ClinicalCommentary2014FIGO staging for ovarian,fallopian tube and peritoneal cancerCancer staging is a core principle in understanding the severity of pa-tients'clinical condition,predicting the outcome,and planning ade-quate treatment.Staging is necessary for explaining epidemiologic changes,de fining the disease at presentation,and evaluating the overall impact of new therapies.In essence,it assigns patients to prognostic groups that require speci fic treatments.The steps of staging typically begin by establishing the histopathologic diagnosis,according to the tumor cell type,and assessing prognosis based on extent of disease and other known prognostic parameters.Recently,the presence of var-ious molecular genetic alterations has been used in the establishment of prognosis and even staging classi fication in some tumors but gyneco-logic cancers have continued to rely on physical,radiographic and surgi-cal findings.This editorial is written to make the readership aware of the recent changes that have been made by the International Federation of Gyne-cology and Obstetrics (FIGO)in the staging classi fication of ovarian can-cer and the reasoning behind those changes [1].Even if the FIGO Committee on Gynecologic Oncology utilized the best evidence current-ly available,this is always a somewhat subjective process.Furthermore,one needs to be aware that FIGO is an international organization that must take into account the needs of women with gynecologic cancers throughout the world,and not just those from countries that are re-source rich.The first FIGO ovarian cancer staging was published in 1973in Volume 15of the FIGO Annual Report.Since that time there have been two other changes including this one in 1988and 2013.Ovarian cancer is not one disease.Several distinct tumors with unique clinical and pathological features may arise in the ovary.Approx-imately 90%of ovarian cancers are carcinomas (malignant epithelial tu-mors)and,based on histopathology,immunohistochemistry,and molecular genetic analysis,at least 5main types are currently distin-guished:high-grade serous carcinoma (HGSC [70%]);endometrioid car-cinoma (EC [10%]);clear-cell carcinoma (CCC [10%]);mucinous carcinoma (MC [3%]);and low-grade serous carcinoma (LGSC [less than 5%][2]).These tumor types (which account for 98%of ovarian car-cinomas)can be reproducibly diagnosed by light microscopy and are es-sentially different diseases,as indicated by differences in epidemiologic and genetic risk factors;precursor lesions;ways of spread;and molecu-lar changes during oncogenesis,response to chemotherapy,and out-come [3]Much less frequent are malignant germ cell tumors (dysgerminomas,yolk sac tumors,and immature teratomas [3%of ovar-ian cancers])and potentially malignant sex cord-stromal tumors (1%–2%,mainly granulosa cell tumors).The biomarker expression pro file within a given histotype is consistent across stages.In short,ovarian cancers differ primarily based on histotype.Primary fallopian tube cancer and primary peritoneal cancer are rare malignancies but share many clinical and morphologic similarities with HGSC;i.e.,the most common type of ovarian cancer (in the past,re-ferred to as “papillary serous carcinoma ”)and the prototype tumor oc-curring in women with BRCA1or BRCA2germline mutations.In these patients,compelling evidence for a tubal derivation of their tumors,mainly those encountered at early stage,has accumulated over the past decade [4–6].Evidence of a tubal origin is weaker in the far more common sporadic HGSCs,and a multicentric origin of these tumors (i.e.arising from ovarian surface mesothelial invaginations or cortical inclusion cysts,implantation of tubal-type epithelium into the ovary [endosalpingiosis],or the pelvic peritoneum [the so-called secondary müllerian system ])cannot be ruled out.Recently,it has been hypothe-sized that cytokeratin7-positive embryonic/stem cells would be capable of mullerian differentiation in cortical inclusion cysts resulting from ovarian surface epithelium (mesothelium)invaginations.Thus,embry-onic progenitors would give rise to immunophenotypically distinct neo-plastic progeny [7]which would support the old concept of “mullerian neometaplasia ”.On the other hand,it has been demonstrated