical pattern of disease in the family is positive, molecular studies are performed to detect microsatellite instabilities and germline mutations (MSH2, MLH1, MSH6) that segregate in affected family members. MSH6 accounts for 10% of Lynch syndrome mutations and is associated with milder disease, but an excess of endometrial cancer. Patients must meet the Amsterdam criteria to be diagnosed, and the Bethesda criteria to undergo microsatellite testing

25. Amsterdam criteria and Bethesda criteria

27. Endometrial Simple Hyperlasia Here is Simple or Cystic Hyperplasia we see proliferation of glands and stroma. Glands vary in size, some are cystic. The epithelial cells are Active with stratification and mitosesHere is Simple or Cystic Hyperplasia we see proliferation of glands and stroma. Glands vary in size, some are cystic. The epithelial cells are Active with stratification and mitoses

28. Endometrial Hyperlasia - Complex With complex hyperplasia there are abnormally shaped glands, in- and out-pouching.With complex hyperplasia there are abnormally shaped glands, in- and out-pouching.

29. Endometrial Hyperplasia - Atypical With Atypical hyperplasia there is an increased gland density and one begins to see nuclear atypia - resembles well differentiated carcinoma.With Atypical hyperplasia there is an increased gland density and one begins to see nuclear atypia - resembles well differentiated carcinoma.

30. Endometrial Hyperplasia Classification and Risk of Progression to Cancer: It is atypia that is the defining feature of the premalignant endometrial lesion. This classic paper by Kurman looked retrospectively at 150 patients with who had an initial diagnosis of endometrial hyperplasia between the years 1940 and 1970. The patients were not treated and had follow-up biopsy for only for symptomatic bleeding. 96 of the patients had at least one additional biopsy. It is from this paper that we know of the 1, 3, 8 and 29% progression rate that everyone memorizes for the CREOGs and board exams. Kurman and his colleagues then pooled these patients into two groups: one with atypia and the other without atypia. They concluded that the group without atypia has no greater risk of developing uterine cancer over 13 years than would be expected from the 2-3% lifetime risk that all women have.It is atypia that is the defining feature of the premalignant endometrial lesion. This classic paper by Kurman looked retrospectively at 150 patients with who had an initial diagnosis of endometrial hyperplasia between the years 1940 and 1970. The patients were not treated and had follow-up biopsy for only for symptomatic bleeding. 96 of the patients had at least one additional biopsy. It is from this paper that we know of the 1, 3, 8 and 29% progression rate that everyone memorizes for the CREOGs and board exams. Kurman and his colleagues then pooled these patients into two groups: one with atypia and the other without atypia. They concluded that the group without atypia has no greater risk of developing uterine cancer over 13 years than would be expected from the 2-3% lifetime risk that all women have.

31. Treatment for Endometrial Hyperplasia without atypia: Medical therapy is generally recommended for patients with non-atypical hyperplasia Women of childbearing age are generally treated with progestin dominant combination OCPs (like Loestrin 1.5/30, Demulen 1/35 or Desogen). Alternatively Depo-Provera at the usual contraceptive dose or oral Provera at 10mg, 10 days per month may be used. Some patients may be diagnosed via biopsy obtained during an infertility work-up. These patients are best treated via ovulation induction after initial treatment with Provera and confirmation of a normalization of the biopsy. Treatment for peri or postmenapausal women is similar except slightly higher doses of progestins are used.Medical therapy is generally recommended for patients with non-atypical hyperplasia Women of childbearing age are generally treated with progestin dominant combination OCPs (like Loestrin 1.5/30, Demulen 1/35 or Desogen). Alternatively Depo-Provera at the usual contraceptive dose or oral Provera at 10mg, 10 days per month may be used. Some patients may be diagnosed via biopsy obtained during an infertility work-up. These patients are best treated via ovulation induction after initial treatment with Provera and confirmation of a normalization of the biopsy. Treatment for peri or postmenapausal women is similar except slightly higher doses of progestins are used.

