UTERINE LEIOMYOSARCOMA

It is one of the deadly sarcomas of uterus which needs to be treated aggressively.

1. UTERINE SARCOMAS Presented by: DR KIRAN PANDEY MBBS MS FRCOG FIMSA FICMCH MAMS PROF & HOD, DEPT OF Obs & Gyne , GSVM MC PRESIDENT KANPUR OB&GYN SOCIETY 2016-18 DR PAVIKA LAL ASSISTANT PROFESSOR DEPT OF Obs & Gyne , GSVM MC

2. Prof. & Head. Department of OB/GY., G.S.V.M Medical College, Kanpur Head of the Department since 10 years DR. KIRAN PANDEY M.D., FICOG, FICMCH, FIMSA, MAMS ACADEMIC ACTIVITIES & RESEARCH ACTIVITIES Published > 100 research Papers in National & International Journals, and presented 45 Research Presentation in National Conferences. Best prize for 3 papers in AICOG . As Secretary KOGS & Scientific Secretary IMA organized several CMEs & workshop. Important Project for in vivo detection of cervical pre cancers with IIT Kanpur . Evaluation of Progesterone vaginal ring (PVR) in India with ICMR Active participation in Govt. programs like ICMR, SIFPSA, PPTCT ,IYCF, NRHM. Special Areas Of Interest-Menopausal problems, Oncology, Infertility, Adolescent health, Gynae plastic surg . Contributed a chapter – Gestational diabetes in “Current trends” in Obst . & Gynae . AWARDS ACHIEVED Received 9 National, 6 State level & 8 District level Awards & more than 25 awards at IMA. Felicitated on World women’s day for being a “WOMEN OF SUBSTANCE ”. MEDICO SOCIAL ACTIVITIES Received 8 awards from various Social Organization & is Actively participating in Health campus, Awareness seminars on female feticide ,organ donation and Adolescent Health. Actively involved in Kanpur Obstetrics & Gynaecological Society in various capacities & is presently working as Honorary President, KOGS. Nominated as central zone coordinator 2013-14 by National Adolescent Health Committee of FOGSI. 1995-AICOG: Chairman poster committee , 2006 - UPCON: Chairman Scientific committee, 2011 - FORCE: Organizing se

3. CLASSIFICATION Mixed mesodermal tumour / Carcinosarcomas (MMT) Arise from both epithelial & mesenchymal components Incidence (.6%)

4. LEIOMYSARCOMA- EMERGING CHALLENGES

5. INTRODUCTION Uterine sarcomas accounts for 3–7 % of all malignant diseases of the uterine corpus Incidence of LMS is <2/100,000women Notorious for their aggressive nature and poor prognosis , because of their location in the vascular myometrium of the uterus early invasion and widespread metastases, particularly to the lungs .

6. Learning objectives- To appreciate the diagnostic challenges faced with LMS especially in view of the similarities with uterine fibroids. To learn about the current views on surgical treatment and adjuvant therapy . To have an understanding of the novel therapies currently under investigation.

7. CLINCIAL PRESENTATION Median Age – 47-56 years Risk factors:- Nulliparity . Increasing age Obesity. History of pelvic radiation. Exposure to tamoxifen .

8. Symptoms:- No symptoms specific for LMS Abnormal vaginal bleeding & Pelvic/abdominal pain are m/c c/p but similar to fibroids further compounds the difficulty in diagnosis Incidental finding of LMS at surgery remains the m/c form of presentation as preop dx remains inadequate.

9. PITFALLS IN DIAGNOSIS As conservative non-surgical techniques ( eg .- Uterine artery embolisation & use of GnRH )of treating fibroids are becoming more popular, non-detection of LMS is a major concern delay in diagnosis delay in instituting the appropriate treatment. Mostly detected at time of HP evaluation of a hysterectomy or myomectomy specimen(incidence of LMS in women operated for uterine fibroids is about 0.5 %*) * Leibsohn S, d’Ablaing G, Mishell DR Jr, Schlaerth JB. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990;162:968–74;discussion 974–6.