that the vast majority of ECs and CCCs arise in the ovary from endometriosis.Based on the putative tubal or peritoneal origin of a number of BRCA +HGSCs,and the fact that they are managed clinically in a similar manner regardless their ovarian,tubal,or peritoneal derivation,most FIGO Committee members felt that FIGO staging of ovarian,peritoneal,and fallopian tube cancers should be considered collectively [8].The pri-mary site (i.e.ovary,fallopian tube,or peritoneum)should be designat-ed where possible.In some cases,it might not be possible to delineate the primary site clearly;such cases should be listed as “undesignated.”The process of updating the staging classi fication of ovarian,fallopian tube,and primary peritoneal cancer started 4years ago with a proposal that was sent to all relevant gynecology oncology organiza-tions and societies throughout the world and input was collated,evalu-ated,and formulated into the staging that is presented below.All suggestions are based on the best available evidence.The committee ac-knowledged that there are areas that are not supported by strong evi-dence and has been careful to ensure that changes are not made without quality evidence when available.The new staging below was reached by consensus of all participating in the FIGO meeting held in Rome,Italy,on October 7th,2012,some of whom were representatives of their organizations.The new staging was presented to the FIGO Exec-utive Board on October 12,2012,and approved two weeks later.Ovarian cancer remains largely a surgically staged disease.The prog-nosis is based on histologic type,radiographic,and operative extent of the disease.The proposed staging system is noted below (Table 1).(See Tables 2and 3).Precise histopathologic diagnosis is mandatory for successful catego-rization and treatment of ovarian cancers,as different histologic types respond differently to treatment.To be practical,the FIGO committeeGynecologic Oncology 133(2014)401–404/10.1016/j.ygyno.2014.04.0130090-8258/©2014Elsevier Inc.All rightsreserved.Contents lists available at ScienceDirectGynecologic Oncologyj o u r na l h om e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /y g y n ochose a staging classi fication system that takes into account the mostrelevant prognostic parameters shared by all tumor types.However,it was agreed on by all that histologic type should be designated at the time of diagnosis and staging.The five agreed upon epithelial histologic types,as well as much less common malignant germ cell and potentially malignant sex cord-stromal tumors,are listed below.Histologic types:Carcinomas (by order of frequency)High-grade serous carcinoma (HGSC)Endometrioid carcinoma (EC)Clear-cell carcinoma (CCC)Mucinous carcinoma (MC)Low-grade serous carcinoma (LGSC).Note:Transitional cell carcinoma is currently interpreted as a mor-phologic variant of HGSC;malignant Brenner tumor is considered a low-grade carcinoma which is extremely rare.Malignant germ cell tumors (dysgerminomas,yolk sac tumors,and immature teratomas)Potentially malignant sex cord-stromal tumors (mainly rare cases of granulosa cell tumors and Sertoli –Leydig cell tu-mors with heterologous sarcomatous elements).The issues discussed and concluded by the FIGO committee will be taken one stage at a time,controversial issues raised,and the available data cited as appropriate.Staging should be considered fluid.As more prognostic features be-come available these should be used to further predict outcomes and determine treatment.The world is getting smaller in the sense that staging systems must be applicable universally and including resource rich as well as resource poor regions.Toward this end,three members of FIGO will now be on the AJCC staging committee and there is repre-sentation of the UICC on the AJCC.The International Gynecologic Cancer Society and the Society of Gynecologic Oncology now have nonvoting representation on the FIGO committee as well.We need to continue to gain consensus internationally by having cross representation on ourTable 12014FIGO ovarian,fallopian tube,and peritoneal cancer staging system and corresponding TNM.I Tumor con fined to ovaries or fallopian tube(s)T1IA Tumor limited to one ovary (capsule intact)or fallopian