32. For women in whom childbearing is no longer an issue, hysterectomy is the treatment of choice for atypical endometrial hyperplasia. The hysterectomy may be abdominal or vaginal, but the specimen should be examined at the time of surgery to rule out a coexistent endometrial carcinoma, which may occur as much as 20% of the time. For women in whom childbearing is no longer an issue, hysterectomy is the treatment of choice for atypical endometrial hyperplasia. The hysterectomy may be abdominal or vaginal, but the specimen should be examined at the time of surgery to rule out a coexistent endometrial carcinoma, which may occur as much as 20% of the time.

33. 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 D&C (possibly with hysteroscopy) should be performed prior to initiation of medical therapy to rule out carcinoma not picked up on office biopsy. The Progestin used has generally been of higher dose or potency than with non-atypical hyperplasiaD&C (possibly with hysteroscopy) should be performed prior to initiation of medical therapy to rule out carcinoma not picked up on office biopsy. The Progestin used has generally been of higher dose or potency than with non-atypical hyperplasia

34. 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 More than 95% of patients with Em cancer will report symptoms. Most commonly PMB, or in premenapausal women changes related to the quantity or duration of flow or to intermentrual bleeding. Endometrial biopsy is the main diagnostic tool either in the office or via D&C in the OR.More than 95% of patients with Em cancer will report symptoms. Most commonly PMB, or in premenapausal women changes related to the quantity or duration of flow or to intermentrual bleeding. Endometrial biopsy is the main diagnostic tool either in the office or via D&C in the OR.

35. Post menopausal bleeding Overall, 15% of the postmenapausal women who are biopsied for abnormal bleeding will be diagnosed with a malignancy. Other causes include hormone replacement induced bleeding, vaginal or uterine bleeding from atrophy, the benign condition of endometrial hyperplasia, or polyps or fibroid induced bleeding. Also included in the miscellaneous category are other genital tract lesions and malignancies (cervical, vafinal, vulvar, etc.)Overall, 15% of the postmenapausal women who are biopsied for abnormal bleeding will be diagnosed with a malignancy. Other causes include hormone replacement induced bleeding, vaginal or uterine bleeding from atrophy, the benign condition of endometrial hyperplasia, or polyps or fibroid induced bleeding. Also included in the miscellaneous category are other genital tract lesions and malignancies (cervical, vafinal, vulvar, etc.)

36. While the overall incidence of cancer is 15% in this population, this will vary greatly according to the age of the patient. Most of our patients with this complaint will fall in the 50-70 year old range and for them the chances of a cancer diagnosis will be in that 10-15% range. For our patients <50 we are still going to do a biopsy, but the chances are much less that their bleeding is from cancer and much more likely to be due to hormonal fluctuations of the perimenapause or a benign functional cause such as a polyp or fibroid. For the more elderly those >70 y/o the chances are obviously much greater that a cancer is presentWhile the overall incidence of cancer is 15% in this population, this will vary greatly according to the age of the patient. Most of our patients with this complaint will fall in the 50-70 year old range and for them the chances of a cancer diagnosis will be in that 10-15% range. For our patients <50 we are still going to do a biopsy, but the chances are much less that their bleeding is from cancer and much more likely to be due to hormonal fluctuations of the perimenapause or a benign functional cause such as a polyp or fibroid. For the more elderly those >70 y/o the chances are obviously much greater that a cancer is present

37. 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) What about other diagnostic tools and what about screening for endometrial ca. -Cervical cytology screening is not satisfactory as we will see and transvaginal sonography, hysteroscopy and uterine biopsy would clearly not be cost effective as screening tools, though they are useful for diagnostic purposes. What about other diagnostic tools and what about screening for endometrial ca. -Cervical cytology screening is not satisfactory as we will see and transvaginal sonography, hysteroscopy and uterine biopsy would clearly not be cost effective as screening tools, though they are useful for diagnostic purposes.

