Uterine Cancer 子宮體癌

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1 Uterine Cancer 子宮體癌 (Endometrial Cancer &. Sarcoma) 北榮婦產趙灌中副院長

2 Endometrial Cancer Developed countries The 1st gynecologic malignancy Developing countries 2nd most common gynecologic malignancy NCI data 49,560 new cases diagnosed 8,190 death Median age 62 y/o NCI &. SEER database Int J Gynecol Obstet 95(1):S , 2006

3 Endometrial Cancer in Taiwan

4 Taiwan &. VGH-TPE 最新國健局全國資料台北榮總資料

5 Risk Factors 危險因子相關風險值 Relative Risk (R.R.) 年齡較大年紀 50 ~70 歲 ( 1.4 ) 雌激素治療 2 ~10 停經時間晚 ( 停經年齡 > 55 歲 ) 2 無生育過 2 多囊性卵巢症候群 3 肥胖 2 to 4 糖尿病 2 Lynch syndrome (hereditary nonpolyposis colorectal cancer) Tamoxifen 2 月經提早來雌激素分泌腫瘤 22 to 50 percent lifetime risk Not available Not available

胖 2 to 4 糖尿病 2 Lynch syndrome (hereditary nonpolyposis colorectal cancer)

6 Histopathology 內膜癌最常見的組織學型態 : endometrioid adenocarcinoma 內膜癌分成 Type 1 及 Type 2 Characteristic Type I(80%) Type II(20%) 雌激素表現有無腫瘤生長速度慢快初期病灶 Atypical hyperplasia Endometrial intraepithelial carcinoma (EIN) 組織學型態 Endometrioid Serous, Clear cell 細胞分級 Low(grade 1,2) High(grade 3) 侵犯深度表層較深基因表現 PTEN or KRAS gene mutation; Microsatellite instability p53 mutation 預後較好較差

Endometrial intraepithelial carcinoma (EIN) 組織學型態 Endometrioid Serous, Clear cell 細胞分級 Low(grade

7 Histopathology endometrial carcinoma serous carcinoma clear cell carcinoma 腺體分佈低核質比細胞 solid growth. 高核質比細胞細胞核形狀多變化 p53 染色呈陽性細胞呈 hobnail 型態細胞內有漿液分佈低核質比細胞細胞核形狀多變化

8 Mechanism of Tumorigenesis 最常為隨機的細胞突變造成 (~90%) 只有 5~10% 為遺傳性的細胞突變造成, 這些會具有以下特點較平均年齡早 10~20 年發生與 Lynch syndrome (HNPCC, heredity non-polyposis colorectal cancer ) 有關係特定 DNA 修補出現問題 MSH2, MSH6, MLH1 mutation EpCAM (CD326) deletion Colorectal cancer, ovarian cancer 這些病人可以採行預防性的子宮併雙側卵巢切除

non-polyposis colorectal cancer ) 有關係特定 DNA 修補出現問題 MSH2, MSH6, MLH1 mutation

9 Clinical Symptoms 最常見的臨床表現不正常陰道出血或停經後出血 75 ~ 90% 停經後出血 : 3 ~ 20 % 發現有內膜癌年齡 >45 歲 ~ 停經的病人要考慮到內膜癌可能 : 經血量過多, 經期間出血, 經期不規則年齡 <45 歲 : 曾使用雌激素治療, 肥胖, 多囊性卵巢 lynch syndrome 但大部分的停經後出血原因為下 ~ Cause of bleeding (PMB) Percentage (%) Endometrial atrophy 60~80 Eestrogen replacement therapy 15~25 Endometrial polyps 2~12 Endometrial hyperplasia 5~10 Endometrial cancer 10 Novak s Textbook

syndrome 但大部分的停經後出血原因為下 ~ Cause of bleeding (PMB) Percentage (%) Endometrial atrophy 60~80 Eestrogen

10 Evaluation of Women Suspected Endometrial Cancer 抹片 35~50% 預測率抹片結果及代表意義 : Adenocarcinoma maybe either cervix or endometrium further evaluation with cervical and endometrial biopsy Atypical glandular cells endometrial and endocervical biopsy (fractional D&C) Endometrial cells more in women 40 y/o normal endometrial cells on cytology in asymptomatic premenopausal women : rarely associated with pathology symptomatic or high risk women requiring further evaluation

$endocervical biopsy (fractional D&C) Endometrial cells more in women 40 y/o normal endometrial cells on cytology in$

11 Evaluation of Women Suspected Endometrial Cancer 腫瘤指數 (CA-125) 篩檢效果差 Overall Survival (VGH-TPE) > 35 U/ml : 只能當作預後較差的指標 Log-Rank: p=.000 CA CA-125 >35

