The Good Uterine Sarcomas: What Do You Need to Know
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- Georgiana Davis
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2 The Good Uterine Sarcomas: What Do You Need to Know Anais Malpica, M.D. Departments of Pathology and Gynecologic Oncology The University of Texas M.D. Anderson Cancer Center Matthew Powell, M.D. Division of Gynecologic Oncology Washington University, St. Louis
3 VERBAL DISCLOSURE
4 The (mostly) Good Uterine Sarcomas: What Do You Need to Know Rare tumors: only 3% of uterine cancers Update on staging of sarcomas Surgical dilemmas for sarcomas: BSO, Nodes Standard therapies Novel targets for current and future development
5 Uterine Sarcomas Endometrial Stromal Sarcoma(ESS) (Low/High) Müllerian Adenosarcoma (+- sarcomatous overgrowth) Uterine Leiomyosarcoma (Benign/STUMP/Low/High grade) Other: Undifferentiated Sarcoma/HGESS Extra-GI Stromal Tumor (GIST) Endometrial Carcinosarcoma
6 Staging uterine sarcomas has changed! FIGO staging for endometrial cancer (1988)/Stanford Stage I Confined to corpus uteri Stage II Confined to cervix Stage III Confined to pelvis Stage IV Invasion of bladder/rectum mucosa Distant M+, incl intraabdominal Mets
7 Sarcoma Staging, FIGO 2009
8 Sarcoma Staging, FIGO 2009
9 Sarcoma Staging, FIGO 2009: Carcinosarcomas
10 Uterine Mass on Ultrasound
11 Surgery for presumed sarcoma: Guidelines vague
12 Surgery for Presumed Sarcoma
13 The Good Uterine Sarcomas: What Do You Need to Know Smooth muscle tumors with no standard designation, but commonly known as benign metastasizing leiomyoma or low grade leiomyosarcoma
14 Smooth muscle tumors with Uterus + Pelvis Lung Soft tissue Bowel Omentum Lymph nodes Bone Bland histologic appearance Synchronous or metachronous involvement of different anatomical sites
15 Case #1 A 48 year-old woman with a previous history of vaginal hysterectomy for uterine leiomyoma presented with a 2 cm left axillary mass A biopsy showed a smooth muscle tumor with a benign appearance
16 Case #1: Which of the following imaging studies should be included in her work-up? 1. CT Chest Abdomen Pelvis 2. MRI of Chest Abdomen Pelvis 3. Whole body PET/CT 4. No imaging is indicated as mass is benign
17 Case #1: Imaging studies: CT showed a 2.0 cm tumor in the right upper lung. Your next course of action is to: 1. Observe and remove if lesion in lung grows 2. Proceed with further surgery 3. Obtain pathology slides from hysterectomy for review 4. Proceed with progestational/hormonal therapy 5. Proceed with chemotherapy
18 Smooth Muscle Tumor in Axilla
19 Smooth Muscle Tumor in Lung WT-1 PR ER
20 Vaginal Hysterectomy, cm rubbery, light tan tumor, without areas of discoloration, necrosis or softening The tumor was sampled correctly 1 section per cm of tumor, considering its largest dimension
21 Uterine leiomyoma
22 Uterine leiomyoma
23 Diagnosis Metastasizing leiomyoma vs. metastatic low grade leiomyosarcoma vs. multifocal leiomyomas
24 Treatment: You recommend: 1. Observation 2. Laparoscopic BSO (given elevated estrogen level and low FSH) 3. Depo-Lupron 4. Aromatase inhibitor 5. Megestrol (Megace) or other progestin
25 Case #1 Additional tumors were detected in a period of 5 years: Pelvic tumor Multiple nodules in both lungs Left buttock tumor and stable lung nodules All tumors with no cytologic atypia, no coagulative tumor cell necrosis, and with 1-2 mitoses
26 Case #1: You recommend: 1. Observation until symptoms develop 2. Excise all tumors 3. Laparoscopic BSO 4. Depo-Lupron 5. Aromatase inhibitor 6. Megestrol (Megace) or other progestin
