En Dome Trial Carcinoma

Changing Concepts in Endometrial Carcinoma David Stanford, M.D.

1

I.

Epidemiology and Risk A.

Incidence: 1996 American Cancer Society projections 1.

Most common gynecologic cancer (after breast)

2.

New cancers in women, all sites (1996)

3.

a.

First: breast (184,000)

b.

Second: lung (78,000)

c.

Third: colorectal (66,000)

d.

Fourth: endometrial 04,000)

Cancer deaths a.

Gynecologic (1) First: breast (44,300) (2) Second: ovary (14,800) (3) Third: endometrium (6,000) (4) Fourth: cervix (4,900)

b.

All sites (1) First: lung (64,300) (2) Second: breast (44,300) (3) Third: colorectal (27,000) (4) Eighth: endometrium (6,000)

B.

Distribution by International Federation of Gynecology and Obstetrics (FIGO) Stage 1.

Stage I: 75%

2.

Stage II: 15%

3.

Stage III: 7%

4.

Stage IV: 3%

C. Estimate of risk 1.

Geographic: the white population in the United States has the highest age-adjusted incidence in the world

2.

3.

4.

Race: United States a.

White peak: 87% in 100,000 at 65-70 years

b.

Black peak: 78 % in 100,000 at 75-80 years

Age a.

Postmenopausal: 75-80%

b.

Mean age at diagnosis: 61 years

c.

<5 % below age 40

Obesity a.

From 20-50 lbs overweight: 3X

b.

Over 50 lbs overweight: 9X

5.

Diabetes: up to 3X increased risk

6.

Hypertension

7.

Parity a.

One-third nulliparous

b.

Risk decreases with increased parity

8.

Menopause, ie, after age 52: 2.5 X

9.

Unopposed estrogen

It is the most common female pelvic malignancy after breast cancer. In 1996 and 1997, we expect about 34,000 cases in the United States, which is the fourth most common malignant site in women. If we look at cancer to related death, we expect about 6,000 deaths, which is the third most frequent gynecologic cause of cancer related death. If we look at cancer related in women at all sites endometrial cancer rates are about 8. It is very prevalent but not terribly lethal for most women. Distribution by stage. About 75% of women will present as stage 1, and this is the reason that the long-term survivals are pretty good and only a small fraction, roughly 1/7 to 1/8 of woman end up dying from the disease. About 15% are stage 2. About 7% are stage 3 and about 3-5% is stage 4. The biggest risk factor is prolonged periods of unopposed estrogen or estrogen predominant states in women. We do know that women from industrialized nations from Northern Europe and the United States do have higher incidences of endometrial cancer. Caucasians in the United States peak at their highest incidence about age 65-70 years of age; however, in black women you don’t see that peak incidence until about 75-80 years of age. It also is interesting that Caucasian women usually have a less virulent tumor; however, they do have more cases of endometrial cancer at a younger age. When black women get endometrial cancer they are usually older, and the histologic subtype is oftentimes much more aggressive. Clearly as you increase your age, you increase your risk of endometrial cancer. The same thing with obesity because long periods of unopposed estrogen, high level of estrone from the peripheral conversion of androstenendione to estradiol. Other risk factor is diabetes and hypertension. These are probably related to the obesity factor. 1/3 of women who have endometrial cancer are an nulliparous. The higher the purity the lower the risk. Other risk factors are late menopause, early menarche, and on periods of unopposed estrogen. The epidemiology of adenocarcinomas of endometrial is that the risk is predominantly and driven by excess of estrogen over progesterone. Now some of the more rare histology subtypes like clear cell cancer, papillary serous, probably is not estrogen driven but is much more biologically driven with alternations in molecular biology like many of the other cancers that we see. Endometrial carcinoma precursors. There is three different subgroups. You have simple hyperplasia, which is synonymous with cystic hyperplasia. The risk of malignant potential or malignant transformation is very low. Complex hyperplasia is also synonymous with adenomyohyperplasia without atypia. The risk there is about 2% of either harboring a malignancy or developing a malignancy within one year following that diagnosis. The risk is extremely low. Atypical hyperplasia or adenomyohyperplasia with atypia carries anywhere from a 15-25% risk. We do know that unopposed high-dose noncyclic estrogen does increase the incidence of hyperplasia. If these are driven by estrogen predominance they can also be reversed by decreasing the ratio of estrogen of progesterone and by overcoming the estrogen predominance with either oral or intra-muscular projective agents. The pathogenesis of endometrial carcinoma is basically involving two theories. The first one is a continuing theory where it is felt, and this is probably true for most of the very low-grade tumors that are predominantly estrogen driven, that they proceed along a continuum from a morphologic spectrum from focal coangular crowding through anaplasia. They develop hyperplasia, develop some atypia and then develop into a cancer. More commonly however, especially for the aggressive histologic subtypes, is the neoplasia theory, which is driven by molecular biologic alterations in the balance between suppressor genes and aqua genes and an imbalance between the accelerator and the breaks, of the molecular genetic material and the cellular division. Screening programs and diagnostic methods. It is very difficult and very non-cost productive to screen the entire population for endometrial cancer. A very small percentage of your screening population will have endometrial cancer at any given time. Only 10% of patients with heavy postmenopausal bleeding will end up having an endometrial cancer. However, 90% of patients diagnosed as having endometrial cancer present with abnormal bleeding. Be aware that they can’t present in other ways, such as hypermenorrhea or polymenorrhea, cramping or with sequella, or symptoms with advanced disease. If you look at sampling of symptomatic patients, office sampling when appropriate, and if you can enter the endometrial cavity and in about 3-5% of patients you can’t because of cervical stenosis, once you have a positive result it clearly and obviously is histologically as accurate as whether or not to proceed with the DNC. Once you have a positive result there is really no point in going any further. Make sure the cervix is fine, that there is no obvious cervical lesions, do a Pap smear, so an endometrial biopsy if possible. If that is positive, then perform, proceed on with a definitive therapy with a hysterectomy. If it is negative, then all those patients, I D and C because they are negative for one or two reasons. Either they are truly negative, or we missed the lesion. I think especially with the medical legal concerns and the fact that office biopsies are 90-95% accurate that is a relatively safe way to do it. I schedule the patients for the DNC the following week. When the biopsy

