POMEN HISTOPATOLOŠKIH ZNAČILNOSTI IN STADIJA NA POTEK IN IZID BOLEZNI Sonja Bebar Ljubljana, 20. maj2021 POMEN HISTOPATOLOŠKIH ZNAČILNOSTI IN STADIJA NA POTEK IN IZID BOLEZNI Rak jajčnikov ima najslabše preživetje med vsemi ginekološkimi raki V zadnjih desetletjih je prišlo do napredka pri zdravljenju (kirurgija, citostatiki, tarčna zdravila) Približno polovica bolnic z rakom jajčnikov je živih 5 let po postavljeni diagnozi (47%) v _ Ce je bolezen odkrita v napredovalih stadijih (FIGO III in IV), je 5 — letno preživetje le okoli 29% Več kot tri četrtine bolezni odkrijemo v napredovalih stadijih Gre za heterogeno skupino bolezni, ki se med seboj razlikujejo po epidemioloških, molekularnih in kliničnih lastnostih HISTOPATOLOŠKA KLASIFIKACIJA EPITELIJSKI RAK JAJČNIKOV (90%) Serozni karcinom visoke stopnje malignosti (70%) Endometrioidni karcinom (10%) Svetlocelični karcinom (10%) Mucinozni karcinom (3%) Serozni karcinom nizke stopnje malignosti (5%) Karcinosarkom Maligni Brennerjev tumor (zelo redki) NEEPITELIJSKI RAKI JAJČNIKOV Stromalni tumorji Germinalni tumorji PREŽIVETJE BOLNIC Z RAKOM JAJČNIKOV Na preživetje bolnic z rakom jajčnikov vpliva več delavnikov: • Stadij bolezni • Velikost ostanka bolezni po citoreduktivni operaciji • Histologija • Starost • Stanje zmogljivosti • Spremljajoče bolezni • Rasna pripadnost PREŽIVETJE BOLNIC Z RAKOM JAJČNIKOV Boljše preživetje Mlajše bolnice Neserozna histologija Zgodnji stadiji bolezni Brez rezidualne bolezni po citoreduktivni kirurgiji Odsotnost ascitesa Nizke vrednosti CA 125 Fig 2. Overall survival curves for patients with early-stage epithelial ovarian cancer. Chang LC, Huang CF, Lai MS, Shen LJ, Wu FLL, et al. (2018) Prognostic factors in epithelial ovarian cancer: A population-based study. PLOS ONE 13(3): e0194993. https://doi.org/10.1371/journal.pone.0194993 47 INVASIVE EPITHELIAL OVARIAN CANCER SURVIVAL BY HISTOTYPE AND DISEASE STAGE JOURNAL OF THE NATIONAL CANCER INSTITUTE, VOLUME 111, ISSUE 1, JANUARY 2019 o O - 1 0 I 12 I 24 I 36 I 48 1 60 I 72 I 84 I 96 I 108 I 120 Months slumber at risk High-grade serous 3939 3378 2892 2395 1942 1525 1177 901 661 418 206 Low-grade serous 330 291 262 226 182 150 110 82 59 42 14 Endometrioid 2452 2151 1867 1615 1378 1122 910 702 520 337 163 Clear cell 1950 1674 1419 1161 932 768 614 469 350 237 113 Mucinous 1935 1618 1391 1176 1000 835 661 536 403 253 134 Carcinosarcoma 342 244 173 140 109 87 71 59 43 25 9 W (M J -1-1- 60 72 Months Number at risk High-grade serous 13898 11098 8173 5622 3824 2526 1710 1150 726 424 179 Low-grade serous 378 320 277 222 181 147 109 87 62 34 16 Endometrioid 330 262 211 166 131 105 80 57 42 21 9 Clear cell 745 464 279 189 117 93 68 45 31 19 10 Mucinous 706 285 181 134 102 76 60 42 34 22 12 Carcinosarcoma 1039 560 319 201 130 84 60 42 26 17 6 High-grade serous Clear cell Low-grade serous Mucinous Endometrioid Carcinosarcoma NIZKO MALIGNI (LOW GRADE) IN VISOKO MALIGNI (HIGH GRADE) TUMORJI JAJČNIKOV 49 T? ?Retrograde Menstruation / Origin Fallopian Tube Epithelium Endometriosis Endometriosis Fallopian Tube Epithelium ?Unknown High-Grade Serous Carcinoma Clear Cell Carcinoma Endometrioid Carcinoma Low-Grade Serous Carcinoma Mucinous Carcinoma % of all Ovarian Carcinomas ~70% ~10% ~10% <5% <5% Precursor Lesions Serous tubal intraepithelial carcinoma (STIC) Clear Cell Borderline Tumor Endometrioid