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Uterine sarcoma mine

  1. 1. Uterine Sarcoma And Its Management G . Lakshmi Deepthi
  2. 2. Sarcoma : ( sarx -"flesh") is a cancer that arises from transformed cells of mesenchymal origin Uterine sarcomas arise from dividing cell populations in the myometrium or connective tissue elements within the endometrium Uterine sarcomas : 1% of female genital tract cancers 3-7% of uterine cancers
  3. 3. WHO classification 2014
  4. 4. WHO classification 2014
  5. 5. Uterine Sarcoma Classification : NCCN 2016 • Low grade endometrial stromal sarcoma(ESS) • High grade ESS • Undifferentiated Uterine Sarcoma(UUS) • Uterine Leiomyosarcoma (uLMS) Other Rare Uterine Mesenchymal Sarcoma Subtypes : • Adenosarcoma • PEComas • Rhabdomyosarcoma
  6. 6. General Features :  Each group of tumors is distinct with respect to pattern of spread, pathologic features, prognostic factors and response to treatment.  Incidence : carcinosarcomas (45%) > leiomyosarcomas, (40%) > endometrial stromal sarcomas(15%)  Age-related incidences vary among the histologic types. The mean age at diagnosis for endometrial stromal sarcoma is 41 years, for leiomyosarcoma 53.5 years, for adenosarcoma 57.4 years, and for carcinosarcoma 65 years  Staging system different for each Leiomyosarcoma and ESS Adenosarcoma Carcinosarcoma
  7. 7. Rare sarcomas  Clinical features  Pathology  Diagnostic workup  Treatment • Leiomyosarcoma • ESS • Carcinosarcoma
  8. 8. Leiomyosarcoma malignant neoplasm composed of cells demonstrating smooth muscle differentiation true sarcomas  1-2% of all uterine tumors  30% of all uterine sarcomas  >40yrs of age  Presentation : vaginal bleeding (56%) pelvic mass(54%) pelvic pain (22%)
  9. 9. Diagnosis:  Preoperative– endometrial sampling pelvic ultrasound MRI CT chest  Postoperative – ---No second surgical procedure for the sole purpose of staging. ---postop CT of the chest, abdomen, and pelvis.
  10. 10.  Pelvic ultrasound is typically the first-line study  S/o sarcoma --mixed echogenic and poor echogenic parts; central necrosis  Color Doppler -- irregular vessel distribution, low impedance to flow, and high peak systolic velocity  CT does not reliably differentiate between leiomyomas and uterine sarcomas
  11. 11. T1 MR T2 MR • MRI vary and include a lobulated mass of high-signal intensity on T2- weighted images, • scattered foci of haemorrhages or necrosis • These necrotic areas are -- slightly higher intensity on T1-weighted images and as heterogeneous areas on T2-weighted images. • A consistent finding -- the absence of calcifications.
  12. 12. Pathology : Gross:  solitary intramural masses  Average 8cm in diameter  fleshy with poorly defined margins.  Cut section : typically soft, bulging, fleshy, necrotic, hemorrhagic, and lacks the prominent whorled appearance of leiomyomas. Microscopic :Stanford criteria High nuclear atypia Coagulative necrosis High mitotic rate
  13. 13. Variants : Epitheloid : Necrosis absent Mild nuclear atypia Less mitotic rate Myxoid : hypo cellular Mild nuclear atypia
  14. 14. IHC :  Positive for smooth muscle markers Desmin ,H-Caldeson , actin, histone deacetylase 8  Epitheloid and myxoid variants are less immunoreactive  Epitheloid –keratin ,EMA positive  ER+,PR +,androgen receptor + --30-40 % of cases  Ki 67 increased  P16 overexpressed – differentiate between benign and malignant
  15. 15. Staging :FIGO 2009
  16. 16. Total abdominal Hysterectomy +/- B/L Salpingo-oopherectomy TREATMENT Disease confined to uterus Disease extending outside uterus TAH with BSO and surgical cytoreduction of intra- abdominal and retroperitoneal disease
  17. 17. Lymphadenectomy ???  If the pelvic nodes are palpably enlarged intraoperatively  there is evidence of extrauterine disease LN involvement <5% 1992
  18. 18. Prognostic factors :  Tumor size (>10cm)  Mitotic rate (20 MF/10HPF)  Ki 67 (>10%)  Bcl 2 (Negative) Overall prognosis :  Poor even in stage I disease  Recurrence – 53-71% ---lungs -40% Pelvis – 13%  5yr survival – 15-25% of cases  Median survival – 10 months STAGE 5YR OS I 76% II 60% III 45% IV 29%
  19. 19. Adjuvant Treatment :  Chemotherapy or Pelvic radiation can be considered following surgery for leiomyosarcoma (LMS).  However, whether any form of adjuvant therapy improves survival compared with observation is not known.  Early stage disease (I or II)– it is not clear if any intervention improves the survival outcomes compared with post-surgical surveillance. Observation is preferred
  20. 20. Neither PFS, nor OS nor pelvic control was improved by radiotherapy. Therefore, radiation therapy is not indicated in patients with stage I or II LMS after complete resection
  21. 21. Stage I or II sarcomas, varied histology • women treated with doxorubicin had a lower recurrence rate compared with those not treated with chemotherapy (41 versus 53 percent), this was not statistically significant. • In addition, adjuvant doxorubicin had no impact on progression-free or overall survival.