38. lets look at some u/s here is endovaginal u/s, clearly normal, with a stripe of 2-3 mm as we have said, up to 5mm can be considered normal in the postmenapausal women, and up to 8mm if she is on HRT in a menstruating woman the stripe will vary in thickness with the cycle and the u/s is not very useful unless it is performed early in the cycle just after the cessation of the menstrual flowlets look at some u/s here is endovaginal u/s, clearly normal, with a stripe of 2-3 mm as we have said, up to 5mm can be considered normal in the postmenapausal women, and up to 8mm if she is on HRT in a menstruating woman the stripe will vary in thickness with the cycle and the u/s is not very useful unless it is performed early in the cycle just after the cessation of the menstrual flow

39. a clearly thickened Em lininga clearly thickened Em lining

40. adding a small amount of fluid creates a sonohysterogram this can be useful to distinguish global thickening from a polyp or focal thickening one might use this information to decide wheter to plan a hysteroscopic procedure to target a polyp or focal abnormality or to just perform a simple office biopsy or D&C for a globally tickened Emadding a small amount of fluid creates a sonohysterogram this can be useful to distinguish global thickening from a polyp or focal thickening one might use this information to decide wheter to plan a hysteroscopic procedure to target a polyp or focal abnormality or to just perform a simple office biopsy or D&C for a globally tickened Em

41. Endometrial Cancer:Transvaginal Ultrasound Screening What about the use of U/S in patients who are symptomatic? -This table is from a paper that examined 250 postmenapausal women who all had bleeding and all were about to have a D&C. -What they found was that among the cases where endometrial pathology was discovered, including benign polyps, hyperplasia and cancer, none had Em stripe <5mm -This led these authors to claim that an u/s cutoff of 5mm was 100% sensitive as D&C for detecting uterine pathology and to propose that a biopsy was unecesary when the Em stripe was <5mm -while we do not advocate forgoing biopsy in postmenapausal women who present with bleeding based on an U/S result, the U/S may be reassuring in the common scenario when office pipelle biopsy is non-diagnostic or unfeasable. What about the use of U/S in patients who are symptomatic? -This table is from a paper that examined 250 postmenapausal women who all had bleeding and all were about to have a D&C. -What they found was that among the cases where endometrial pathology was discovered, including benign polyps, hyperplasia and cancer, none had Em stripe <5mm -This led these authors to claim that an u/s cutoff of 5mm was 100% sensitive as D&C for detecting uterine pathology and to propose that a biopsy was unecesary when the Em stripe was <5mm -while we do not advocate forgoing biopsy in postmenapausal women who present with bleeding based on an U/S result, the U/S may be reassuring in the common scenario when office pipelle biopsy is non-diagnostic or unfeasable.

42. Cytology � Not sensitive, nor specific Only 2-3% of Em Ca are diagnosed in asymptomatic women -Usually these cases are discovered either by investigation of Em cells on a pap, investigation of an abnl u/s or as an incidental finding at the time of hysterectomy for another indication Cervical cytology screening has extremely poor sensitivity for detecting Em Ca since <50 % of women with Em Ca have Em cells seen on a pap Even when Em cells are present they have PPV for Endometrial pathology of only 30% in postmenopasual women and < 10% in premenopausal women. Nevertheless, a finding of endometrial cells on a pap warrants further investigation.Only 2-3% of Em Ca are diagnosed in asymptomatic women -Usually these cases are discovered either by investigation of Em cells on a pap, investigation of an abnl u/s or as an incidental finding at the time of hysterectomy for another indication Cervical cytology screening has extremely poor sensitivity for detecting Em Ca since <50 % of women with Em Ca have Em cells seen on a pap Even when Em cells are present they have PPV for Endometrial pathology of only 30% in postmenopasual women and < 10% in premenopausal women. Nevertheless, a finding of endometrial cells on a pap warrants further investigation.