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a.

Teen: anovulatory cycles

b.

Polycystic ovary: 25% of endometrial cancer in women under 40

c.

Functional ovarian tumors, eg, granulosa, thecoma (1) 10% will have endometrial cancer (2) 40% precursors

d.

Unopposed estrogen replacement (1) Conclusion: unopposed, high-dose, noncyclic estrogen increases the incidence of hyperplasia (2) Opposed estrogen replacement therapy (ERT) lends a protective effect against endometrial cancer

III. Endometrial Carcinoma Precursors A.

B.

Nomenclature, histology, and malignant potential 1.

Simple hyperplasia

2.

Complex hyperplasia (AH without atypia): 2%

3.

Atypical hyperplasia (AH with atypia): 25%

Pathogenesis of endometrial carcinomas 1.

Continuum theory a.

Morphologic spectrum: focal glandular crowding through anaplasia

b. 2.

Coexistence of hyperplasia and carcinoma

Neoplasia theory a.

Progression is tied to cellular biology, ie genetic material

b.

Cytologic (nuclear) atypia distinguished by (1) Pleomorphic macronuclei (2) Aneuploid DNA content (3) Distinguishable even in simple hyperplasia

IV. Diagnostic Methods A.

Population 1.

10% of patients with peri- or postmenopausal genital bleeding will have endometrial carcinoma

2.

90% of patients diagnosed as having endometrial carcinoma present with abnormal bleeding

B.

Evaluation of symptomatic (bleeding) patients 1.

Office sampling when appropriate: histologically accurate as dilation and curettage (D&C)

2.

Fractional D&C: 95% accurate

3.

Hysteroscopy: may be of benefit only if diagnosis of cancer is unclear

4.

Transvaginal ultrasonography-sensitivity of 93 % was obtained for patients with myometrial invasion >50%. May allow preoperative knowledge of invasion and allow