  22. 22. • To estimate 2yr and 3yr PFS….n=46 • 4 cycles of gemcitabine plus docetaxel f/b 4 cycles of doxorubicin • 2yr PFS – 78% 3yr PFS – 57% • median time to recurrence was 27 month N=27 Single arm,phase II Completely resected I-IV2yr PFS-59% Median PFS -39months
  23. 23. Advanced stage – Radiotherapy?? • Sampath et al.--significantly reduced local failure rate at 5 years of 2%, compared with 16% in the surgery-alone group
  24. 24. NCCN– 2B Recommendation in LMS  high rates of initial metastatic failure in LMS  adjuvant pelvic radiotherapy does not appear to have a survival benefit in LMS,  although it may reduce local pelvic recurrences, possibly for disease that has spread beyond the uterus (FIGO stages II–IV) so might be considered for these higher risk women in order to improve local disease control.
  25. 25. Chemotherapy In Uterine Leiomyosarcomas : GOG 277
  26. 26.  chemotherapy with doxorubicin or docetaxel/gemcitabine is now used for advanced or recurrent disease, with response rates ranging from 27% to 36%
  27. 27. • Early-stage --leiomyosarcoma, carcinosarcoma, and endometrial stromal sarcoma • CRT arm--increased 3-year DFS (55% vs 41%; P=0.048), • But no improvement in 3-year OS Combined Modality
  28. 28. Metastatic or inoperable disease :  Palliative intent.  Chemotherapy --good performance status and in whom organ function permits the use of cytotoxic chemotherapy.  For other patients--palliative care  Doxorubicin-based treatment first-line choice.  Gemcitabine plus docetaxel--first- or second- line therapy
  29. 29. Alternatives Or Second Line Therapy:  Doxorubicin based  Gemcitabine alone RR-20%  Ifosfamide alone – RR-17%  Ifosfamide + Doxorubicin – RR 30%  Trabectedin –progression on anthracyclines –ORR- 16%  Pazopanib  Erbulin  Endocrine Therapy– ORR<10%--Aromatase inhibitors can be considered for ER/PR- expressing uLMS
  30. 30. Follow Up:  Physical exam every three to four months and chest, abdomen, and pelvic imaging every three to four months for two to three years,  every 6 to 12 months for the next two years. Recurrence
  31. 31. STUMP :Smooth Muscle Tumors Of Uncertain Malignant Potential  Have high malignancy features but not falling into diagnostic criteria for leiomyosarcoma .  Microscopic : tumor cell necrosis necrosis of uncertain type >10 MF/10HPF diffuse atypia borderline mitotic counts  Favorable prognosis  Treatment – only follow up after total hysterectomy
  32. 32. Endometrial Stromal Sarcoma • 0.2–1% of all uterine malignancies • 6–20% of all uterine sarcomas
  33. 33. Norris and Taylor 1965 (old terminology)  Endometrial Stromal Nodule  Endometrial Stromal Sarcoma – Low grade (< 10 mits/10 hpf) High grade (>10 mits/10 hpf)  Undifferentiated Uterine Sarcoma Mitotic rate does not predict recurrence WHO Classification 2004
  34. 34. WHO 2004  Endometrial Stromal Nodule  Endometrial Stromal Sarcoma (“low grade”)  Undifferentiated Uterine Sarcoma WHO 2014  Endometrial stromal nodule (ESN)  Low grade ESS  High grade ESS  Undifferentiated Cytogenetics
  35. 35.  2nd most common mesenchymal uterine tumors (<10%)  ESN and low grade ESS are similar in morphologic ,IHC , molecular features differentiation based on the myoinvasive growth pattern and LVI
  36. 36. ESN :  Rare ,benign  Premenopausal  Presentation – abnormal bleeding or abdominal or pelvic pain  10% - asymptomatic  Gross – well circumscribed non encapsulated fleshy yellow to tan nodule  Location – myometrium ,protruding into endometrium  Infarct type necrosis – 60%  Cyst formation – 30%
