Uterine sarcoma is a rare and challenging type of cancer that grows rapidly. It accounts for 2-5% of uterine malignancies and is diagnosed in about 17 per 1000 women annually. Risk factors include prior pelvic radiation and black race. Long-term tamoxifen use also increases the risk. The most common presenting symptom is vaginal bleeding. Surgery is the primary treatment but the benefits of adjuvant radiation and chemotherapy are unclear due to limited data. Prognosis is generally poor, especially for later stages, and more research is needed to determine optimal adjuvant therapies.

1. Uterine Sarcoma

2. Challenging Rare -> Limited data Rapidly growing (doubling time is 4 weeks) tend to be increasing (Nordal & Thoresen 1997)

3. Epidemiology Rare 2% to 5% of all uterine malignancies 17 per million women annually [Platz, & Benda, 1995] Between 1989-1999, 2677 women were diagnosed with uterine sarcoma (Brooks et al, April, 2004)

4. Risk Factors prior pelvic radiation (10%-25% of cases) 3X increase in risk among black women (Brooks et al, April, 2004) Data regarding parity and time of menarche and menopause as risk factors are inconclusive (Sherman & Devesa ,2003)

5. long-term adjuvant tamoxifen An increase in the risk of uterine sarcomas appears to accompany the use of long-term adjuvant tamoxifen in women with breast cancer [Wickerham et al, 2002, Wysowski et al, 2002]. Since 1978, when tamoxifen was first marketed in the United States, 159 cases of uterine sarcoma worldwide have been reported

6. Histologic Classification Mixed mesodermal sarcoma Carcinosarcoma Mixed Liposarcoma (ii) Endometrial stromal sarcoma Osteosarcoma (i) endolymphatic stromal sarcoma Chondrosarcoma Stromal sarcoma Rhabdomyosarcoma Leimyosarcoma Pure Heterologous Homologous Type

7. GOG , 1993 Mixed mullerian sarcomas - 50% homologous heterologous Leiomyosarcoma (30%). Endometrial stromal sarcoma (15%) Others (Adenosarcoma 5%)

8. Leiomyosarcoma Arise from smooth muscles of the uterus usually de novo appear grossly as a large (>10 cm) yellow or tan solitary mass with soft, fleshy cut surfaces exhibiting hemorrhage and necrosis [Viereck et al, 2002].

9. Leiomyosarcoma

10. Leiomyosarcoma: Low or high grade Frequent mitotic figures significant nuclear atypia, presence of coagulative necrosis of tumor cells. [ Bell et al, 1994 ]

11. Endometrial stromal Sarcoma : A pure homologous neoplasm Subtypes: low and high grade Low grade : slow growing tumors with infrequent metastasis or recurrence after therapy. [Oliva, et al, 2000]. high grade : enlarge and metastasize quickly and are often fatal.

12. Mixed mullerian sarcomas Both carcinomatous and sarcomatous elements must be present in this type of sarcoma. metastasize early in the course of the disease via hematogenous and lymphatic pathways grows as a polypoidal mass with a broad base

13. Subdivided homologous ( carcinosarcoma ) contain only tissue elements that are native to the uterus. heterologous ( mixed mesodermal sarcoma ) contain tissue element that is foreign to the uterus.

14. MMT

15. Adenosarcoma both malignant stromal and benign epithelial components a significantly increased occurrence of this tumor (Seidman et al, 1999) present as polypoid masses

16. Clinical Diagnosis Vaginal bleeding is the most common presenting symptom of a uterine sarcoma. On pelvic examination, the uterus is enlarged and, in some patients, part of the tumor may protrude from the uterine cavity through the cervical os.

17. Rapidly growing!! Among 341 women with a rapidly growing uterus by clinical or ultrasound examination, only one (0.27 percent) had a uterine sarcoma . [Parker et al, 1994].

18. Should be considered in postmenopausal women with a pelvic mass, abnormal bleeding, and pelvic pain, where the incidence of sarcoma is 1 to 2 percent [Leibsohn et al, 1990]

19. Evaluation Ultrasound examination, MRI, or CT scan cannot reliably distinguish between a sarcoma, leiomyoma or endometrial cancer [Rha et al, 2003]. The diagnosis of uterine sarcomas is made from histologic examination of the entire uterus

20. Staging: surgical Sarcoma has spread outside the true pelvis IV Sarcoma has spread outside the uterus but is confined to the true pelvis III Sarcoma is confined to the corpus and cervix II Sarcoma is confined to the corpus I Description Stage based on FIGO staging for endometrial cancer

21. Lymph node Biopsy patients with uterine sarcoma grossly confined to the uterus/cervix showed lymph node metastases in 5 of 101 patients should be reserved for women with clinically suspicious nodes [Leitao et al, 2003 ]

22. Further support In one series of 208 women with uterine leiomyosarcoma, only four of 36 who underwent lymph node sampling had positive nodes [Giuntoli et al, 2003].