comes back being negative then we get all the blood work and normally we will have chest x-rays and EKGs just because of anesthesia requirements, and we will proceed on with the DNC. If it is positive then we cancel the DNC and proceed on with definitive therapy. Fractional D and Cs about 95-98% accurate. Transvaginal ultrasonography has been used extensively. It has also been used not only for diagnostics but also to plan therapeutics. It has a sensitivity of about 93% for deep penetration. The symptoms of endometrial cancer, are abnormal vaginal bleeding, usually postmenopausal, can be intermenstrual usually it is prolonged and heavy, but you also have to think about endometrial cancer whenever you see hematuria or a purulent vaginal discharge. The initial evaluation good history and physical, pap smears. If there is any question that the cervix may be involved do an endocervical scrap, endometrial biopsy in the office and then routine blood work. This can all be done on the same day because you are either going to a hysterectomy or a DNC depending on the results. Treatment is basically broken down into four different categories. Surgery is the main stay. Radiation for the majority of patients will be given based on the operative findings and the operative staging. There is a very small subset of patients who are candidates for preoperative radiation, and we will talk about those in a few minutes. Hormonal therapy basically is high-dose progesterones either with intra-muscular Depo-Provera or oral Megace. Chemotherapy is individualized and utilized for stage 3 and stage 4 disease. Endocervical curettage has a very high false-positive rate of roughly 50%. It also has a very high false-negative rate of roughly 35-30%. External radiation therapy does have some side effects. By using preoperative radiation you are delaying surgery, you increase the total treatment time, increase the cost for a significant percentage of patients, and you also increase the potential complications because doing hysterectomy following whole pelvic radiation also has inherent risks with fistulization between the bladder and the rectum. The staging system was changed, and it was adopted in 1988. It looked at several of the other risk factors that were much better defined by the GOG study. A lot of different prognostic factors were incorporated into the staging system. For stage 1 disease, it is clear that if the tumor is confined to the uterus, the risk node involvement and risk of microscopic extra uterine disease is based on how deeply the myometrium is penetrated. Stage 1 was broken into stage 1 A, B, and C with no invasion inner-half and outer-half. Stage 2A was broken down into microscopic involvement of the endocervical glands and 2B was involving the cervical stroma so that is you looked in the vagina you would see an abnormality on the ectocervix. Stage 3 disease is with regional spread. 3A is to the uterine serosa or if you have positive cytology. 3B is if you have vaginal metastases, and 3C is if you have pelvic or periaortic lymph node involvement. Stage 4A is bladder or bowel mucosa, and 4B if you have distant involvement, including the momentum, the diaphragm, abdominal spread or if you have positive inguinal lymph nodes. All stages should have their grade differentiated and reported when staging.

It has never been proven yet that doing the lymph nodes really offers any benefit to the patients. It has never been proven in any study that whole pelvic radiation actually improves survival. It will improve local control. It does improve patient’s quality of life. Most gynecologists will have a differing approach, and they will balance the risk to the patient against the histologic subtype, the grade of the tumor and then oftentimes do an analysis or call pathologist to the operating room and cut the uterus and then make some decisions. The same thing with the precursors. It has been felt and written about, and this has really been based on Kermen’s study from almost 30 years ago on how to manage the hyperplasia, especially the atypical adenoma hyperplasia. Most of these hyperplastic lesions can be reversed with progestin. If the patients are young, and they are teenagers, and they have polycystic syndrome, then progestins clearly will help, but they probably need to get in a regimen of weight loss. They probably need to be seen by the endocrinologist and be evaluated. If they are of childbearing age and want to preserve that potential then clearly progestins are needed. If they want to preserve the uterus use continuous progestins. Depending on their age, it is fine for postmenopausal women to be put on opposed estrogen therapy as well. If there is any concern, proceed with a vaginal hysterectomy in a perimenopausal or postmenopausal woman, especially the group that has hyperplasia with atypia. Perform a DNC to rule out cancer. If there is cancer, you stage in 3. If it is simple then progestin therapy. If complex or atypical, hysterectomy or progestins are okay. For endometrial adenoma carcinomas, perform an appropriate preoperative evaluation. Evaluate their other medical risks and proceed with a laparotomy for most circumstances. Then hysterectomy, THBSO is the standard of care for endometrial cancer. You also should obtain washings, perform a hysterectomy and evaluate the diaphragm. I like to get washings from the right diaphragm, right and left paracolic spaces and also

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gynecologist an opportunity to select when patients may gain from referral to gyn/oncologist (Prompeler, 1994) V.

FIGO Staging A.

Surgical staging, FIGO: 1988 1.

2.

3.

4.

Stage II: corpus a.

Endometrium

b.

Inner half of the myometrium

c.

Outer half of the myometrium

Stage n: endocervix a.

Endocervical glands

b.

Stroma

Stage III: regional spread a.

Uterine serosa, adnexa, positive cytology

b.

Vaginal metastasis

c.

Pelvic and/or aortic nodes

Stage IV: advanced pelvic/distant a.

Bladder/bowel mucosa

b.

Distant, abnormal spread, inguinal nodes

5. All stages: G1, G2, G3 VI. Treatment Approach A.

Primary surgical guidelines 1.