  37. 37. CD 10+ Microscopic :  Expansile  non infiltrative border  Compresses surrounding myometrium and endometrium  Has finger like projections into myometrium Length -3mm Number < 3
  38. 38.  If length >3mm number > 3 LVI +  satellite nodules focal infiltrative growth Treatment :  Hysterectomy only– Benign  Follow up Low grade ESS ESN with limited invasion
  39. 39. LGESS  History and presentation same as ESN  Premenopausal  Intial presentation – mostly intrauterine rarely with metastasis to lungs and ovaries  lymph node metastasis – 10%  Gross – involves endometrium soft ,tan to yellow polyp- infarcted/haemorrhagic Invades myometrium
  40. 40. Microscopic :  Formation of irregular , pink ,tan yellow cords or nodules of tumor  Involves endometrium and infiltrates myometrium as irregular tongues with LVI  Well differentiated endometrial stromal cells  Mild nuclear atypia  Necrosis rare
  41. 41. IHC :  ER+ PR+ Androgen + WT-1 +  CD 10 ++  Smooth muscle actin +  Desmin less positive,30%  Negative – HDAC8 , H caldesmin  Nuclear Beta catenin + in 40% of cases
  42. 42. Cytogenetics :  The most common translocation involves the short arm of chromosome 7 and the long arm of chromosome 17 [t(7;17)] leading to fusion of two zinc finger genes, JAZF1 and JJAZ1 (also referred to as SUZ12), and the production of the JAZF1/JJAZ1 gene fusion protein.  This is characteristic of ESS  Function of JAZF1, JJAZ1, or the JAZF1/JJAZ1 gene fusion has not been determined; however, in cultured cells, the fusion gene appears to modulate cell survival and proliferation  Other gene fusion proteins : t(6;7) JAZF1/PHF1 t(6;10) EPC1/PHF1
  43. 43. Nature : LGESS  low grade  Favorable prognosis  Stage is prognostic STAGE 5Yr survival I, II 90% III, IV 50% Course :  Indolent  Late recurrences – early stage – 36-56% recurrences  Median time for recurrence – stage I-65months stage III,IV -9 months
  44. 44. High Grade ESS :  Features between low grade ESS and undifferentiated  Age -28-67yrs  Presentation – abnormal vaginal bleeding enlarged uterus pelvic mass  Gross – intracavitatory polypoid and pelvic mass size upto 9cm  Shows extrauterine extension at time Of diagnosis
  45. 45. Cut section :  Fleshy with extensive areas of necrosis and haemorrhage Microscopic:  High grade round cells with low grade spindle cell component – fibromyxoid  Mitotic activity - >10/10HPF  Necrosis +
  46. 46. IHC :  C Kit + ER - PR - CD 10 - CYCLIN D1 ++
  47. 47. Cytogenetics :  The t(10;17) rearrangement results in a 14-3-3 fusion to FAM22 (known as YWHAE-FAM22), leading to aberrant localization of 14-3-3 in the nucleus and possible oncogenic transformation  is associated with a high-grade variant of ESS  Clinically more aggressive and carries a worse prognosis  However, it does not display prominent nuclear pleomorphism, which is generally seen with UES
  48. 48. Undifferentiated :  Heterogeneous group of sarcomas lacking diagnostic criteria for: ESS LMS Adenosarcoma with sarcomatous overgrowth Carcinosarcoma/poorly differentiated carcinoma  UES also expresses the receptor tyrosine kinase CD117 (c-KIT) and human epidermal growth factor receptor 2 (HER2 or ERBB2), which are not typically found in ESS.  Unlike ESS, there are no known chromosomal abnormalities associated with UES.