Borderline Tumor Serous Borderline Tumor Mucinous Borderline Tumor Inherited Syndromes BRCA1/2, Hereditary Breast and Ovarian Cancer (HBOC) Lynch Syndrome Lynch Syndrome ? ? Common Mutations and Molecular Aberrations TP53 BRCA1/2 and HRD Chromosomal instability Aneuploidy (100%) ARID1A PIK3CA CTNNB1 PPP2R1A MSI PTEN CTNNB1 ARID1A PPPR2R1A MSI KRAS BRAF KRAS HER2 amplification Potential Molecular Targeted Therapies PARP inhibitors, immune checkpoint inhibitors Tyrosine kinase inhibitors mTOR inhibitors MEK1/2 inhibitors Trastuzumab 50 VPLIV RASE NA PREŽIVETJE • Rasna pripadnost vpliva na preživetje • Serozni karcinom je v svetovnem merilu najpogostejši s 70% deležem, na Tajskem je ta delež le 20 do 30%, je pa toliko večji delež svetloceličnih, endometrioidnih in mucinoznih karcinomov • Azijke, ki živijo v ZDA imajo boljše 5-letno preživetje, zbolevajo mlajše, z zgodnejšimi stadiji bolezni, ki so neseroznega tipa • Svetlocelični karcinom je redek na zahodu, a veliko pogostejši med Japonkami in Tajkami, kjer dosega delež 19% do 25% • Delež endometrioidnega karcinoma je na zahodu 19%, med azijsko žensko populacijo pa preko 27% 51 NOVA IN STARA FIGO KLASIFIKACIJA g 5C g QC N O S -J 0 CQ S 1 QC CQ O CL e £ CL CQ o O O FIGO (2013) FIGO (ovary. 1988) 1 Tumor confined to ovaries or fallopian tuhe(s) 1 Tumor limited to ovaries IA Tumor limited to 1 ovary (capsule intact) or fallopian tube IA Tumor limited to 1 ovary IB Tumor limited to both ovaries or fallopian tubes IB Tumor limited to both ovaries IC Tumor limited to 1 or both ovaries or fallopian tubes, with any of the following IC Tumor limited to 1 or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface: malignant cells in ascites IC1 Surgical spill ICO/2) Malignant cells in peritoneal washings/ascites IC2 Capsule ruptured before surgery or fumor on ovarian or fallopian tube surface ICla/b) Capsule ruptured before surgery/surgical spill IC3 Malignant cells in the ascites II Tumor involves 1 or both ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer II Tumor involves 1 or both ovaries with pelvic extension IIA Extension and/or implants on uterus and/or fallopian tubes and/or ovaries IIA Extension and/or implants on uterus and/or tube(s) IIB Extension to other pelvic intraperitoneal tissues IIB Extension to other pelvic tissues HC Pelvic extension with malignant cells in ascites III Tumor with spread to peritoneum outside the pelvis and/or metastasis to retroperitoneal lymph nodes III Tumor with peritoneal metastases outside pelvis and/or regional lymph node metastasis IIIA1 Positive retroperitoneal lymph nodes only MIA Microscopic peritoneal metastasis beyond pelvis IIIAI(i) Metastasis £ 10 mm IIIAI(ii) Metastasis > 10 mm IIIA2 Microscopic extrapelvic peritoneal involvement HIB Macroscopic peritoneal metastasis beyond pelvis <2 cm HIB Macroscopic peritoneal metastasis beyond pelvis <2 cm nie Macroscopic peritoneal metastasis beyond pelvis >2 cm IIIC Peritoneal metastasis beyond pelvis >2 cm and/or regional lymph node metastasis IV Distant metastasis excluding peritoneal metastases IV Distant metastasis (excludes peritoneal metastasis) IVA Pleural eflusion with positive cytology IVB Parenchymal metastases and metastases to extraabdominal organs 52 OVARIAN CANCER survival rates Invasive Ovarian epithelial stromal ovarian cancer tumors Ovarian germ cell