27 Benign Appearing Smooth Muscle Tumors in the Uterus and Other Anatomical Sites They can represent a true paradox and a management challenge Clinically, growing or recurring neoplasms Histologically, benign appearance Excision of the tumor is required to ensure a thorough histological examination
28 Conventional Approach The extrauterine tumors represent metastases from the uterine tumor The extrauterine disease is usually seen in the lungs Patients are women in their reproductive years Other reported sites of involvement include: lymph nodes, soft tissue, omentum, mediastinum, subcutaneous tissue, intestine, mesentery, heart and bone
29 Conventional Approach Metastasizing leiomyoma vs. metastatic low grade leiomyosarcoma The disease has a less aggressive course than conventional leiomyosarcoma Regression or resolution of the condition has been reported after or during pregnancy after oophorectomy with the use of hormonal therapy, such as progesterone or luteinizing hormone-releasing hormone (LH-RH) analogue
30 Conventional Approach Also, familial and sporadic syndromes in which there is an association of multiple cutaneous and uterine leiomyomas have been described Horluchi, K et al. Am J Surg Pathol 1998
31 Emergent Approach The occurrence of extrauterine tumors is independent of the uterine tumor as an example of multifocal disease It can occur as a synchronous or metachronous event
32 Emergent Approach Lung involvement might not be necessarily present Extrauterine tumors have been detected in mediastinum, subcutis, soft tissue, gastrointestinal tract, mesentery, retroperitoneum, paravertebral region and pelvis with extension into the adjacent bone
33 Emergent Approach The tumors usually have a benign appearance; however, the extrauterine tumors can eventually show high grade features Attention to the latter is utmost importance for therapeutic considerations Surgical resection and hormonal ablation/blockade is the typical therapy
34 Emergent Approach The interval between the uterine tumor and the extrauterine tumors can be quite long (>10 years) Protracted clinical course Cho KR, Woodruff D, Epstein JI. Hum Path, 1989 Posligua L, Silva EGS, Deavers MT, Merino MJ, Malpica A. Int J Gyn Path, 2012 in press
35 Differences Between Low Grade Smooth Muscle Tumors (LGSMT) and High Grade Leiomyosarcomas (HGL) LGSMT, 19 cases HGL, 31 cases Mean age of patients (pts) Pelvis as first site of extrauterine involvement Lung as first site of extrauterine involvement 79% 19% 16% 70% Mt in other sites 21% 81% Mean time to recurrence 52 months 19 months Pts who died of disease 3 (16%) 27 (87%) Posligua L, Silva EGS, Deavers MT, Merino MJ, Malpica A, Int J Gyn Path, 2012 in press
36 Case #2 A 35 year-old, gravida 4, para 4, underwent a vaginal hysterectomy for CIN III extending to the endocervical margin of a cervical cone No residual CIN III was found A 3 cm polypoid mass was present in the uterine cavity
37
38 Endometrial Stromal Sarcoma, infiltrative pattern
39
40 Endometrial Stromal Sarcoma, vascular/lymphatic invasion
41 PR + Immunoperoxidase Studies
42 Immunoperoxidase Studies CD 10 + Desmin
43 Case #2: You recommend 1. Laparoscopic BSO 2. Open or laparoscopic BSO and full staging including nodes 3. Pelvic radiation 4. Imaging with CT or MRI and surgery only if suspicious areas. 5. Progestational /hormonal therapy
44 Case #2: The patient has enlarged nodes on scan. You now recommend: 1. Progestational / hormonal therapy 2. Tumor cytoreductive surgery followed by observation as all disease is removed. 3. Tumor cytoreductive surgery followed by pelvic XRT. 4. Tumor cytoreductive surgery followed by progestational / hormonal therapy.