  49. 49.  Rare  Post menopausal -60yrs  Presentation : post menopausal bleeding complaints secondary to extra-uterine disease  Usual presentation with Stage III,IV disease UES is always a diagnosis of exclusion
  50. 50. Microscopic :  Myometrial invasion  Nuclear pleomorphism  High mitotic activity  Tumor cell necrosis lack smooth muscle or endometrial stromal differentiation  They lack the typical growth pattern and vascularity of low grade ESS and displace the myometrium in contrast to the infiltrative pattern of low grade ESS
  51. 51. Uniform type Pleomorphic type
  52. 52. Imaging : • Ultrasound—non specific typically characterized as a heterogeneous hypoechoic endometrial mass, which can show extensive myometrial involvement
  53. 53. larger size, more contrast enhancement, irregular margin, nodular extension into the myometrium, and marginal nodularity due to tumor extension along vessels and lymphatics
  54. 54. Staging :FIGO 2009
  55. 55. Diagnosis BIOPSY POST HYSTERECTOMY • Baseline imaging • Confined to uterus– TAH+BSO • Extra uterine disease + Maximal Cytoreduction NO MORCELLATION NO Ovary Sparing • Baseline imaging • No second surgery for staging
  56. 56. 2
  57. 57. Role of Cytoreduction !!! • High-grade ESS, <2 cm of residual disease -- longer median OS – 52 versus 2 months • Low grade ESS – No clear role
  58. 58.  older patients  black race  advanced stage  higher grade  lack of primary surgery,  nodal metastasis
  59. 59. Adjuvant Therapy :  ESN – None  Low grade ESS – Stage I –observation Stage II-IV – hormonal therapy Radiotherapy can be given to reduce local recurrences  High grade ESS and Undiferrentiated ESS Adjuvant therapy to be given in all stages
  60. 60. Low Grade ESS : no significant differences in the rate of recurrence between surveillance vs. adjuvant RT vs. progestin therapy STAGE 5yr OS 10yr OS I 84% 77% II 62% 49% III 58% - IV 37% - STAGE I
  61. 61. Hormonal Therapy  Only in Low grade ESS Options :  Progestins--megestrol/medroxy progesterone  Aromatase inhibitors– Letrozole/Anastrazole  Gnrh Analogues Tamoxifen, as well as hormonal replacement therapy containing estrogens are contraindicated in patients after treatment of ESS
  62. 62. Basis : Primary ESS ER α PR α PR β ERα ERβ PRα PRβ STEROIDS Proliferation and Differentiation of endometrial Stromal cells Normal endometrium Recurrent ESS ER α PR α PRβ Progestin's -- antiestrogenic activity after binding to progesterone receptor Medroxyprogesterone acetate (MPA)(250mg daily) Megestrole acetate (160mg daily) • Side effects : dramatic weight gain related to glucocorticoid activity, severe depression and thrombo- embolic complications
  63. 63. • Aromatase inhibitors :-- reduce estrogen levels by inhibiting estrogen synthesis in peripheral sites and tumor tissues, which leads to reduced receptor-mediated growth stimulation 1st generation—aminoglutethemide 2nd generation—formestan,fadrozol 3rdgen. –nonsteroidal -- exesmestane(25mgday) letrozole(2.5mg/day) steroidal– anastrazole(1mg/day) • Gnrh Analogues :-they suppress ovarian estrogen production. additional growth inhibitory effect via intratumoral modulation of mitogenic signaling of growth factor receptors leuprolide, gosereline, triptorelin
  64. 64. Drug of choice –Aromatase inhibitor
  65. 65. Cytotoxic chemotherapy: ifosfamide , doxorubicin –most active  Hormonal options is exhausted  in the absence of hormonal receptors  when progression into a high-grade malignancy occurs Duration???
