Gynecological sarcoma

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Cameron Palmer
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Gynecologic Oncology, KU Leuven, Belgium Center Gynecologic

1 Gynecological sarcoma Therapy of the gynecological sarcoma Treatment gynecologist s update view Frédéric Amant MD PhD Gynecologic Oncology, KU Leuven, Belgium Center Gynecologic Oncology Amsterdam (CGOA), Netherlands Cancer Institute (NKI), The Netherlands

2 Take home message LMS: Hysterectomy, aggressive entity ESS: hysterectomy, indolent and hormone sensitive Morcellation of uterine leiomyomas poses risk of spreading undetected cancerous tissue in women with unsuspected cancer: TRIAGE!

3 3

4 Agenda Uterine leiomyosarcoma Endometrial stromal sarcoma Morcellation of apparent uterine leiomyomas

5 Uterine sarcomas: subtypes Including carcinosarcoma Excluding carcinosarcoma

6 Uterine leiomyosarcoma, FIGO 2009 staging Pecorelli, Int J Gyn Obstet 2009 Stage I I A I B II II A II B III III A III B III C IV A IV B Definition Tumor limited to uterus < 5cm > 5cm Tumor extends to pelvis Adnexal involvement Tumor extends to other pelvic structures Tumor invades abdominal tissues One site > One site Metastasis to pelvic/para-aortic lymph nodes Tumor invades bladder and/or rectum Distant metastasis Overall survival: 30-70% stage I 30-40% stage II < 30% stage III < 10% stage IV

7 Leiomyosarcoma: Prognosis Gadducci, et al. Gynecol Oncol. 1996;62:25-32.

8 Preoperative diagnosis Transvaginal sonography No pathognomonic signs What may help: Myoma Shape Round Oval LMS Echogenicity Frequent calcifications Central necrosis Rara Yes Inhomogeous Doppler Circular flow Irregular distribution blood vessels, low resistance, high velocity

9 Leiomyosarcoma: Surgical Treatment Series Lymph node Meta Ovarian Meta N Nr pos (%) N Nr pos (%) Major et al., (1993) 57 2 (3.5) 59 2 (3.4) Goff et al., (1993) 9 0 (0.0) - - Chen et al., (1989) 4 3 (75.0) - - Gadduci et al., (1996) 4 0 (0.0) - - Leitao et al, (2003) 27 0 (0.0) 71 2 (2.8) Total (5.0) (3.1)

10 Prognostic factors and survival in 1,396 patients with u-lms Oophorectomy and lymphadenectomy were no independent prognostic factors on survival Prognostic factor HR 95% CI P Age <.001 Race Surgery Stage <.001 Grade <.001 Kapp DS, et al. Cancer. 2008;112:

11 Leiomyosarcoma: Adjuvant chemotherapy 156 uterine sarcomas (CS + LMS) Only 48 LMS Stage I-II disease Pelvic irradiation was optional Adriamycin 60mg/m², 3 weekly, x8 No survival benefit Different pattern of recurrence: pulmonary (LMS) vs. extrapulmonary (CS) Omura GA, et al. J Clin Oncol 1985;3:

12 Leiomyosarcoma: Radiotherapy Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: EORTC (RT vs observation) 100 Overall survival by treatment Overall Logrank test: p= (years) O N Number of patients at risk : No treatment Radiotherapy Reed NS, et al. Eur J Cancer. 2008;44:

13 CI Cumulative Incidence Risk of loco-regional Cumulative Incidence Risk of Distant Mets Cumulative incidence Risk : loco-regional recurrence or same time Gray test P-value= Cumulative incidence Risk : distant metastases Gray test P-value= ,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 No RT RT Years CI RT No RT Years Radiotherapy No treatment Radiotherapy No treatment