Appropriate preoperative evaluation

2.

Surgery per FIGO, 1988 a.

Peritoneal washings

b.

Total abdominal hysterectomy, bilateral salpingooophorectomy

c.

Pelvic, aortic lymph node biopsies

d.

Papillary serous histology: dictates ovarian-like operation (1) Peritoneal biopsies (2) Omentum (3) Appendectomy (4) Debulking

3.

Lymph node discussion (in order) a.

FIGO (1988) obligates pelvic/aortic nodes

b.

Pelvic lymph nodes controversy (1) Selective vs all vs none (2) Others treat on known prognostic factors (a) Histologic grade (b) Myometrial invasion (c) Eliminates pelvic node surgical morbidity (d) 37% pelvic node metastasis #2 mm (Girardi 1993)

c.

Aortic nodes: fewer, positive aortic nodes survival

the pelvis, but the right and left paracolic spaces is probably adequate. Pelvic and paraaortic lymph node biopsy, Fegal would say that all patients should have biopsies performed. A papillary serous histology. Will oftentimes spread and act like an ovarian carcinoma. Stage it similar to ovarian carcinoma getting multiple peritoneal biopsies, performing an infracolic lymphadenectomy. Always examine the appendix especially if you get a frozen section or any mention of mucinous histology to make sure the appendix is fine. If there is any question, remove the appendix. Regarding pelvic lymph node controversy, it has been written and argued in SGO and among several of the senior people within the gynecologic-oncologic community selective lymph nodes is what should be done. If there is no proven benefit in removing the lymph nodes, then a biopsy is all that is warranted. 5 to 9 lymph nodes will be removed from each side of the pelvis and about 3 to 5 from the periodic area. One of the problems that have been proven is that about 37-40% of normal metastases is less than equal to 2 mm. If a selective lymph node biopsy is performed, and the majority are at least a large percentage of the metastatic deposits are very small, the likelihood of picking those up is also very small. This is one of the major arguments for removing all of the lymph nodes. If we look at periaortic lymph nodes, and we look at survival for those patients who have positive nodes, fewer are reported several years ago on 46 patients. The five year survival with radiation extended field whole pelvis plus periaortic nodal area included up to L1. If they were microscopically involved, a five year survival of 67%. If they were grossly involved, the survival fell to 17%. Having big nodes in the periaortic area is not good. There has been several other studies published, and it is the standard answer for what is the survival of five years for positive periaortic nodes. It is around 35-40%. There have been several other papers that have published, trying to combine laparoscopic evaluation of lymph nodes with either a laparoscopic hysterectomy or the laparoscopically assisted vaginal hysterectomy. He reported on 59 patients all that had clinical stage 1 disease. The mean age was 69. The mean weight was 153, which I can’t remember the last patient I saw who weighed 163 or less, at least in our population. 29 patients had lymph node biopsies. He reported it has lymphadenectomy, but it would be hard for believe that he was able to accomplish a complete lymphadenectomy with a laparoscope based on grade and depth of invasion similar to the protocol I just discussed with you. The mean length of stay was 2.9 days. 2 patients require a laparotomy. One had a transected uterus, and one had a cystotomy. These were his initial 59 patients, and his learning curve has became much better since then, and it can be pretty safely done. Mean weight was 153. His next group of patients was both patients who had endometrial and ovarian cancer. They were either doing primary surgery or second, and the majority of the ovarian cancer patients for laparoscopic seconds. He combined the 29 patients from the endometrial, and he added those to his second ovarian patients that had 61 women, 57 of those node sample, 4 had failure because of obesity or adhesions and one had a laparotomy to control bleeding of the vena cava. They all weighed less than 184 pounds with a mean weight of 137. There was an average of 3 periotic lymph nodes removed. It can be done. We have only done it a couple of times in our population because we don’t have patients that we feel we can do it safely who are about 140 and 185 pounds. It is very difficult an adequate evaluation, I think, in patients who are heavy and that is just the majority of patients that we see. If we look at histologic prognostic factors, the greatest predictor of survival when the tumor was confined to the uterus was the grade of the tumor, the depth of myometrial invasion being the outer third, and the presence of cervical stroma invasion. Those are the things that we look for which are high grade tumors, deep invasion, or if they have cervical stroma involvement, do poorly. If they have any evidence of gross cervical involvement or adnexal involvement they also do poorly. Histologic subtypes, papillary serous, clear cell, the adenosquamous types were much more aggressive, and they need to be treated much more aggressively. Nonsurgical prognostic factors, cervical cytology, if the pap smear was positive, then the patients were much more likely to have nonendometrial histologic subtypes, higher grades and a higher stage of tumor. They also had a higher incidence of nodal involvement. This is very interesting data in hormone receptors, and it is oftentimes used and published in the manuscripts that are written about endometrial cancer. It seems fairly clear that patients who have high progesterone receptor positively do better. It is a much more treatable and less aggressive histologic subtype when the progesterone receptors are positive. The problem is even if they are negative, anywhere from 15-20% of patients will respond to high do progestin even if their receptors are negative. It is interesting data to collect. I think it drives the cost up, and it is information they really don’t know what to do with once we get it. CA 125 levels are also very helpful for advanced stage patients because they can predict recurrent disease, and they can also predict extra uterine disease and spread.