  66. 66. Radiotherapy??? Radiotherapy helps to improve local control Can be given in stage II-IV ESS
  67. 67. ESS :  Sampath et al.--showed a significant decrease in 5- year local–regional recurrence rate  Most studies--improvement in local control with adjuvant radiotherapy
  68. 68. Undifferentiated ESS:  Poor OS regardless of stage  Due to high risk of recurrence regardless of stage , adjuvant chemotherapy should be given to all patients with UES.  Combination regimen eg: gemcitabine plus docetaxel is preferred STAGE MEDIAN PFS MEDIAN OS I 15months 27months II-IV 7months 12months
  69. 69. Follow Up : NCCN • physical exam every three months for the first two years and then every 6 to 12 months. • CT scans of the chest, abdomen, and pelvis every 6 to 12 months (or as clinically indicated) for the first five years • Long term surveillance with CT scans shouldn't be done.
  70. 70. Recurrent disease :  abdomen/pelvis (40 to 50 %)  lung ( 25 %)  Rare- spine  Treatment naïve --- hormone therapy • Recurrent disease post treatment • Metastatic disease Cytotoxic chemotherapy STAGE MEDIAN TIME I AND II 65 months III AND IV 9 months
  71. 71. Carcinosarcoma
  72. 72. Mixed epithelial and mesenchymal tumours : Tumours of the uterine corpus composed of an epithelial and a mesenchymal component.  Carcinosarcoma **  Adenosarcoma  Carcinofibroma  Adenofibroma  Adenomyoma Atypical polypoid variant
  73. 73. Carcinosarcoma(MMMT)  composed of an admixture of malignant epithelial and mesenchymal components.  <5 percent of all uterine malignancies  7th decade  Most common among sarcomas  Risk factors : obesity , diabetes , nulliparity,tamoxifen prior pelvic radiation  Presentation : vaginal bleeding >abdominal mass>pelvic pain  Examination : polypoid mass protruding through cervix and presents as upper vaginal mass
  74. 74. There are 4 main theories regarding the histogenesis of CS: (1) the collision theory, (2) the combination theory, (3) the conversion theory (4) the composition theory . Now its clear that CS arises through conversion and metaplasia Dedifferentiated or Metaplastic endometrial carcinoma
  75. 75. Imaging :  Ultrasound - hyperechoic compared with the myometrium. In addition, expansion of the endometrial canal is seen • CT scan —a heterogenous, ill defined, hypodense mass with concomitant dilatation of the endometrial canal..
  76. 76. MRI :  enlarged uterus with a widened endometrial cavity and evidence of deep myometrial invasion.  Heterogenous bulky mass protruding into cervix  Prolonged intense enhancement CT
  77. 77.  FDG PET/CT –useful for diagnostic and initial staging purposes. CS is generally positive on PET scan; the mean standardized uptake value (SUV) of 10+/-5.5  CA-125:  Preoperative CA125 elevation is a marker of extrauterine disease and deep myometrial invasion.  Postoperative CA125 elevation is an independent prognostic factor for poor survival
  78. 78. Macroscopic : Polypoid , bulky, necrotic and hemorrhagic filling endometrium and invading myometrium Epithelial Mesenchymal Glandular Non glandular Homologous Heterologous endometroid squamous Undifferentiated Endometrial sarcoma Rhabdomyosarc oma serous undifferentiated Leiomyosarcoma chondrosarcoma Clear cell ESS liposarcoma Microscopic – Biphasic • Most common combination : high-grade serous carcinoma and an endometrial stromal sarcoma
  79. 79. Uterine carcinosarcoma is a histologic diagnosis IHC : epithelial—anticytokeratin + mesenchymal –vimentin +
  80. 80. Staging :FIGO 2009