14 Secondary debulking: peroperative findings No peritoneal metastasis Tumoral resection without any organ resection

15 Results of Clinical Trials in u-lms Study Drugs N Prior CT RR TTP (months) Median OS (months) Sutton 92 ifosfamide % Miller 00 topotecan % 3 ND Sutton 05 PLD % 4.1 ND Sutton 96 doxo+ifos % 4 ND Leyvraz 06 doxo+ifos % Hensley 08 gem+doc % Gallup 03 paclitaxel 53 yes 8% Anderson 05 temozolomide % ND ND Pautier 12 gemcitabine % Hensley 08 gem+doc % Pautier 12 gem+doc % Total % 5 to st line 1st line combo > 1st line mono > 1st line combo Ray-Coquard I. Int J Gynecol Cancer. 2011;21(10 Supl 1):S3-S5. Hensley ML, et al. Gynecol Oncol 2008;109: Hensley ML, et al. Gynecol Oncol 2008;109: Pautier P, et al. Oncologist. 2012;17:

16 u-lms: Treatment Algorithm Localised stage Hysterectomy with oophorectomy +/- RT Cure (40 50%) Metastases (50 70%) Surgery (15%) 1st line Doxorubicin Ifosfamide Combination Trabectedin* 2nd line Ifosfamide Doxorubicin Trabectedin? 3rd line Trabectedin Trabectedin?? *if doxorubicin or ifosfamide are not recommended Ray-Coquard I. Int J Gynecol Cancer. 2011;21(10 Supl 1):S3-S5.

17 Agenda Uterine leiomyosarcoma Endometrial stromal sarcoma Morcellation of apparent uterine leiomyomas

18 Endometrial Stromal Sarcoma soft yellowish mass protruding in the cavity

ESS/adenosarcoma FIGO 2010 staging Stage Definition I IA IB IC Tumor limited to uterus Tumor limited to endometrium/endocervix with no myometrial invasion Less than or equal to half myometrial

19 ESS/adenosarcoma FIGO 2010 staging Stage Definition I IA IB IC Tumor limited to uterus Tumor limited to endometrium/endocervix with no myometrial invasion Less than or equal to half myometrial invasion More than half myometrial invasion II IIA IIB Tumor extends to the pelvis Adnexal involvement Tumor extends to extrauterine pelvic tissue III IIIA IIIB IIIC Tumor invades abdominal tissues (not just protruding into the abdomen) One site > one site Metastasis to pelvic and/or para-aortic lymph nodes IV IVA IVB Tumor invades bladder and/or rectum Distant metastasis

20 Stage distribution Chang et al., Am J Surg Pathol 1990 Stanford series Shah et al., Obstet Gynecol Stage 1 80% Stage 2Stage 3Stage 4 3% 10% 7% 106 ESS Stage I Stage II Stage III Stage IV 384 ESS

21 Primary advanced - Chang series: 7% Recurrence Frequent: 36-56% (Chang, 1990; Piver, 1984) Indolent: mean DFI is 65 mts

22 Preoperative diagnosis: Transvaginal sonography No pathognomonic signs What can help: ESS Form Mass derived from endometrium with irregular lining Echogenicity Central necrosis Hypoechogenic No Doppler Irregular central or circular

23 ESS: Hormone sensitive disease Biochemical (Baker et al., 1984; Sabini et al., 1992) Immunohistochemistry (Tosi et al., 1989; Sabini et al., 1992; Reich et al., 2000): N = 21, 71% ER +, 95% PR +: 100% hormone sensitive ESS adenosarcoma, 2003

24 Clinical management of ESS * Retention of the ovaries can be considered in young women with small ESS

25 ESS: a population-based analysis Chan et al., Br J Ca 2008;99: Ovarian sparing surgery and lymphadenectomy did not affect survival in a series of 831 women (10% positive nodes). Prognostic factor Hazard ratio 95% CI P Age <.007 Race Surgery <.001 Stage <.001 Grade <.001

26 Adjuvant progestins? Chu et al., Gynecol Oncol 2003:90:170-6 Recurrence Adjuvant Progestins 4/13 (31%) No adjuvant progestins 6/9 (67%)

27 Clinical management of ESS * Retention of the ovaries can be considered in young women with small ESS

28 Hormonal treatment in recurrent setting 30 patients with hormonal treatment (Cheng et al Gynecol Oncol 2011) 5 (17%) CR 3 (10%) PR 16 (53%) SD 6 (20 %) PD median time to progression was 24 months Case reports using progestins, GnRHa, aromatase inhibitors Adnexectomy in premenopausal patients