45 Endometrial Stromal Sarcoma: Patient managed on megesterol therapy for 3 years then lost to follow-up. Isolated recurrence in pelvis : Plan: 1. Pelvic XRT 2. Surgical resection followed by progestin/hormonal therapy 3. Progestin/ hormonal therapy alone 4. Chemotherapy 5. Hospice referral
46 Endometrial Stromal Sarcoma: staging Chang et al., Am J Surg Pathol 1990;14:
47 Role of lymphadenectomy? ONLY 15% Dx made Pre-op 5/15 (33%) LNM+ at some stage in their disease (Riopel et al., Gynecol Oncol 2005;96:402-6) Lymphadenectomy most likely to be beneficial in advanced stage ESS (Reich et al., Gynecol Oncol 2005)
48 Role of BSO in ESS: Recurrence rates N (%) BSO No BSO Gaducci, /6 (33) 1/6 (17) Chu, /14 (43) 4/8 (50) Li, /24 (42) 4/12 (33) Amant, /15 (20) 1/7 (14) Kim, /11 (45) 5/11 (45)
49 ESS: a population-based analysis: 831 women Prognostic factor Hazard ratio 95% CI P Age <.007 Race Surgery <.001 Stage <.001 Grade <.001 Ovarian sparing surgery and lymphadenectomy did not affect survival Chan et al., Br J Ca 2008;99:1210-5
50 Pattern of relapse in stage I patients Chang et al., Am J Surg Pathol 1990;14: % NED 26% local ONLY 15% Dx made Pre-op 10% Lung 79% 21%
51 Endometrial Stromal Sarcoma Incidence of lymph node metastasis 19% to 33% Incidence of adnexal metastasis 13% Dos Santos LA, et al. Gynecol Oncol, 2011 Riopel J, et al. Gynecol Oncol, 2004
52 Endometrial Stromal Sarcoma The estimated actuarial 5-and 10-year survival for stage I cases is: 98% (89%) 90% (75%) 80% (70%) 80% (50%) Chang KL, et al. Am J Surg Pathol, 1990
53 Endometrial Stromal Sarcoma The estimated actuarial 5-and 10-year survival for stage III cases is: 38% (38%) 40% (20%) 30% (20%) 30% (15%) Chang KL, et al. Am J Surg Pathol, 1990
54 ESS: Hormone sensitive disease Immunohistochemistry Tosi et al., 1989 Sabini et al., 1992 Reich et al., 2000 N = 21 71% ER +, 95% PR + 100% hormonal sensitive
55 Agents for Recurrent ESS: Progestins 19 of 25 (76%) Response Amant, Lancet Oncology, 2009
56 Agents for Recurrent ESS: AIs (8 of 9 (88%) RR), GnRH Amant, Lancet Oncology, 2009
57 Post-operative therapy 36% relapse?
58 Targeted Therapy: Adjuvant progestins? Chu et al., Gynecol Oncol 2003:90:170-6; NCCN 2011 Recurrence Adjuvant Progestins 4/13 (31%) No adjuvant progestins 6/9 (67%) How many currently use adjuvant therapy for all ESS patients? NCCN recommends observation for stages I-II and hormone therapy for stage III-IV (megace, provera, tamoxifen, GnRH, AIs) Routine surveillance Imaging NOT RECOMMENDED
59 ESS: Delayed Diagnosis 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 Mean delay was 143 mts and resulted in 5/6 in stage IV disease in young women (mean was 34-years) Amant et al., Gynecol Oncol 2003;90:37-43
60 ESS: Estrogen therapy to manage menopausal symptoms? 10/22 (45%) women recurred 4/5 (80%) women who used HRT recurred 4/8 (50%) with retained ovaries recurred Probably should avoid estrogen therapy in these patients?? Chu et al., Gynecol Oncol 2003;90:170-6
61 Endometrial Stromal Sarcoma: Summary *Full imaging indicated Amant, Lancet Oncology, 2009
62 Endometrial Stromal Sarcoma: Future Agents/Targets Possible: Mifepristone: no response one case Fulvestrant: ER antagonist not tested WT1 overexpression in ESS common possible immunotherapy? Unlikely: ERBB-2 expression is absent PDGFR-α : no oncogenic mutations Tamoxifen linked to induction of ESS: Avoid? NCCN suggest as possible useful agent? Amant, Lancet Oncology, 2009
63 Endometrial Stromal Sarcoma C-kit (+ ) by immunohistochemical studies in 11% to 27% of cases However, no c-kit mutations have been detected This limits the value of the immunohistochemical finding in making therapeutic decisions Wang l, et al. Gynecol Oncol, 2003 Geller MA, et al. Gynecol Oncol, 2004 Nakayama M, et al. Int J Gynecol Pathol, 2005
64 Case #3 A 52 year-old woman present with a 3 week history of uterine bleeding An endometrial curettage was obtained
65 Adenosarcoma
66 1. BSO Case #3: During your pre-op discussion you recommend: 2. full staging including nodes 3. Pelvic radiation to follow surgery so nodes are not necessary 4. Imaging with CT or MRI and surgery directed only to suspicious areas. 5. Progestational /hormonal therapy
67 Case #3:What is the risk of finding metastatic adenosarcoma in a lymph node? 1. 20% 2. 15% 3. 10% 4. 3% Arend R, et al. Gynecol Oncol, 3010
68 The hysterectomy specimen showed an adenosarcoma with involvement of the inner half of the myometrium with no vascular/lymphatic invasion Case #3
69 Case #3: Patient with a stage IB tumor. You now recommend: 1. Progestational / hormonal therapy 2. Tumor cytoreductive surgery followed by observation as all disease is removed. 3. Tumor cytoreductive surgery followed by pelvic XRT. 4. Tumor cytoreductive surgery followed by progestational / hormonal therapy.