  81. 81. Treatment :  Complete surgery -- total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, cytology of peritoneal washings, omentectomy, and biopsies of peritoneal surfaces • Lymphadenectomy is significantly associated with improved overall survival in patients with Stage I- III uterine carcinosarcoma • No survival benefit with radiotherapy
  82. 82. Adjuvant therapy : Stage Ia :  No trials have evaluated the value of adjuvant chemotherapy specifically in women with stage IA disease  GOG 20– adjuvant doxorubicin vs surveillance. Low recurrence rates  GOG 55874- Adjuvant RT vs surveillance low local recurrence
  83. 83. Stage IB-IV :  Adjuvant chemotherapy is preferred rather than RT or observation . Local relapse-- 44%-24%
  84. 84.  whole abdominal- pelvic irradiation - 30.6 Gy to the whole abdomen and pelvis, f/b a 19.8 Gy pelvic boost or three cycles of cisplatin, ifosfamide and mesna (CIM)  No statistically significant difference was found in OS (45% CIM v 35% WAI) or DFS---58% WAI v 52% CIM  WAI led to a decline - vaginal failures (4% v 10%), no difference in pelvic failures (13%).  Estimated 5yr survival– 35% (WAI) vs 45% ( chemotherapy)  Adjuvant radiotherapy –more late complications Uncertain Role
  85. 85. Chemotherapy regimen: Single Agent Chemotherapy :  Ifosfamide (36%) • etoposide (6.5%) • doxorubicin (9.8%) • cisplatin (18%) • paclitaxel (18%) • topotecan (10%) The regimen of chemotherapy recommended for use in early stage disease is the same as for late stage disease
  86. 86. GOG trials for Carcinosarcoma: GOG 261, a Phase 3 randomized trial of ifosfamide and paclitaxel versus carboplatin and paclitaxel is ongoing…
  87. 87. Role of radiotherapy!!! • Smith et al. & Nemani et al.—no survival benefit associated with adjuvant radiotherapy in stage I–III carcinosarcoma, • whereas Smith et al-- overall survival benefit -stage IV disease • Sampath et al.-decrease in local failure no change in overall survival
  88. 88. EORTC : GCG 55874 study –CS • 224 patients –LMS(99), CS(92), and ESS(30). • External beam pelvic radiotherapy with observation in FIGO stage I and II disease . • With a median follow- up of 6.8 years, no difference was found in overall survival or disease-free survival . pelvic recurrences local recurrences Surgery alone 24% 47% Surgery + RT 4% 24%
  89. 89. Rare Sarcomas :  Adenosarcoma  PEComa  Rhabdomyosarcoma
  90. 90. Adenosarcoma :  Mixed tumor of low malignant potential  Benign glandular elements +low grade sarcoma  5-10% of all sarcomas  all ages, ranging from 15-90 years --median age at diagnosis of 58.  Risk factors :tamoxifen therapy for breast cancer prior pelvic radiation  Origin : endometrium in lower uterine segment rare-endocervix  Presentation :abnormal vaginal bleeding, an enlarged uterus and tissue protruding from the external os
  91. 91. Gross : polypoid tumors of approximately 5–6 cm in maximum diameter (range, 1–20 cm) that typically fill and distend the uterine cavity Cut section – • tan brown with foci of haemorrhage and necrosis. • Small cysts • mostly do not invade myometrium
  92. 92. Microscopic :  Periglandular cuffs—stroma concentrates around glands  Mild nuclear atypia  Few or no mitosis  Mesenchymal elements -10- 15% cases • Adenosarcoma With Sarcomatoid Overgrowth : Pure sarcomatous component >25% of total tumor volume • IHC : CD 10+ PR+ Ki 67+ cytokeratins
  93. 93. FIGO staging 2009 :
  94. 94.  low grade  Recurs --25-40% of cases, typically in the pelvis or vagina, and distant metastasis 5%  Poor prognostic -- extrauterine spread, deep myometrial invasion sarcomatous overgrowth. Vascular invasion  Long- term follow-up is necessary because recurrences may manifest after many years. TREATMENT :  TAH+BSO  If sarcomatous overgrowth – adjuvant pelvic radiotherapy.