10. DIAGNOSIS MRI&CECT are not specific difficult to distinguish LMS from degenerating uterine fibroids. Combined use of dynamic MR( gd enhanced)I and serum measurement of LDH(3) isozyme the diagnostic value to 100 %. T1 T2 Fibroid homogeneous and hypointense homogeneous and hypointense LMS heterogeneous hyperintense irregular borders and areas of haemorrhage or necrosis

11. Dynamic MRI Image (gadolinium enhanced) T2-weighted imaging in preop pelvic MRI (A ) Sagittal slice showing an irregular tumor with high-signal intensity extending from the cavity to the right posterior wall of the uterus (arrow 1). (B) Axial slice showing extension of the tumor to the right adnexa and vessels (arrow 2) and the right internal iliac vein (arrow 3).

12. MRI image of uterine fibroid A degenerating fibroid MRI showing normal fibroid

13. . LMS LEIOMYOMA CYTOLOGICAL ATYPIA + Moderate to severe - HIGH MITOTIC INDEX + ≥10 per 10 HPF +/- COAGULATIVE TUMOUR CELL NECROSIS + - Leiomyoma showing spindle shaped cells with elongated nuclei uniform in size with Varying amount of connective tissue HISTOLOGY

14. Leiomyosarcoma 1- Interface between viable and necrotic tumor is sharp 2&3- Cytologic atypia is noted within the necrotic area.

15. STUMP s(smooth muscle tumours of unknown malignant potential) have some characteristic features of LMS, but do not meet full criteria The absence of coagulative necrosis and atypia suggest a fibroid, even if the mitotic count is as high as 20 Histological diagnosis by endometrial sampling is unreliable as it cannot provide an accurate result unless the tumour has reached the surface of the endometrial cavity which gives a low sensitivity of approximately 30%

16. IMMUNOHISTOCHEMISTRY LMS stain + ive for SMA(smooth muscle actin), desmin and caldesmon . ER and PR expression is significantly lower in LMS than leiomyoma ( ER: 40%vs78 %; PR: 38% vs 88%). Immunopositivity for p16 and p53 with a high Ki-67 proliferation index also has been shown to have high sensitivity and specificity for differentiating LMS and leiomyomas. ( Differentiates LMS from leiomyoma )

17. A&B- IHC staining of diagnosed LMS for antibodies Against smooth muscle Actin and Desmin . C&D- Staining negative for SMA and Desmin (leiomyoma)

18. FDG SUV correlates with greatest dimension of tumor & tumor grade . So it is important in terms of prognostication

19. FIGO( International Federation of Gynecology and Obstetrics) STAGING I Tumour limited to the uterus IA Tumour 5 cm or less in greatest dimension IB Tumour more than 5 cm II Tumour extends beyond uterus but within pelvis IIA Tumour involves adnexa IIB Tumour involves other pelvic structures III Tumour infiltrates abdominal tissue IIIA One site IIIB More than one site IVA Tumour invades bladder and/or rectum IVB Tumour with distant metastasis FIGO STAGING(2009)

20. Tumour stage and grade main prognostic factors that have been shown to influence disease specific mortality. Role of other factors unproven Overall, tumour stage has been confirmed as the strongest prognostic variable . The 5-year OS is 62–65% in studies that included predominantly stage I disease, but in studies with a higher proportion of advanced disease it is as low as 29 %.* * Kapp DS, Shin JY, Chan JK. Prognostic factors and survival in 1396 patients with uterine leiomyosarcomas : emphasis on impact of lymphadenectomy and oophorectomy. Cancer 2008;112:820–30 .

21. Other Prognostic factors Age Vascular space involvement Mitotic count Residual disease at surgery Adjuvant chemotherapy

22. PRINCIPLES OF MANAGEMENT It is universally accepted that surgery is primary treatment for LMS. A TAH and BSO and appropriate surgical staging, including peritoneal washings and sampling of suspicious nodules, should be carried out . It is recommended that aggressive surgical cytoreduction at the time of initial diagnosis offers the best possibility of prolonged survival.