tumors Fallopian tube carcinoma Stage 1 Stage 2 Stage 3 Stage 4 90% 70% 39% 17% 95% 78% 65% 35% 98% 94% 87% 69% 87% 86% 52% 40% Source: https://wwwxancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.html healthline 53 PREŽIVETJE PO STADIJIH BOLEZNI • Stage IA-87% • Stage IB -71% • Stage IC-79% • Stage IIA- 67% • Stage IIB- 55% • Stage IIC-57 • Stage IIIA-41% - Stage IIIB - 25% - Stage IIIC - 23% - Stage IV-11% • Overall survival rate - 46% EUROCARE — 5 (2015) Aea-atandanJiaad 1 yaar, 5yaar raiatrva aurvtval, and 5-yaar ralattva survival conditional to wfvMftj 1 yaar. with 95% cofiMmci Intarvaia In paranthaaaa Aga-standard i»ad 5 yaar ralattva survival (%) Ovary and uterine adncia Europaan aga-apadflc and aga-atandanftaad obaarvad (oba, %) and ralattva (rat. %) survival Numb* oft 1 Northern Europa Danmr* Finland c------- Ira land and UK UK. 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Waaa Cantral Europa AjUrta Balpun Franco Garmany MtanM ira Nairanarw Southam Europa Crest* Portuga Eaatam Europa Bulgaria CncftRapUAc Estonia laMa Ltfuanta Sovakia Europa 11.724 4.637 3.937 ISO 3.71« 6.281 11.024 2.599 39.620 1793 4,752 2.760 37.796 5.932 4.563 2.945 1X307 1.536 9.491 21.971 3.672 11.750 266 2.396 1.446 ■w 27.879 6.206 6.825 U17 2.205 2.788 3.704 2.931 157.394 764 705 764 71.6 763 811 62.7 614 626 627 651 S98 73.7 719 771 773 737 769 71.6 •9.1 61.7 709 596 716 62.2 571 655 632 636 5S2 633 630 70.3 717 991 750 65.1 749 801 62.2 596 622 602 638 561 737 708 759 757 729 74.9 70.7 68.5 601 702 542 096 72 7( 70 3- 75 otNiHt 616 557 645 604 61 5 574 616 610 09.9 77.0 71J 77.7 79.1 77.7 821 63.1 633 631 953 664 616 742 731 783 788 74 4 79.0 72.5 997 63.3 71.7 655 736 752 16 628 586 666 660 659 61.1 661 660 707 41.1 35.5 43.1 39.1 41.4 44.1 31.0 30.3 30.6 323 340 317 405 41.4 424 40.1 40.3 38.9 39.9 38.0 38.6 38.1 39.3 41.0 37 9( •3T 33.4 363 341 337 31.7 345 34.5 37.6 40.3 339 41.3 31.5 395 426 30.6 284 300 294 325 797 399 400 407 382 393 36.1 38.7 37.3 366 37.2 328 387 350 • 33.7 31.7 351 310 313 298 325 322 37.2 42.0 37.2 45.0 48.5 434 456 31.8 32.5 31.1 355 356 337 41.1 429 441 42.1 41.3 42.0 41.1 38.7 407 391 47.0 434 v • ■3ft 351 357 376 376 363 33J 365 368 380 I 53.9 50.4 56.5 54.5 54.3 543 49.5 49.4 46.8 51.5 523 529 550 576 560 51.9 547 50.6 567 55.0 62.5 53.7 65.9 577 527 527( m 553 56.5 554 54 0 529 53.6 544 54.7 53.5 52.8 482 543 44.9 520 526 46.9 465 49.1 473 502 500 54.3 558 530 497 535 477 547 54.1 598 525 595 544 486 54.3 559 537 49 5 496 507 517 516 52.9 60 80 100 Eaatam Europa | I buttara ■B Crteh RecxjNc MM Ettona ^B ■1 UfVa H ■H Iguana m mt Poland H mh Sbva.a ^m mm Europa A«a group 1544 45-54 S5-64 66-74 7V AJI Hum bar ol( 1-yoar J-yaar 5-yaar 14.549 ota 909 787 70 S ral 910 784 70.9 25.887 oba 882 677 56 3 rH 89 5 68 3 561 37.744 ota 82 4 56 3 431 ral 82 8 57.3 44.5 40.137 oba 707 43.5 31.3 ral 719 455 33 9 39,076 Ota 43 6 219 14 5 ral 46 4 29 2 201 157,390 ota 69 0 45 5 349 ret 703 477 37.6 MUTACIJE BRCA1/2 ij> a» 0 8- a 4- a> Mlajše bolnice, BRCA1 Serozni karcinomi Ni mejno malignih tumorjev Boljši odgovor na terapijo s preparati platine Boljši odgovor na zdravljenje s PARP inhibitorji Daljši interval brez ponovitve bolezni Nosilke BRCA2 mutacije imajo boljše preživetje kot nosilke BRCA 1 mutacije ali spontano obolele 000 12 OD 24,00 XJX> 4BOO 00.00 77OO 04,00 9£0C >00,00 120,00 months