  95. 95. PEComa(Perivascular epithelioid cell tumor):  Poorly defined, rare tumors characterized by varying amounts of epithelioid and spindle cells with clear to eosinophilic, granular cytoplasm that is HMB45+ in a diffuse or focal pattern  Mean age of 45 years (range, 9 - 79 years)  ~50 cases reported in English language literature  Sites-uterus and retroperitoneum  2 types – Benign & Malignant  Etiology unknown  Aggresive in nature and recurs post hysterectomy
  96. 96. Gross:  polypoid mass  Solitary or rarely multifocal mass in uterine corpus from 0.6 to 12.0 cm (mean of 4.7 cm)  Cut sections may be grayish white, tan or yellow with whorled or soft, fleshy, ill defined or rarely circumscribed margins BENIGN: • tongue-like growth pattern similar to LGESS; • well defined cell borders, abundant granular or clear to eosinophilic cytoplasm, • Usually no / mild pleomorphism.no mitotic figures,no necrosis • Strong, diffuse cytoplasmic HMB45 expression and focal muscle marker expression Microscopic : BENIGN OR MALIGNANT
  97. 97. Malignant :  diffuse sheets of cells, separately by occasional small, hyalinized bundles and plaques of stroma;  contain primarily perivascular epithelioid cells (> 50% are round or polygonal)  focal HMB45 expression, and  strong, extensive muscle marker expression  malignant features include mitotic activity > 1/10 HPF, necrosis, tumor size > 5 cm, infiltrative growth pattern, high nuclear grade, cytologic atypia, high cellularity, lymphovascular invasion, infiltration
  98. 98. Positive Stains :  HMB45, SMA (73%), p53 (50%), melanA / MART1 (24% - 67%)  Also calponin, vimentin, h-caldesmon; PR (50%), desmin (49%), muscle specific actin (36%), ER (33%), CD10 (25%) Treatment : Hysterectomy, with or without adjuvant chemotherapy and radiotherapy
  99. 99. Rhabdomyosarcoma :  Pure rhabdomyosarcoma arising in the uterus is a very rare tumor  mainly in elderly women,  highly malignant tumors with frequent extrauterine spread at presentation.  Patients rarely survive beyond 15 months.
  100. 100.  uterine cervix and corpus are the most frequent locations of RMS in adult women.  Three categories: embryonal, alveolar, and pleomorphic  In postmenopausal women, uterine RMSs appear to be entirely the pleomorphic type with extremely poor clinical outcome.  The median progression-free survival (PFS) and disease- specific survival was 9 months and 21 months respectively.  The 5- year disease-specific survival was only 29%
  101. 101. Radiotherapy practice:  No role of upfront Radiotherapy  It is given in adjuvant settings post surgery Indications :  High grade and undifferentiated endometrial sarcomas  Adenosarcomas, especially with sarcomatous overgrowth.  Carcinosarcomas early-stage comprehensively staged patients, intravaginal RT and chemotherapy stage III concurrent pelvic RT and cisplatin followed by carboplatin/paclitaxel.
  102. 102. Technique :  CT based planning with CT taken with full bladder
  103. 103. PTV final = ITV Vault + PTV total
  104. 104. Dose to PTV final : 50Gy/25#/5wks  In case of carcinosarcoma We usually give Radiotherapy in a sandwich pattern with chemotherapy
  105. 105. Chemotherapy in practice:  LMS  High grade ESS  Carcinosarcoma – Inj paclitaxel 175mg/m2 Inj carboplatin 5 AUC  Low grade ESS – Letrozole 2.5mg OD IAP 3 weekly for 6 cycles Inj ifosfamide 1.2gm/m2 Inj adriamycin 20mg/m2 Inj Cisplatin 50mg/m2
  106. 106. Targeted Treatment :
  107. 107. • Retrospective review of medical records of patients of uterine sarcoma (20022007) • 42 (15 CS, 12 ESS, 11 LMS, 3 UES, and 1 mixed sarcoma • Adjuvant radiation, chemoradiation, and chemotherapy were offered. Pelvic radiation: 46 Gray/23 fractions/4.5 weeks and vincristine, adriamycin, cyclophosphamide (VAC) regimen were most commonly used • Median OS of only 6.57, 6.8, and 9.38 months, respectively, in patients with carcinosarcoma, leiomyosarcoma, and UES • Disease stage (p = 0.005) and response to therapy (p = 0.01)—predictors of OS • Small series, poor treatment compliance and socioeconomic constraints in the indian scenario were the limiting factors
  108. 108. Conclusion :  Uterine sarcomas are very aggressive neoplasms  No imaging modality can offer a reliable preoperative diagnosis  As a result, centralisation, large series, and randomised trials are problematic.  Aggressive surgical cytoreduction at the time of initial diagnosis offers the best survival  To date, no effective adjuvant therapy has been found to prolong the survival of women with uterine sarcomas.  More RCTs are needed to determine the value and regime of adjuvant therapy
  109. 109. Thank you…

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