tube,No tumor on ovarian or fallopian tube surface No malignant cells in the ascites or peritoneal washingsT1a IBTumor limited to both ovaries (capsules intact)or fallopian tubesNo tumor on ovarian or fallopian tube surfaceNo malignant cells in the ascites or peritoneal washingsT1b ICTumor limited to one or both ovaries or fallopian tubes,with any of the following:IC1Surgical spill intraoperativelyIC2Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface IC3Malignant cells present in the ascites or peritoneal washingsT1c II Tumor involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim)or peritoneal cancer (Tp)T2IIA Extension and/or implants on the uterus and/or fallopian tubes/and/or ovaries T2a IIB Extension to other pelvic intraperitoneal tissuesT2bIIITumor involves one or both ovaries,or fallopian tubes,or primary peritoneal cancer,with cytologically or histologically con firmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodesT3IIIA Metastasis to the retroperitoneal lymph nodes with or without microscopic peritoneal involvement beyond the pelvis T1,T2,T3aN1IIIA1Positive retroperitoneal lymph nodes only (cytologically or histologically proven)IIIA1(i)Metastasis ≤10mm in greatest dimension (note this is tumor dimension and not lymph node dimension)T3a/T3aN1IIIA1(ii)Metastasis N 10mm in greatest dimension IIIA 2Microscopic extrapelvic (above the pelvic brim)peritoneal involvement with or without positive retroperitoneal lymph nodes T3a/T3aN1IIIB Macroscopic peritoneal metastases beyond the pelvic brim ≤2cm in greatest dimension,with or without metastasis to the retroperitoneal lymph nodes T3b/T3bN1III C Macroscopic peritoneal metastases beyond the pelvic brim N 2cm in greatest dimension,with or without metastases to the retroperitoneal nodes (Note 1)T3c/T3cN1IVDistant metastasis excluding peritoneal metastasesStage IV A:Pleural effusion with positive cytologyStage IV B:Metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of abdominal cavity)(Note 2)Any T,Any N,M1(Note 1:includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)(Note 2:Parenchymal metastases are Stage IV B)T3c/T3cN1)Notes:1.Includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ.2.Parenchymal metastases are Stage IV B.Table 2Carcinoma of the ovary –fallopian tube –peritoneum —stage grouping.FIGOUICC(Designate primary:Tov,Tft,Tp or Tx)Stage T N M IA T1a N0M0IB T1b N0M0IC T1c N0M0IIA T2a N0M0IIB T2b N0M0IIIA T3a N0M0T3a N1M0IIIB T3b N0M0T3b N1M0IIIC T3c N0–1M0T3c N1M0IV Any T Any N M1Regional nodes (N)Nx Regional lymph nodes cannot be assessed N0No regional lymph node metastasis N1Regional lymph node metastasis Distant metastasis (M)Mx Distant metastasis cannot be assessed M0No distant metastasis M1Distant metastasis (excluding peritoneal metastasis)Notes:1.The primary site –i.e.ovary,fallopian tube or peritoneum –should be designated where possible.In some cases,it may not be possible to clearly delineate the primary site,and these should be listed as ‘undesignated ’.2.The histologic type of should be recorded.3.The staging includes a revision of the stage III patients and allotment to stage IIIA1is based on spread to the retroperitoneal lymph nodes without intraperitoneal dissemina-tion,because an analysis of these patients indicates that their survival is signi ficantly bet-ter than those who have intraperitoneal dissemination.4.Involvement of retroperitoneal lymph nodes must be proven cytologically or histologically.5.Extension of tumor from omentum to spleen or liver (Stage III C)should be differentiat-ed from isolated parenchymal splenic or liver metastases (Stage IVB).402Clinical Commentaryentire representative staging committees.This will help us standardize care and staging systems throughout the world.In the future it is hoped that organizations such as UICC,AJCC,and FIGO will continue to work together to achieve this goal.Conflict of interest statementThe authors declare that there are no conflicts of interest.References[1]Prat J.Staging classification for cancer of the ovary,fallopian tube,and peritoneum.Int J Gynecol Obstet2014;124:1–5.