70 ESS: Patient managed with close observation for 3 years then lost to follow-up. Isolated recurrence in pelvis 5 years from diagnosis Plan: 1. Pelvic XRT 2. Surgical resection followed by progestin/hormonal therapy 3. Progestin/ hormonal therapy alone 4. Chemotherapy 5. Hospice referral
71 Sarcoma Staging, FIGO 2009
72 Stage I Adenosarcoma Stage IA Tumor Stage IB Tumor Stage IC Tumor 50% Uterine wall
73 Müllerian Adenosarcoma Benign epithelial component, stromal component is typically a low-grade sarcoma 56% ESS-like 9% mixture ESS-like with fibrosarcoma Cases without sarcomatous overgrowth: 18 of 20 with ER or PR receptor. Conclusion: If ESS-like, then treat in similar fashion. Those with sarcomatous overgrowth unlikely hormone sensitive.
74 ER/PR endometrial adenosarcoma N (%) Amant et al., Gynecol Oncol 2004;93:680-5 ER epithelial ER sarcoma PR epithelial PR sarcoma EA (n=20) 17 (85%) 16 (80%) 13 (65%) 12 (60%) EA + Sarc (n=8) Recurrent EA (n=2) 4 (50%) 0 (0) 2 (25%) 1 (12%) NA 2 (100%) NA 0 (0)
75 Adenosarcoma, 5-year survival Stage 5-year survival IA 84% IB 69% IC 63% II 69% III 48% IV 15% Arend R, et al. 2010
76 Adenosarcoma With sarcomatous overgrowth Sarcoma represents more than 25% of the tumor
77 Adenosarcoma with Sarcomatous Overgrowth Adenosarcoma Recurrence Rate 44% 14% Pts who died of disease 31% 7% Arend R, et al. 2010
78 Same patient but D&C pathology: Adenosarcoma with Sarcomatous Overgrowth. 1. TAH BSO followed by XRT or Progestin/H tx 2. TAH BSO full staging followed by XRT 3. TAH BSO full staging followed by Progestin/Hormonal therapy 4. TAH BSO full staging followed by chemotherapy 5. TAH BSO full staging followed by XRT and Chemo
79 Extra-Gastrointestinal Stromal Tumors Rare, but might be more common than is currently recognized. Misdiagnosis can lead to inappropriate therapy Consider EGISTs in the differential diagnosis of mesenchymal neoplasms in the uterine, fallopian tubes, or vulvovaginal or rectovaginal septum. Tumor KIT/PDGFRA kinase genotype predicts response to imatinib therapy
80 Summary- Low Grade Smooth Muscle Tumors Most likely multifocal Protracted course Attention to the low grade features of the tumor to determine tx Bland histologic appearance Uterus + Pelvis Lung Soft tissue Bowel Omentum Lymph nodes Bone Synchronous or metachronous involvement of different anatomical sites
81 Conclusions New FIGO staging system Many surgical and therapeutic aspects remain controversial given rarity of tumors Limited to no role for radiation except for palliation for patients with uterine sarcoma
82 Summary: Therapy Benign metastasizing Leiomyoma Endometrial stromal sarcoma Adenosarcoma Adenosarcoma with sarcomatous overgrowth Extra-GI stromal tumors
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
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