(1) 46 patients

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(2) 5 year survival with radiation therapy (RT) (a) Microscopic: 67% (b) Macroscopic: 17% d.

Recommended approach (1) Open corpus at operating room table (2) Frozen section (a) Histology (b) Grade (c) Invasion (3) If high risk, do aortic nodes only

C. Histologic prognostic factors 1.

GOG Protocol No. 33: greatest predictor of survival when tumor confined to uterus is Grade 3 tumor, myometrial invasion outer one-third, presence of cervical stromal invasion

2.

Histologic

subtypes--papillary

serous,

clear

cell,

adenosquamous more aggressive types D. Nonsurgical prognostic factors 1.

Cervical cytology--if positive then patient is more likely to have nonendometrioid histology, higher grade of tumor, higher stage, positive nodal spread

2.

Hormone receptor (Vecek, 1994)- PR > 25 fmol/mg was powerful predictor of survival, ER levels did not correlate

3.

CA 125 levels--if elevated is an important marker for recurrent disease, especially those with papillary serous histology (Scambia, 1994)

E.

Management guidelines (Creasman, 1994)

Table 1 Management Guidelines Anticipated Frequency of Positive Pelvic Lymph Patient Subset

Nodes (%)

Surgery

Comment

Low risk--Stage

3

Total abdominal or laparoseopic-

Grade 1 with deep

assisted hysterectomy, bilateral

has 10% positive pelvic

invasion IA-B, grade 1 node (30%)

salpimgo-oophorectomy

rate

Total abdominal or laparoscopic-

Grades 2 and 3--indication

Stage IB, grades

assisted hysterectomy; bilateral

for selective pelvic or

2 and 3 (50%)

salpingo-oophorectomy; selective

periaortic node dissection

Moderate risk--

9

pelvic or periaortic node dissection High risk--Stage IC, grades 1,2 or

18

Total abdominal or laparoscopic-

Deep myoinvasion--

assisted hysterectomy; bilateral

indication for selective

salpingo-oophorectomy;

selective

pelvic 3 (20%)