23. SURGICAL MANAGEMENT Three areas of contention with regard to surgery are:- i ) Oophorectomy in the premenopausal women. II) Incidental finding of LMS in myomectomy specimen. iii) R ole of Pelvic lymphadenectomy(PLND) in early LMS

24. DILLEMMAS IN SURGICAL Mx 1.Oophorectomy in the premenopausal women(still debatable) ?????? Some LMS express ERs with concern for the effect of hormonal stimulation of tumour inclination to BSO Low reported incidence of ovarian mets in uterine LMS. Several studies show no difference in OS and recurrence rates in early stage disease with ovarian conservation consider ovarian conservation in young women with early stage disease

25. 2.Incidental finding of LMS in myomectomy specimen? a completion procedure with total hysterectomy, trachelectomy and/or bilateral salpingo -oophorectomy is recommended. A conservative approach following myomectomy should only be taken for specific and accurately selected women who strongly desire pregnancy and well counselled about the risks involved .

26. ETHICAL ISSUE (effect of morcellation ) morcellation may lead to dissemination of undiagnosed malignancies , in particular LMS . Risk of undetected uterine malignancy is 0.27% in women undergoing minimally invasive hysterectomy for presumed benign disease*, & 0.09% in women undergoing myomectomy with morcellation ** *Wright JD, Tergas AI, Burke WM, Cui RR, Ananth CV, Chen L, et al.Uterine pathology in women undergoing minimally invasive hysterectomy using morcellation . JAMA 2014;312:1253–5 . **Wright JD, Tergas AI, Cui R, Burke WM, Hou JY, Ananth CV, et al. Use of electric power morcellation and prevalence of underlying cancer in women who undergo myomectomy. JAMA Oncol 2015;1:69–77

27. THE MORCELLATION CONTROVERSY Amy Reed (an anesthesiologist) was diagnosed with fibroids and was advised TLH with morcellation but things didn't go as expected . Dr. Reed learned that she had a uterine leiomyosarcoma and THE MORCELLATION MAY HAVE WORSENED HER PROGNOSIS Since then, Dr. Reed's husband, has led a  campaign calling for a ban on morcellation .   FDA on April 2014 announced that it discourages the use of laparoscopic power morcellators in most hysterectomy and myomectomy procedures especially in suspected or confirmed uterine malignancies/ peri or post menopausal women with fibroid because of the risk of spreading unsuspected cancerous tissue.

28. Role of Pelvic lymphadenectomy(PLND) in early LMS Incidence of LN mets from uLMS is very low & unlikely in the absence of extrauterine disease. R outine PLND is not usually done for women with the disease confined to the uterus and with normal LNs on observation and palpation LN status may have a role as a staging procedure & in determining the need for adjuvant pelvic RT but its therapeutic benefit is still to be proven

29. Management of Early uterine LMS SURGERY ADJUVANT PELVIC RT SYSTEMIC CT EORTC trail(55874) – 13 years study -224 patients- 2 groups – observation & RT(51Gy in 28# over 5 weeks) No beneficial impact on OS Premenopausal women :- TAH +/- PLND ( in presence/absence of extrauterine disease respectively) Postmenopausal female :- TAH + BSO

30. Limited studies available- ongoing phase III trial(NCTO1533207*) Observation 4 cycles of adjuvant GEMCITABINE+ DOXORUBICIN additional 4 cycles of DOXORUBICIN( regimen well tolerated) This trial is still underway *A RCT of adjuvant CT vs observation to determine if adjuvant CT can improve OS in early uLMS CT

31. ADVANCED OR METASTATIC UTERINE LMS SURGERY ADJUVANT PELVIC RT No role LMS recurs only at Metastatic sites Secondary cytoreduction surgery Pulmonary mets resection Improved OS SYSTEMIC CT met. disease beyond the Pelvis- not surgical candidates OTHER MODALITIES gemcitabine + docetaxel - best regimen

32. OTHER MODALITIES Targeted therapies Hormonal therapies Epigenetic regulators Pazopanib , Bevacizumab, Alisertib Expression of ER and PR -70–80 % of uterine LMS Aromatase inhibitors Belinostat , ( HDAC inhibitor) Needs further research

33. Conclusion- m/c uterine sarcoma Notoriously aggressive in nature. Preop dx is difficult & usually detected as an incidental finding at surgery. Tumour stage is the most important prognostic factor. P rimary treatment is surgical (in early/ advanced/ recurrent ) while role of adjuvant therapy(RT/CT) is still to be clearly defined . G emcitabine + docetaxel- best regimen for adjuvant CT.