43. One last study to review, this one is a meta analysis of 6,000 all symptomatic women some on HRT, some not on HRT Again 5mm used as a cutoff And again the sensitivity is decent at a 5mm cutoff, but the specificity drops off with HRT use. The specifictiy refers to patients who are negative for disease and the test correctly identifies them as negative so what we see for HRT users with bleeding who have no pathology on biopsy, 23% will screen + via u/s One last study to review, this one is a meta analysis of 6,000 all symptomatic women some on HRT, some not on HRT Again 5mm used as a cutoff And again the sensitivity is decent at a 5mm cutoff, but the specificity drops off with HRT use. The specifictiy refers to patients who are negative for disease and the test correctly identifies them as negative so what we see for HRT users with bleeding who have no pathology on biopsy, 23% will screen + via u/s

44. Here we see a normal hysteroscopic view of the tubal ostia and surounding normal endometrial liningHere we see a normal hysteroscopic view of the tubal ostia and surounding normal endometrial lining

45. A polyp seen hysteroscopically If one removes this polyp with a polyp forceps or a currette, it's important to remember to put the scope back in, to ensure that the polyp has been removed entirely. Sometimes one needs to use the recection loop to get the stalk at its baseA polyp seen hysteroscopically If one removes this polyp with a polyp forceps or a currette, it's important to remember to put the scope back in, to ensure that the polyp has been removed entirely. Sometimes one needs to use the recection loop to get the stalk at its base

46. This has the appearance of something clearly abnormal, although microscopy is necessary to make the diagnosis. The large polyp was benign and the globally abnormal endometrium was atypical hyperplasiaThis has the appearance of something clearly abnormal, although microscopy is necessary to make the diagnosis. The large polyp was benign and the globally abnormal endometrium was atypical hyperplasia

47. Here is a small focus of hyperplasia that could easily have been overlooked or mistaken for a small submucous fibroidHere is a small focus of hyperplasia that could easily have been overlooked or mistaken for a small submucous fibroid

48. This red lesion was a small Grade 3 Endometrial cancer in a background of endometrial atrophy�.the classic Type II lesion This also could have been easily missed if the hysteroscopic view were not clearThis red lesion was a small Grade 3 Endometrial cancer in a background of endometrial atrophy�.the classic Type II lesion This also could have been easily missed if the hysteroscopic view were not clear

49. Hysteroscopy without biopsy- as a screening tool or for diagnosis of abnormal uterine bleeding- is not adequate. In a handful of studies the reported sensitivity and specificity vary widely Hysteroscopy may be useful in conjunction with other modalities.Hysteroscopy without biopsy- as a screening tool or for diagnosis of abnormal uterine bleeding- is not adequate. In a handful of studies the reported sensitivity and specificity vary widely Hysteroscopy may be useful in conjunction with other modalities.

50. 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 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 Patients with persistent PMB after negative office biopsy should have D&C ( D&C is the gold standard sampling method preoperative D&C will agree with diagnosis at hysterectomy 94% of the time 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 Patients with persistent PMB after negative office biopsy should have D&C ( D&C is the gold standard sampling method preoperative D&C will agree with diagnosis at hysterectomy 94% of the time

51. 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. Summary of hysteroscopy- Not for screening due to cost and potential operative risk It is a useful adjunctive procedure at the time of D&C to address or localize focal pathology It should probably be used sparingly in light of the fact that it may possibly contribute to extrauterine dissemination of disease- the consequences of which are uncertain.Summary of hysteroscopy- Not for screening due to cost and potential operative risk It is a useful adjunctive procedure at the time of D&C to address or localize focal pathology It should probably be used sparingly in light of the fact that it may possibly contribute to extrauterine dissemination of disease- the consequences of which are uncertain.