12 Evaluation of Women Suspected Endometrial Cancer 陰道超音波生育年齡 : 8-16 mm 停經後 4-8 mm 4~5 mm: 危險性小 (1/997) 從內膜增生型態推測 Type of Hyperplasia Cystic without atypia - Simple Adenomatous without atypia -Complex Cystic with atypia - Atypical simple Adenomatous with atypia - Atypical complex Progression to Cancer 1 % 3 % 8 % 29 % Novak s Textbook

Simple Adenomatous without atypia -Complex Cystic with atypia - Atypical simple

13 Diagnosis 內膜切片 False-negative rate : nearly 10% 內膜括搔 Gold standard 子宮鏡檢查 For endometrial mass-like or polyp-like lesions

14 FIGO staging system(2009) NCCN 2013

or nonmorular growth pattern > 50% nonsquamous or

15 Pathological grade Grade 1 Grade 2 Grade 3 < 5% nonsquamous or nonmorular growth pattern 6~50% nonsquamous or nonmorular growth pattern > 50% nonsquamous or nonmorular growth pattern Novak s Textbook Clinical Gynecology Oncology 2012

16 Primary treatment 手術後接續化學治療分期手術 (staging surgery) TAH (total abdominal hysterectomy) BSO (bilateral salpingo-oophorectomy) PLND (pelvic lymph nodes dissection) PALNS (para-aortic lymph node sampling) Washing cytology 根除性子宮切除 (Radical hysterectomy ) Cervix is grossly involved, stage 2 腹腔鏡分期手術 (Laparoscopic staging surgery) Conventional Robertic

PALNS (para-aortic lymph node sampling) Washing cytology 根除性子宮切除 (Radical hysterectomy

17 Importance of LN dissection 淋巴轉移對內膜癌的重要性骨盆腔及主動脈淋巴在 Stage 1 時就有轉移的可能性 2012 NCCN : 骨盆腔淋巴結需要做到腎臟血管的高度, 預後較好 NCCN 2012 Int J Gyn Oncol 2007

18 Importance of other risk factors 年紀 > 60 歲淋巴血管侵犯 LVSI (lymph-vascular space invasion) 腫瘤大小 2 公分子宮頸或子宮內頸侵犯子宮肌層侵犯腹腔細胞採樣陽性子宮附屬器官侵犯

19 Choice of adjuvant therapy 依疾病發展程度決定之後治療方式 Low-risk 不需進一步的化學或放射治療 ( 包含 Endometrioid histology, grade 1 / 2, confined to endometrium ) Intermediate-risk 臨床局部復發率高, 但遠處轉移機率低 Post-operative radiation therapy ( 包含 Myometrial invasion (stage IA,IB), cervical stromal invasion (stage II), outer one-third myometrial invasion, grade 2 or 3 disease, lymphovascular invasion) High-risk disease 須合併化學及放射治療 ( 包含 Gross involvement of cervix, stage III / IV, uterine serous carcinoma / clear cell carcinoma, lower uterine segment involvement)

cervical stromal invasion (stage II), outer one-third myometrial invasion, grade 2 or 3 disease, lymphovascular invasion) High-risk disease 須合

20 Chemotherapy 化學治療藥物種類 Cisplatin/Doxorubicin/Paclitaxel (category 1) Cisplatin/Doxorubicin (category 1) Ifosfamide/Paclitaxel (category 1 for carcinosarcoma) Carboplatin/Paclitaxel Cisplatin Carboplatin Doxorubicin Liposomal doxorubicin Paclitaxel Ifosfamide NCI &. SEER database

for carcinosarcoma) Carboplatin/Paclitaxel Cisplatin Carboplatin

21 Radiotherapy 放射治療 National Cancer Institute (NCI) 可以控制局部復發但對於存活率無影響陰道內放射治療對於早期內膜癌 (stage I ) 有治療效果 NCI &. SEER database

22 Choice of Radiotherapy Novak s Textbook

23 Hormone therapy 治療機轉 Produce a secretory differentiation 減少雌激素受體的功能減少內膜細胞的分化促進細胞凋亡有些可以減少血管增生 Progestational agent Tamoxifen Aromatase inhibitor Megestrol NCI &. SEER database

24 Prognosis &. Overall survival Global data : VGH-TPE data : Stage 1 Stage 2 Stage 3 Stage 4 Log-Rank: p=.000 Novak s Textbook Clinical Gynecology Oncology 2012