34. ENDOMETRIAL STROMAL SARCOMA

35. ESS - very rare(.2%) of all uterine malignancies Annual incidence - 1–2 per million women  A n indolent tumor with local recurrences and d istant metastasis can occur even 20 years after initial diagnosis . Median age- 36-48yrs

36. ENDOMETRIAL STROMAL NODULE : Well circumscribed, non encapsulated Finger like projections into the myometrium <3mm & <3 in no. No vascular invasion LOW GRADE ESS: irregular nodular growth in endometrium Infiltrates(worm like) myometrium, myometrial & parametrial veins Cellular atypia & pleomorphism absent Mitotic activity <5/10HPF UNDIFFERENTIATED ESS (earlier k/a high grade ESS ) Resemble sarcomatous component of c arcinosarcomas Lack typical growth patterns and vascularity Displaces myometrium(in contrast to infiltration in low gr ESS) Abundant mitotic activity & marked cellular atypia Shows prominent hemorrhages & necrosis within polypoidal fleshy endometrial masses.

37. CLINICAL FEATURES abnormal uterine bleeding (90%) pelvic pain dysmenorrhoea asymptomatic in 25% individuals 30 to 50% cases - extra uterine spread at the time of the diagnosis Rarely ESS is initially present at an extra uterine site(m/c ovary) – primary/ metastatic lesion from an occult tumor of endometrium or from a previously undiagnosed case where a hysterectomy was done for a benign leiomyoma of the uterus.

38. DIAGNOSIS similarity of ESS with normal endometrium+ the lesion is almost always intra-myometrial impossible to diagnose it with certainty on curettage fragments definitive diagnosis can be made only on a hysterectomy specimen RADIOLOGY: USG –unreliable; MRI useful in preop diagnosis. Bands of low signal intensity within myometrium. Continuous extension of lesions into adjascent structures(vessels & ligaments)

39.  Endometrial stromal nodule- Multiple collagen bundles are interspersed among the neoplastic stromal cells high-grade endometrial stromal sarcoma. Tumor cells with an epithelioid morphology (left) are juxtaposed to areas of endometrial stromal neoplasia with a fibroblastic appearance. HISTOLOGY

40. IMMUNOHISTOCHEMICAL FEATURES Low-grade endometrial stromal sarcoma with smooth muscle differentiation. Desmin immunoreaction highlights the smooth muscle component (‘starburst’) with minimal reaction of the background endometrial stroma high-grade endometrial stromal sarcoma. CD10(cell surface neutral endopeptidase) Positivity- helps in differentiating from leiomyoma .H-ESS is almost always + for ER & PR IMMUNOHISTOCHEMISTRY: Strong and/or diffuse positivity for CD10  ; ESS is almost always positive for both ER & PR

41. MRI image of ESS showing increased intensity of the tumor In comparison to normal endometrium. It also shows Continuity of tumor into broad and round ligaments

42. stage Definition Stage 1 CONFINED TO UTERUS 1A Tumor limited to endometrium/ endocervix . No myometrial invasion 1B <= half of myometrial invasion 1C >half of myometrial invasion Stage 2 EXTENDS TO PELVIS 2A Adnexal involvement 2B Extra uterine pelvic tissues Stage 3 INVADES ABDOMINAL TISSUES 3A One site 3B > One site 3C Metastasis to pelvic & para aortic lymph nodes Stage 4 4A Invades bladder &/or rectum 4B Distant metastasis FIGO STAGING OF ESS

43. PROGNOSTIC FACTORS older patients (>50 yrs ) black race advanced stage nodal metastasis high mitotic count(>5/10HPF) CD10 negative lack of ER&PR Lack of primary surgery INDEPENDENT POOR PROGNOSIS ESS has a better life expectancy than other sarcomas

44. TREATMENT TAH + BSO (aggressive cytoreduction ) is the most effective treatment for ESS Considering the adverse effects of early surgical menopause, retention of ovarian function may be an option for premenopausal women with stage-I ESS . In all other stages, BSO is recommended PLND - for both prognostic and treatment purposes