52. 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 In review: Who needs an endometrial biopsy? Any patient with Postmenopausal bleeding Perimenopausal intermenstrual bleeding Abnormal bleeding with history of anovulation Postmenopausal women with endometrial cells on Pap Thickened endometrial stripe via sonographyIn review: Who needs an endometrial biopsy? Any patient with Postmenopausal bleeding Perimenopausal intermenstrual bleeding Abnormal bleeding with history of anovulation Postmenopausal women with endometrial cells on Pap Thickened endometrial stripe via sonography

53. 20% of patients will have elevated Ca 125- a finding that correlates with greater surgical stage CXR to r/o pulm mets- especially common with sarcomas Both breast and colon cancer are more common in women with Em Ca and they are more common cancers in general than Em Ca, therefore women with Em Ca should be routinely screened for these diseases, preferably prior to surgical tx for Em Ca 20% of patients will have elevated Ca 125- a finding that correlates with greater surgical stage CXR to r/o pulm mets- especially common with sarcomas Both breast and colon cancer are more common in women with Em Ca and they are more common cancers in general than Em Ca, therefore women with Em Ca should be routinely screened for these diseases, preferably prior to surgical tx for Em Ca

54. Most oncologists advocate some imaging test to estimate the depth of invasion and to look for the presence or absence of extrauterine disease prior to surgery -The value of this preoperative information isn't totally clear -It may be useful in deciding on an approach- abdominal vs. vaginal approach, and possibly in deciding simple vs. radical hysterectomy -May be useful for the general gynecologist in deciding whether to refer to a gyn oncologist or just have someone on standby incase LN sampling is necessaryMost oncologists advocate some imaging test to estimate the depth of invasion and to look for the presence or absence of extrauterine disease prior to surgery -The value of this preoperative information isn't totally clear -It may be useful in deciding on an approach- abdominal vs. vaginal approach, and possibly in deciding simple vs. radical hysterectomy -May be useful for the general gynecologist in deciding whether to refer to a gyn oncologist or just have someone on standby incase LN sampling is necessary

55. Endometrial Carcinoma, Axial T2-weighted MRI section expansion of the endometrial cavity by a large carcinoma. A focus of deep myometrial invasion is also evident (arrow).Endometrial Carcinoma, Axial T2-weighted MRI section expansion of the endometrial cavity by a large carcinoma. A focus of deep myometrial invasion is also evident (arrow).

57. This summarizes the frequency with which each stage of endometrial cancer is encountered. Approximately 85% will be locally confined within the uterus and cervix leading to the overall good prognosis of this diseaseThis summarizes the frequency with which each stage of endometrial cancer is encountered. Approximately 85% will be locally confined within the uterus and cervix leading to the overall good prognosis of this disease

58. Surgical staging replaced clinical staging in 1989 and has since proved more reliable, more accurate for prognosis and more useful for defining the need for adjuvant therapy than clinical staging. This is primarily because surgical staging more accurately defines the extent of a patient�s disease with respect to metastases, depth of invasion, cervical involvement, etc.Surgical staging replaced clinical staging in 1989 and has since proved more reliable, more accurate for prognosis and more useful for defining the need for adjuvant therapy than clinical staging. This is primarily because surgical staging more accurately defines the extent of a patient�s disease with respect to metastases, depth of invasion, cervical involvement, etc.

59. 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 Uterine Cancer: Surgical Staging Clinical Stage I disease 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 or abdominal disease) Clinical Stage II or III will be upstaged 60% of the time at laparotomyClinical Stage I disease 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 or abdominal disease) Clinical Stage II or III will be upstaged 60% of the time at laparotomy

60. There is no contoversy that all Grade 3 regardless of depth of invasion and all deeply invasive tumors regardless of grade, require complete surgical stagingThere is no contoversy that all Grade 3 regardless of depth of invasion and all deeply invasive tumors regardless of grade, require complete surgical staging