pelvic or

periaortic or periaortic node dissection

node dissection

How do we manage patients? Basically we do the surgery and then once we get the pathology report back, we categorize patients into three groups. The three groups are low-risk, intermediate-risk and high-risk. The low-risk patients it is pretty well understood and felt that they have an excellent prognosis, and there is no further treatment that is warranted. These are basically patients with grade 1 lesions with less than one-third and oftentimes it will be written less than even one-half of the myometrial muscle thickness if negative cytology and have the variety histologic subtype. The intermediate risks are your grade 2 lesions or your grade 1 lesions with outer half myometrial invasion with negative cytology and the grade variety. You have the grade 1 and grade 2 with middle third or outer third involvement. Grade 1 with cervical or isthmic invasion, negative cytology, no lymphovascular space involvement, and no evidence of any metastatic treatment. These patients we pretty much treat with postoperative vaginal brachytherapy with high-dose rate implants. You’re high-risk patients we recommend radiation therapy, whole pelvic radiation, which has a complication risk of about 3.5-5.5%. If you have grade 1 lesions with outer third or almost to the serosa, grade 2 or 3 lesions that have low utero segment involvement and vascular space involvement, or greater than 50% invasion, grade 2 is greater than 50% or grade 3 of any invasion would be considered high-risk. If they have vascular space involvement or have the more aggressive histologic subtypes then they ought to be all treated as well with postoperative radiation. Other high-risk features are positive paraaortic nodes or grossly involved pelvic nodes. In those patients, we would treat with whole pelvic radiation with an extended field boost of the periotic area, which generally is extended up to the T12-L1 interface. For stage 2 endometrial cancers, most of those patients would be treated, especially if they have gross cervical involvement with preoperative radiation to the whole pelvis, and then this is followed by an extra fascial hysterectomy. For stage 3 and 4, it really needs to be individualized, and oftentimes it incorporates using many of the different modalities that we have available, and we either incorporate with radiation with hormones or radiation with chemotherapy. There are several protocols currently activated within the GOG and with the Southwest oncology group looking at the value if intraperitoneal P32, whole abdomen radiation versus different chemotherapy regimens using platinum and adriamycin cis-platinum. For most of the patients with stage 3 and 4 disease, we try to enter them on a protocol because we just don’t know which of the modalities is better, if any of them are better. For positive cytology, there has been a tremendous argument about if everything else is negative, but you have positive washings, is this significant prognostic piece to the puzzle. For stage 1 disease about 10-30% of patients will have positive cytologic washings. Basically it is felt that there is two different ways you get positive washings. One is if the cells just break loose and speak out and fall out of the end of the fallopian tube and don’t really implant, that patient is at very low-risk for that being a potential future problem. However, if the patient has an anaplastic aggressive tumor, and the cells have escaped, usually there will be other risk factors that will be present. There is a independent variable the positive cytology as it stands by itself is not really is what it is going to drive the future status of the disease, but it is the other risk factors, such as the high-grade, very aggressive subtypes, or the extent of the disease. It has not been proven as a statistically independent risk factor for recurrence, cytology alone. The new surgical staging will virtually eliminate the decisions to adjuvant treatment based on positive cytology alone. Most patients will have other high-risk factors if they have positive cytology. However, it still becomes difficult if you have a patient who has a grade 3 tumor with less than 50% invasion, 40% invasion, who has positive cytology. There are several GOG protocols or a couple of GOG protocols looking at that trying to answer that question, and it is basically a whole adjuvant radiation protocol versus chemotherapy. Hopefully this will help to answer that question. Malignant tumors, peritoneal fluid and extra pelvic metastases affect survival in stage 3 and 4 disease. If either factor is present, the two-year survival is 25%. If it absent, it is 82%. If you look at survival of stage 1 disease all grades and all substrates, it is about 76%. For stage 2 is it about 60%. Stage 3 is 30% and stage 4 is around 10%. Estrogen replacement therapy and endometrial cancer is big huge area of debate. There are several protocols that have just been started. They are only being done in a couple of institutions. Many of the decisions that we have made about hormone replacement therapy have been driven by the medical legal community and the medical legal risk. If you have 75% of patients are cured at five years, we are denying basically 75% of women those that are cured of the beneficial effects of hormone replacement not only in their general well being but as far as osteoporosis and cardiovascular disease prevention is concerned. They have theorized that for the majority of patients with endometrial cancer, at least those that have low-grade tumors with minimal invasion, that these patients ought to be entered under a protocol to find out if they in fact will benefit from hormone replacement therapy. I think it is a little bit dangerous at this time to be getting too aggressive with offering to most patients. I think it is something that should be documented in our charts that we discussed it. What I am currently doing is for patients is I discuss with them and give them some literature about the pros and the cons, especially the benefits of hormone replacement. If the patient is kind of in a

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VII. Postoperative Consideration for Adjunctive Therapy A.

Stage I 1.

2.

Low risk, good prognosis: no further treatment a.

Grade 1: < one-third myometrial invasion

b.

Negative cytology

c.

Adenocarcinoma

d.

Adenocanthoma

High risk: RT (whole pelvic RT severe complication. risk is 5.5 %) a.

Grade 1: > one-third myometrial invasion

b.

Grade 2, 3

c.

Lower uterine segment involvement

d.

Vascular space involvement

e.

Adenosquamous

f.

Clear cell

g.

Papillary

serous:

chemotherapy

vs radiation

(Mallipeddi 1993) B.

Stage II:RT

C. Stage III: IV 1.

Individualized

2.

Multimodal

3.

Protocol

D. Positive cytology (McLellan 1989; Kadar 1994) 1.

Stage I: 10-30%

2.

Inconsistent findings

3.

Probably at increased risk for recurrent disease

4.

Not proven as a statistically-independent risk factor for recurrence

5.

New surgical staging will virtually eliminate the decision of adjuvant treatment based on positive cytology alone

6.