25 Prognostic biomarkers 臨床上不常用但也可以用來預測預後的生物指標 Level of evidence Biomarker From P Reference Consistently in several DNA ploidy IHC, F Cancer Mar 1;109(5): studies AJOG Oct;155(4): ER PR IHC Gynecol Oncol Aug;106(2): AJOG Apr;196(4):386.e1-9 P53 IHC J Clin Oncol May;17(5): Ki-67 IHC Hum Pathol Jun;35(6): Bcl-2 IHC Hum Pathol Jun;35(6): MMP-2 IHC GO;104(1) January 2007.p In some studies, inconsistently In a few studies, but with potential Treatment relevance EGFR IHC Gyecol Oncol 1994; 53:84. HER-2 neu IHC J Clin Oncol May 20;24(15): PTEN IHC Int J Cancer Jan 1;91(1):22-6. MSI IHC Cancer Res Mar 15;60(6): β-catenin IHC J Clin Oncol Apr 1;22(7): K-ras IHC Mod Pathol Apr;15(4): Angiogenic IHC Cancer Res Mar 15;66(6): phenotype (VEGF-A, etc) E-cadherin IHC J Clin Oncol Apr 1;22(7):

26 Fertility preserve (new issue) 小於 45 歲 : 約佔內膜癌 3~14 % 大部分為慢性不排卵多為早期及低分化型 (early stage &. low grade) 生育保留治療 Stage IA, grade 1, endometrioid adenocarcinomas LVSI (-), myometrial/ cervical invasion (-), LN (-) 手術後使用六個月荷爾蒙治療 MPA ( mg) Megestrol ( mg) Tamoxifen (30 mg) Resolution : 50 ~ 80 %, recurrence : 30 ~ 40 %

27 Uterine Sarcoma 子宮肉癌北榮婦產趙灌中副院長

28 Uterine Sarcoma 全世界年發生率 : /100,000 從基質或內膜層或肌肉層生長出來表現像一般子宮肌瘤合併陰道出血快速生長的肌瘤轉變成惡性的可能? 40y/o 0.2%, 50y/o 0.9%, 60y/o 1.4%, 70y/o 1.7% 需要手術後病理診斷惡性肌肉瘤與放射線照射的相關性很大

29 WHO Classification of Uterine Sarcoma Leiomyosarcoma (LMS) 血型及淋巴轉移早期就會轉移 Endometrial stromal sarcoma, low grade (ESS) 容易局部延伸到子宮旁組織及附屬器官和韌帶復發時間較長 Undifferentiated stromal sarcoma (UDSS) 與 leiomyosarcoma 表現相似

30 Evaluation of Uterine Sarcoma 超音波邊緣不銳利, 內部呈不均質的影像 (50%) 邊緣不規則突出且有侵犯至肌肉層 (30%) 腫瘤中間成空洞狀 (10%) 年紀輕的女生表現子宮肌肉層增厚併不正常出血 (10%)

31 Evaluation of Uterine Sarcoma Contrast-enhanced CT 低密度腫瘤併中央壞死異質性影像表現有時合併鈣化顯影 PET : 100% positive for the five sarcomas MRI : 80% positive, US : 40% positive The mean standardized uptake value (SUV) of the sarcomas : 惡性肉瘤 SUV values: 4.5 +/ (Normal range < 2.5) 正常肌瘤 SUV values : all negative

32 LMS (Most common of ut. sarcoma) 肌肉層內腫瘤 65% 開刀前以為是良性肌瘤與正常肌瘤基因表現不同 0.1~0.5% 肌瘤會轉變成 LMS 曾生速度快非必要不需做 BPLND, PALNS, RH LN for suspicious invasion only 對於部分病患可保留卵巢不可用腹腔鏡的絞肉機若手術範圍內有懷疑之腫瘤建議施行 Debulking 術後放射治療可控制局部復發 OVS: not clear Doxorubicin : 最有效的單一化療藥物

33 ESS (endometrial stromal sarcoma) 肌肉層內 (more) 或內膜長出 (less) 75% 術前診斷為良性肌瘤 Low mitotic rate, diploid DNA context, low proliferative index 對 progestin 有治療反應預後較好 40% 在一開始發現時就已侵犯至子宮外

34 UDSS (undifferentiated stromal sarcoma) 分化不特定且無內膜分化之特性. 內膜可見一顆到多顆灰至灰黃色的腫瘤, 有時會有出血或是壞死的表現組織學表現 : 明顯的細胞異型性細胞分裂明顯. 與 low grade ESS 相比, 較無典型的生長模式且侵犯內膜較不規則大部分術後三年內會死亡 5 years survival rate: 25%

35 FIGO staging system NCCN 2013

36 Treatment Uterine Sarcoma Medical inoperable Operable Pelvic RT± brachytherapy and /or Chemotherapy or Hormone therapy (only for ESS) TAH/BSO * Pelvic / paraaort LA** Additional surgial resection for extrauterine disease *Oophorectomy individualized for reproductive age patients **Lymphadenectomy if nodes are positive

37 Chemotherapy &. Hormone therapy LMS Doxorubicin Ifosfamide Paclitaxel Gemacitabine UDSS Doxorubicin Ifosfamide ESS MPA / Megestrol Aromatase inhibitor GnRH analoges Tamoxifen

38 謝謝聆聽

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