29 Clinicopathologic data of women in whom the diagnosis of endometrial stromal sarcoma was initially missed: all patients with stage 4 disease underwent secondary/tertiary debulking surgery with organ resection Amant et al., Gynecol Oncol 2003;90:37-43 Case Age Primary D/ ESS D/ DDD Stage at D&C (n) IAS Status (mths) ESS D/ 1 30 Cellular LM yes NED 2 18 Myxoid LM yes NED 3 28 LM no NED 4 39 Lymphatic N.A. yes DOD 5 53 LM yes NED 6 36 Myxoïd LM yes AWED Also in: Yokoyama 2004 (n=1), Gadducci 2008 (review); Thomas 2009 (n=2) mean follow-up of 16 years (range, 5-43)

30 Fertility preservation: resection followed by adjuvant progestins 6 succesfull cases Literature review Laurelli et al., 2015 EJOGRB N=40 (age range, years) 19 relapses 2 DOD 1 AWED 19 live births Experimental procedure! Individualisation (motivation, ESS in polyp, resection margin) Pregnancy itself is a natural and high-dose progestin therapy

Uterine adenosarcoma Stromal component low grade ESS or fibrosarcoma like (Clement 1990, McCluggage, 2010) ER and PR positive (Amant 2003, Amant 2004, Soslow

31 Uterine adenosarcoma Stromal component low grade ESS or fibrosarcoma like (Clement 1990, McCluggage, 2010) ER and PR positive (Amant 2003, Amant 2004, Soslow 2008, Gallardo 2009) Indolent, 50% > 5y (Clement 1990) In the absence of evidence on treatment outcomes, similar treatment as ESS seems fair (Amant, Lancet Oncol)

32 Uterine adenosarcoma with sarcomatous overgrowth Poor prognostic marker with malignant potential similar to other high grade sarcomas (LMS, undiff sarcoma) (Clement 1990, McCluggage 2010) Sarcoma component hormone receptor negative (Amant 2004) In the absence of series, extrapolation of treatment modalities of these high grade sarcomas.

33 Agenda Uterine leiomyosarcoma Endometrial stromal sarcoma Morcellation of apparent uterine leiomyomas

34 Hot topic (I) Amy Reed, MD, an anesthesiologist at Beth Israel Hospital in Boston. The Wall Street Journal: morcellation of LMS may have worsened her prognosis. Campaign calling for a ban on morcellation.

35 Smooth muscle cell tumor pathology can be challenging (figures from Seidman et al PLOS ONE 2012)

37 Intraoperative images of nodules on the peritoneal surface Seidman et al. PLoS ONE 2012

38 Metastatic leiomyosarcoma involving the omentum and pelvic side wall Oduyebo T et al., GO 2014

39 Patient triage UZ Leuven recommendations on morcellation Amant F et al., Lancet Oncol 2015 Discourage Oval, solitary lesions Central necrosis Irregular lining High blood flow Fast growth (3 months) Atypical growth Postmenopausal Post embolisation GnRH analogues In favor Round lesion Many small lesions Regular lining Low blood flow Calcifications Ovarian fibroma

40 Take home message LMS: Hysterectomy, aggressive entity ESS: hysterectomy, indolent and hormone sensitive Morcellation of uterine leiomyomas poses risk of spreading undetected cancerous tissue in women with unsuspected cancer: TRIAGE!

41 Conclusion ENITEC European Network for Individualised Treatment of Endometrial Cancer RUCaRe: Rare Uterine Cancer Registry

3/25/2019. Rare uterine cancers ~3% Leiomyosarcoma Carcinosarcoma (MMMT) Endometrial Stromal Sarcomas Aggressive tumors High Mortality Rates

3/25/2019. Rare uterine cancers ~3% Leiomyosarcoma Carcinosarcoma (MMMT) Endometrial Stromal Sarcomas Aggressive tumors High Mortality Rates J. Anthony Rakowski D.O., F.A.C.O.O.G. MSU SCS Board Review Coarse Rare uterine cancers ~3% Leiomyosarcoma Carcinosarcoma (MMMT) Endometrial Stromal Sarcomas Aggressive tumors High Mortality Rates Signs