Malignant cells in peritoneal fluid and extra pelvic metastases affect survival in Stage III and IV disease. If either factor was present, 2-year survival was 25 %; if absent, it was 82 %

VIII. Uterine Sarcoma A.

Lethal

B.

50% of Stage I recur; 90% of Stages II-IV

C. Histogenic classification

Table 2

Homologous: Native

Heterologous: Foreign

Pure (1 cell type) Endometrial stroma sarcoma (ESS)

Rhabdomyosarcoma

intermediate risk area, I will ask them to hold off for a short period of time usually anywhere from 18 to 24 months because about 90% of recurrences will occur within that time period. For patient who have very low volume disease, low grade and low stage disease, I think it is acceptable, and there are a few patients who I have had who have suffered horribly from abrupt estrogen withdrawal from surgery that we have gone ahead and started them on hormone replacement. This basically is a survey that was undertaken in Society of gynecologist and oncologist, and it is basically this addressing this concern and this issue. 83% of gynecologist and oncologists favor hormonal replacement in stage 1 grade 1 disease; however, it drooped to 56% in stage 1 grade 2 disease, and 40% in stage 1 grade 3 disease. It is strictly an emotional response not based on any literature, and in fact you can argue that the patients who are at most risk to have hormone sensitive tumors are the grade 1 because of the higher estrogen-progesterone receptor positivity. If anybody based on the stimulation of growth theory, you would want to hold off hormone replacement in your low-grade lesions because the number of grade 3 tumors that have estrogen receptor positivity is very small. You can see the general attitudes. It is felt that for some patients that it is acceptable. It is the same medications as other women. You have to individualize the assessment based on risk and benefit, prognostic indicators, and the acceptance of risks by the patient. It really wasn’t because I was afraid the patient was going to sue me, but if she ended up getting a recurrence it was really a protection against the survivors, her sons, her daughters, and her husband. We wanted some documentation that we had discussed the issue at length, and this was really the patient’s choice. I stopped doing that, and I don’t really know why. I guess I felt that it was a little bit overdone. Hopefully we will get that data in a trial and be able to have much more scientific faces for either doing it or not doing it. Let’s switch really quickly to uterine sarcomas. They are pretty rare tumors. They are about 3% of the uterine malignancies that we see. Treatment protocols have generally not been terribly standardized because of the rarity and the limited number of events that any one institution or any one individual has had throughout their career. Basically if there is one issue or one thing I could get across to you today is that the treatment is surgical and once these sarcomas have escaped outside the uterus the prognosis is poor. Surgical staging is the most important prognostic variable. We pretty much try to stage them similarly to endometrial cancers; however, there really is no formal staging system that has been universally adopted. For stage 1 tumors for example, confined to the uterus, the five-year survival is about 50%. For stage 2-4 the five-year survival is about 20%. There is no known predisposing risk factors except possible prior pelvic radiation therapy. The ones that follow prior pelvic radiation are typically leiomyosarcomas. The prediction of biologic behavior is based on the number of mitosis per 10 HPF, and the mesodermal derivatives predominate and that is how they are classified. The mesodermal derivatives of a uterus include the uterine smooth muscle, endometrial stroma, the blood vessels, and the lymphatic vessels. They are broken down into basically two types, the pure uterine sarcomas and the only malignant elements that are present are those that are typically found within the uterus. The mixed tumors are malignant mesodermal components as well as a malignant epithelial component such as a carcinoma sarcoma. They have both, epithelial cancer and sarcoma elements present. Then you have homologous or native tumors and heterologous, foreign or non-native tumors, and then you have pure and mixed. You have homologous tumors, which are leiomyosarcomas, stroma sarcomas, and endolymphatic stromal myosis or endometrial stroma sarcomas. These are pure sarcomas with no epithelial components and homologous because they contain elements that are present in the uterus. Mixed homologous tumors are a carcinoma sarcoma. The heterologous tumors, pure, are the Rhabdomyosarcoma, chondrosarcomas, osteosarcomas or liposarcomas. The heterologous mixed sarcomas are the mixed mesodermal sarcoma. Those are the ones where you can see a malignant epithelial component plus oftentimes a combination of mixed sarcoma elements where you can see rhabdomyosarcoma combined with chondrosarcoma and also an epithelial component. Endometrial stroma sarcomas can be broken down into three different histologic subtypes or grades. Benign stroma nodule is treated primarily with surgical removal. If low grades stroma sarcoma, which have less than mitosis per 10 HPF, primarily surgical excision and hysterectomy again treat these. Highgrade endometrial sarcomas are also treated with surgical excision, but if you are concerned or worried about recurrence, high-dose progestins oftentimes will suppress these tumors as well. Endometrial stroma sarcoma is about 15-25% of the uterine sarcomas. Most patients are perimenopausal, so 50% will be premenopausal and 50% are postmenopausal. They’ll present with abnormal bleeding as the most common symptom, and the primary treatment is surgical resection. It is important to remove the ovaries and the indigenous source of sturgeon in the low grades. In the high grades you also can use an anti-estrogen or a high dose progestin in your therapeutics.