23. Treatment because of their rarity, uterine sarcomas are not suitable for screening. (Levenback, 1996)

24. Surgery is the only curative therapy for uterine sarcomas [Morice et al, 2003]

25. Modalities Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy). Surgery plus adjuvant chemotherapy. Surgery plus adjuvant irradiation

26. Is it beneficial !! Interpretation of the possible benefit of different modalities is hampered by the difficulty in comparing outcomes from series in which patients of varying stages and histologies were reported

27. The five year survivals Surgery alone (46 %) Surgery and radiotherapy (62 %) Surgery and chemotherapy (43 %) Radiation alone (8 %) Weitmann et al, 2001

28. three-year local recurrence rates No adjuvant treatment 62 % Whole pelvis external beam radiation therapy 31 % Chemotherapy alone 71 percent [Livi et al, 2003]

29. Massachusetts General Hospital 1990-1999 Adjuvant therapy after optimal cytoreduction does not decrease the rate of recurrence [Dinh et al, 2004]

30. Adjuvant radiation therapy Some studies of postoperative radiation suggest a survival benefit [Moskovic et al, 1993 Knocke et al, 1998, Weitmann et al, 2001]. Other studies showed cure rate was similar for those treated with surgery alone or followed by radiation, regardless of the stage of disease [Giuntoli et al, 2003]

31. Complications of Radiation Tx: Acute: Perforation Fever Diarrhea Bladder spasm Chronic: Proctitis Cystitis (a/w UTI) Fistula Enteritis

32. Adjuvant chemotherapy Current studies consist primarily of Phase II chemotherapy trials for advanced disease The role of chemotherapy in the treatment of uterine sarcomas has been limited

33. This is because Adjuvant chemotherapy following complete resection (stage I and II) has not been established to be effective in RCT But some nonrandomized trials have reported improved survival following adjuvant chemotherapy with or without radiation therapy Piver et al, 1988 ,van Nagell , et al, 1986, Peters et al, 1989

34. Leiomyosarcoma doxorubicin is an effective drug for advanced leiomyosarcoma combinations with doxorubicin increase the objective response rate but add substantial toxicity A very recent small trial showed promising results with gemcitabine plus docetaxel [Hensley et al, 2002].

35. Carcinosarcoma benefit from cisplatin-based chemotherapy particularly combinations of cisplatin with doxorubicin and ifosfamide, or single agent paclitaxel [ Gallup et al, 2003 , van Rijswijk et al, 2003, Harris et al, 2003]

36. Mixed mesodermal tumors Cisplatin and ifosfamide appear to have greater activity than does doxorubicin alone [Ramondetta et al, 2003]. In a very small uncontrolled trial : cisplatin, doxorubicin, and dacarbazine give three year survivals of 51 % [Baker et al, 1991].

37. Hormone therapy Estrogen and/or progesterone receptors are present in leiomyosarcomas and endometrial stromal sarcomas but do not predict hormone responsiveness. In fact, only one of 28 patients with residual or recurrent disease following surgery had an objective response to hormone therapy (Wade 1994)

38. Recurrent Disease Most relapses occur in the pelvis, followed by lung and abdomen currently no standard therapy for patients with recurrent disease Doxorubcin in leiomyosarcoma ? Cisplatin in carcinosarcoma ?

39. In a recent RCT 2000 ifosfamide with or without cisplatin for recurrent sarcoma demonstrated a higher response rate on the combination arm However,use of the combination was not justified because of increased toxic effects [Sutton et al, 2000]

40. Prognosis poor prognosis the 5-year survival : stage I less than 50% remaining stages : 0% to 20%. strongest predictor of survival was menopausal status at time of diagnosis [Major et al, 1993]

41. leiomyosarcoma age over 50 years was a poor prognostic factor, as was size greater than 5 cm [Giuntoli et al, 2003].

42. Conclusion Aggressive surgical cytoreduction at the time of initial diagnosis offers the best survival More RCTs are needed to determine the value and regime of adjuvant therapy

43. Thank You