61. Other surgical principles are as follows: If we are not certain preoperatively about the need for lymph node sampling we want to be sure to have frozen section available and a pathologist who can accurately evaluate the tumor for grade and depth of invasion as well to rule out as cervical involvement If extrauterine disease is present we should be prepared to resect itOther surgical principles are as follows: If we are not certain preoperatively about the need for lymph node sampling we want to be sure to have frozen section available and a pathologist who can accurately evaluate the tumor for grade and depth of invasion as well to rule out as cervical involvement If extrauterine disease is present we should be prepared to resect it

62. As I alluded to, there is some controversy over Grade 2 tumors and whether they always need LNS. Some oncologist have proposed that if the tumor is small (<2cm) & minimally invasive, then grade 2 tumors also can also avoid LNSAs I alluded to, there is some controversy over Grade 2 tumors and whether they always need LNS. Some oncologist have proposed that if the tumor is small (<2cm) & minimally invasive, then grade 2 tumors also can also avoid LNS

67. 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. A number of studies have looked at the feasibility of performing surgical treatment and staging via laparoscopy instead of via laparotomy. These studies have typically shown: 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. The GOG is currently undertaking a large multicenter prospective randomized trial to address these issues more rigorously. When completed the GOG trial will have recruited more than 2,500 patients and issues related to selection bias will have been reduced by the randomization process. A number of studies have looked at the feasibility of performing surgical treatment and staging via laparoscopy instead of via laparotomy. These studies have typically shown: 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. The GOG is currently undertaking a large multicenter prospective randomized trial to address these issues more rigorously. When completed the GOG trial will have recruited more than 2,500 patients and issues related to selection bias will have been reduced by the randomization process.

68. -While the grade of the tumor may be known in advance of surgery, the depth of invasion cannot be accurately known until the uterus is removed. -Because of the very low rate of lymph node metastases in patients with G1 tumors who have no or superficial myometrial invasion, LNS is not necessary and the risk from the procedure may outweigh the benefits -LNS is currently advocated by most oncologists in all other circumstances although some controversy exists with respect to small non invasive or minimally invasive G2 tumors-While the grade of the tumor may be known in advance of surgery, the depth of invasion cannot be accurately known until the uterus is removed. -Because of the very low rate of lymph node metastases in patients with G1 tumors who have no or superficial myometrial invasion, LNS is not necessary and the risk from the procedure may outweigh the benefits -LNS is currently advocated by most oncologists in all other circumstances although some controversy exists with respect to small non invasive or minimally invasive G2 tumors

69. While stage and grade are the most important prognostic factors, some of the other important factors are shown here -The most important being the aggressive histologic subtypes likely to metastasize early and often -Advanced age at diagnosis is correlated with the so called type II tumors which we spoke of earlier -additionally, many people are studying altered gene expression in these tumors in order to come up with a genetic pattern which predicts treatment failure, and to help tailor adjuvant treatment, a concept known as molecular stagingWhile stage and grade are the most important prognostic factors, some of the other important factors are shown here -The most important being the aggressive histologic subtypes likely to metastasize early and often -Advanced age at diagnosis is correlated with the so called type II tumors which we spoke of earlier -additionally, many people are studying altered gene expression in these tumors in order to come up with a genetic pattern which predicts treatment failure, and to help tailor adjuvant treatment, a concept known as molecular staging

70. Prognosis for endometrial cancer is generally good, owing to the early stage at presentation of most patients the overall 5 yr survival for all grades, stages and histologies is 84% Stage of disease is by far the most important predictor of survival, followed by grade.Prognosis for endometrial cancer is generally good, owing to the early stage at presentation of most patients the overall 5 yr survival for all grades, stages and histologies is 84% Stage of disease is by far the most important predictor of survival, followed by grade.