45. ADJUVANT THERAPY

46. HORMONAL & TUMOR DIRECTED THERAPY The mechanism of action of progestins is to bind progesterone receptors and down regulate gene transcription leading to decreased endometrial gland and stromal proliferation. GnRH agonists down regulate GnRH receptors in the anterior pituitary leading to a hypoestrogenic state . megestrol / medroxy progesterone(160mg/d) gonadotropin releasing hormone (GnRH) analogues(7.5mg/month IM) aromatase inhibitors

47. MALIGNANT MIXED MÜLLERIAN TUMOURS

48. MALIGNANT MIXED MÜLLERIAN TUMOURS

49. MMT is a rare(0.6/1,00,000 women), highly aggressive, rapidly progressing neoplasm associated with a poor prognosis MMT is a biphasic tumour of the female genital tract, composed of epithelial and mesenchymal tissues. Median age - 62yrs. two categories: homologous and heterologous.

50. RISK FACTORS Nulliparity A dvanced age Obesity Exposure to exogenous estrogens Long-term use of tamoxifen Pelvic RT

51. Stage Extent Stage 1 Tumor confined to corpus uterii 1A <half of myometrium 1B >= half of myometrium Stage 2 Invasion of cervical stroma but does not extend beyond uterus Stage3 Loco-regional spread 3A Invades serosa of uterus / adnexa 3B Vaginal or parametrial involvement 3C Mets to pelvic &/or para aortic nodes 3C1 Pelvic nodes + 3C2 Para aortic nodes + Stage4 Distant metastasis 4A Invasion of bladder orbowel mucosa 4B Intra abdominal &/ or inguinal nodes CLASSIFICATION - MMTs are staged like CA endometrium

52. TYPICAL PATIENT PROFILE PRESENTING WITH UTERINE CARCINOSARCOMA Elderly female (usually 60–70 years), usually postmenopausal Presents with pyometra with vagina bleeding , bloody/watery discharge , abdominal pain , and/or mass (symptom triad) Often past history of tamoxifen use May be obese, hypertensive, nulliparous , and/or diabetic No previous history of uterine problems

53. DIAGNOSIS HISTOLOGY: unique biphasic morphology-both epithelial and mesenchymal elements IHC: express epithelial membrane antigen (EMA), pancytokeratin and stromal lineage markers in relation to their histological appearances such as desmin in muscle differentiation or S100 in areas with chondroid or lipomatous differentiation Overexpression of tyrosine kinase receptors such as HER-2( human epidermal growth factor receptor  ), EGFR( Epidermal growth factor receptor ), and KIT(a part of tyrosine kinase receptor)

54.   A-F:Homogeneous hyperintense intrauterine mass, enhancing with gadolinium,invades the myometrium. Lymphadenopathies are present, Surgery : large irregular mass Gross specimen: endometrial cavity completely occupied by a polypoid lobulated tumor gray and dun with white areas (4,5x3,5 cm). It invades the whole thickness of the uterine wall on the left side. On microscopic exam poorly differentiated areas predominate over areas of adenocarcinoma with squamous spots mixed with sarcomatous areas with muscular differentiation

55. on MRI uterine MMTs may be indistinguishable from endometrial carcinomas Enhancement equal to or greater than that of the myometrium suggests the possibility of this tumour -type CECT & 18 F-Fluorodeoxyglucose Positron Emission Tomography ( 18 F-PDG PET ) Scans are other modalities useful in diagnosis

56. TREATMENT The primary treatment option is surgery High rates of relapse and metastases postoperatively necessitate effective adjuvant therapies surgical practice recommended for uterine carcinosarcoma is surgical staging with TAH with BSO, pelvic lymphadenectomy, and para-aortic lymph-node sampling with peritoneal washings.

57. R adiotherapy contributes to decreased pelvic recurrences Controversies still remain regarding the techniques of radiation: localized pelvic radiation by vaginal brachytherapy versus whole abdominal radiation by external beam chemotherapy has a definitive role to minimize both local and distal recurrence A combination of paclitaxal & carboplatin results in RR of 80% and median disease free interval of 18months

58. CYTO-REDUCTION SURGERY + RADIATION (VAGINAL BRACHY/ EB RT) ? ROLE OF CYTO-REDUCTION SURGERY ADJUVANT CHEMOTHERAPY +HARMONAL THERAPY+MOLECULAR TARGETED THERAPY