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Leiomyosarcoma (LMS)

Chondrosarcoma Osteosarcoma

Mixed Carcinoma (CS)

Mixed

mesodermal sarcoma

(MMS)

D. ESS 1.

Benign stromal nodule: nodule of pure, neoplastic

MMNT’s usually are older patients. The majority is postmenopausal, and I would say the majority is over the age of 70. They grow rapidly. Symptoms include postmenopausal bleeding, necrotic foul smelling discharge, pain, often times with palpable mass, which oftentimes will be the omentum replaced by tumor and also parametria. The treatment is surgery with complete excision is the only modality with proven long-term curative value. Surgical staging offers prognostic information with no evidence that improve survival. There is no evidence to adjuvant chemotherapy with any long-term benefit. You can’t see some short-term responses to cis-platinum, adriamycin, and ifosfamide either signally or in combination as shown some promise with short-term responses. You do see partial responses in the range of 33-73% and probably the mean durational response is somewhere around 9 months to a year.

endometrial stroma 2.

3.

E.

Endolymphatic stromal myosis a.

Indolent, infiltrating stromal sarcoma

b.

<5-10 M/10 HPF

c.

Surgical disease

ESS a.

Aggressive, infiltrating stroma sarcoma

b.

>10 M/10 HPF

Leiomyosarcomas must distinguish from a cellular myoma. Most patients are in the 45 to 55 age ranges. 30% of uterine sarcomas will be leiomyosarcomas. They usually arise from smooth muscle; rapid enlargement of the uterus or of a single fibroid is a possible sign of malignancy. Symptoms will include pain, pelvic pressure, abnormal uterine bleeding and a lower abdominal mass, which oftentimes is rapidly growing. Pap smears are not terribly sensitive or are endometrial biopsies. Uterine curetting will only detect about 10-20% of tumors. Diagnosis is really made preop. Leiomyomatosis peritonealis disseminata is numerous nodules of histologically benign smooth muscle on the peritoneal surfaces. It is really not known why this happens, and it is often associated with there term pregnancy or the use of oral contraception and when you stop the oral contraceptives or the pregnancy is terminated, they oftentimes involute and become asymptomatic.

What is the role of radiation therapy? For patients with carcinoma sarcoma, if you have surgery alone, this was 187 patients in this study and 367 in the survey plus radiation, if you look at site of recurrence, pelvis or distant, the group that had the radiation had a much lower rate of pelvic recurrence, 16% versus 34% in the group of surgery alone. For the distant recurrence basically you had similar. Long-term survival was not any different. Pelvic control and pelvic recurrence was improved in a group that had radiation.

LMS 1.

Cellular leiomyomatosis

2.

IV leiomyomatosis

3.

Benign metastasizing leiomyoma (lung)

4.

Leiomyomatosis peritonealis disseminata

5.

LMS mitosis criteria a.

> 10 M/10 HPF problem

b.

Some authors think grade and cellular atypia are more prognostic

F.

MMS 1.

Homologous

and

heterologous

malignant

mixed

müllerian, mesodermal tumors 2.

Carcinoma and sarcoma

3.

When heterologous, rhabdomyoblasts or osteoblasts worsen prognosis

4.

Chondrosarcoma better

G. Stage I ESS, LMS, MMS

1.

Surgery vs surgery with RT: equal

2.

Problem: RT controls pelvis, but distant failure

Table 3 Endometrial Hyperplasia Type of Hyperplasia Premenopausal

Completed Childbearing Postmenopausal

Simple

1. Progesterone

1. Progesterone + resample

2. Ovulation induction (if

2. Abnormal bleeding: D&C

applicable)

Complex

Same as above

3. Hysterectomy option if persists

Same as above

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Atypical

1. D&C to r/o carcinoma

1. Hysterectomy, BSO

2. Progesterone + resample

2. Progesterone if not surgical

3. Hysterectomy if persistent

candidate

atypia

8