71. The mainstay of adjuvant therapy for Em ca is Radiation Radiation may be delivered as either vaginal brachytherapy or whole pelvic teletherapy or both may be given Hormonal therapy, principally with progestins, and cytotoxic chemotherapy are generally reserved for advanced disease or recurrent diseaseThe mainstay of adjuvant therapy for Em ca is Radiation Radiation may be delivered as either vaginal brachytherapy or whole pelvic teletherapy or both may be given Hormonal therapy, principally with progestins, and cytotoxic chemotherapy are generally reserved for advanced disease or recurrent disease

72. In order to determine who would benefit from adjuvant therapy, patients are stratified into risk for recurrence based on Gr, Stage and histology -Low Risk: Stage IA, Grade 1 or 2 and no LVSI -these patients require no further treatment after surgery -Intermediate Risk: Grade 1 with middle third myometrial invasion or LVSI or the Grade 2 with superficial myometrial invasion & no LVSI. No consensus exists for this group. Some advocate WPR, or brachy or no therapy. -High Risk: Any Grade 3, Any Stage IC or greater, Grade 2 with middle third or greater invasion or LVSI- these patients should get adjuvant RT with WPR 4,500-5000 cGy and/or vaginal brachy therapyIn order to determine who would benefit from adjuvant therapy, patients are stratified into risk for recurrence based on Gr, Stage and histology -Low Risk: Stage IA, Grade 1 or 2 and no LVSI -these patients require no further treatment after surgery -Intermediate Risk: Grade 1 with middle third myometrial invasion or LVSI or the Grade 2 with superficial myometrial invasion & no LVSI. No consensus exists for this group. Some advocate WPR, or brachy or no therapy. -High Risk: Any Grade 3, Any Stage IC or greater, Grade 2 with middle third or greater invasion or LVSI- these patients should get adjuvant RT with WPR 4,500-5000 cGy and/or vaginal brachy therapy

73. In patients who receive post operative pelvic radiation, most recurrences will be out of the pelvis- distant lymph nodes or in the lungs In patients who have not received radiation, pelvic and vaginal recurrences are much more likely, comprising more than half of the casesIn patients who receive post operative pelvic radiation, most recurrences will be out of the pelvis- distant lymph nodes or in the lungs In patients who have not received radiation, pelvic and vaginal recurrences are much more likely, comprising more than half of the cases

74. For those with widely metastatic disease chemotherapy is the mainstay of treatment Response rates vary for single agent therapy from 11 to 37% Response rates are better for multiple agents but toxicity is grater as well For those with widely metastatic disease chemotherapy is the mainstay of treatment Response rates vary for single agent therapy from 11 to 37% Response rates are better for multiple agents but toxicity is grater as well

75. -Most recurrences occur in the first 3 years after treatment -most patients are symptomatic (pain, wgt loss, vag bleeding) -recurrences at the vaginal cuff can often be salvaged with radiation or surgery -patients who recur with distant metastases are unlikely to be cured. They are best treated for palliation with chemotherapy.-Most recurrences occur in the first 3 years after treatment -most patients are symptomatic (pain, wgt loss, vag bleeding) -recurrences at the vaginal cuff can often be salvaged with radiation or surgery -patients who recur with distant metastases are unlikely to be cured. They are best treated for palliation with chemotherapy.

76. -There is no consensus among gynecologic oncologists as to what the optimal follow-up should be after completion of therapy - Periodic pelvic exam and pap are advocated. -Most gynecologic oncologists will examine these patients every 3-6 months for the first 2-5years after treatment then annually Following Ca-125 values may be useful in patients who had extrauterine disease and/or an elevated pre-operative Ca-125 level. -There is no consensus among gynecologic oncologists as to what the optimal follow-up should be after completion of therapy - Periodic pelvic exam and pap are advocated. -Most gynecologic oncologists will examine these patients every 3-6 months for the first 2-5years after treatment then annually Following Ca-125 values may be useful in patients who had extrauterine disease and/or an elevated pre-operative Ca-125 level.