[2]Lee KR,Tavassoli FA,Prat J,Dietel M,Gersell DJ,Karseladze AI,et al.Surface epithelialstromal tumours:tumours of the ovary and peritoneum.In:Tavassoli FA,Devilee P,ed-itors.World Health Organization Classification of Tumours:pathology and genetics of tumours of the breast and female genital organs.Lyon:IARC Press;2003.p.117–45.[3]Prat J.Ovarian carcinomas:five distinct diseases with different origins,genetic alter-ations,and clinicopathological features.Virchows Arch2012;460(3):237–49.[4]Piek JM,van Diest PJ,Zweemer RP,Jansen JW,Poort-Keesom RJ,Menko FH,et al.Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer.J Pathol2001;195(4):451–6.[5]Callahan MJ,Crum CP,Medeiros F,Kindelberger DW,Elvin JA,Garber JE,et al.Prima-ry fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction.J Clin Oncol2007;25(25):3985–90.[6]Kindelberger DW,Lee Y,Miron A,Hirsch MS,Feltmate C,Medeiros F,et al.Intraepithelial carcinoma of thefimbria and pelvic serous carcinoma:Evidence fora causal relationship.Am J Surg Pathol2007;31(2):161–9.[7]Crum CP,Herfs M,Ning G,Bijron JG,Howitt BE,Jimenez CA,Hanamornroongruang S,McKeon FD,Xian W.Through the glass darkly:intraepithelial neoplasia,top-down differentiation,and the road to ovarian cancer.J Pathol2013;231(4):402–12. [8]Cannistra SA,Gershenson DM,Recht A.Ovarian cancer,fallopian tube carcinoma,and peritoneal carcinoma.In:De Vita VT,Lawrence TS,Rosenberg SA,editors.De Vita,Hellman,and Rosenberg's cancer:principles and practice of oncology.9th ed.Philadelphia:Lippincott,Williams,Wilkins;2011.p.1368–91.[9]Yemelyanova AV,Cosin JA,Bidus MA,Boice CR,Seidman JD.Pathology of stage I ver-sus stage III ovarian carcinoma with implications for pathogenesis and screening.Int J Gynecol Cancer2008;18(3):465–9.[10]Seidman JD,Yemelyanova AV,Khedmati F,Bidus MA,Dainty L,Boice CR,et al.Prog-nostic factors for stage I ovarian carcinoma.Int J Gynecol Pathol2010;29(1):1–7.Table3Explantation of the Staging ChangesStage IDisease confined to the ovary after comprehensive staging T1–N0–M0 Stages IA and IB are unchanged from the1988staging.T1a–N0–M0 IA remains tumor limited to one ovary(capsule intact)or fallopian tube.There can be no disease on the ovary or fallopian tube surface.There are no malignant cells inthe ascites or peritoneal washings.Primary peritoneal has no Stage IA.1B is unchanged and remains tumor limited to both ovaries with capsule intact or fallopian tubes;and there can be no malignant cells on ovarian or fallopian tubesurfaces.There are no malignant cells in the ascites or peritoneal washings.T1b–N0–M0 IC represents a change for the1988staging system.It still designates positive cytology but,if possible,must designate the reason for malignant cells being present;hence,this substage is divided into three groups.T1c–N0–M01C1represents disease confined to one or both ovaries with capsule rupture during surgery1C2represents rupture before surgery or tumor excrescences on the surface of the tube or ovary.1C3represents malignant cells in the peritoneal cavity regardless of cause.CommentsSpecific issues surrounding stage I tumors need to be considered when evaluating Stage I patients surgically and pathologically.Bilateral tumors that are large on oneside and multiple or small on the other could represent metastases up to one third of the time[9,10].The significance of positive cytology is poorly understood andis one of the reasons that the committee elected to divide it into three categories.Some studies have found that intraoperative rupture portends a worse prognosisthan if the capsule is unruptured.In one multivariate analysis,both capsule rupture and positive cytology were independent predictors of worse disease freesurvival[11].Surface involvement of the ovary or fallopian tube should be considered present only when excrescences have cancer cells in direct contact with theperitoneal cavity,breaking through the surface of the ovarian capsule.Tumors with a smooth surface usually don't show an exposed layer of neoplastic cells.Histologic grade influences survival and is given with the histotype except for endometrioid carcinoma and mucinous cancers which should be graded.Practicallyall clear cell carcinomas are high grade.Stage IIStage II ovarian cancer includes disease confined to the pelvis(below the pelvic brim).It involves one or both ovaries or fallopian tubes with pelvic extension orprimary peritoneal cancer.T2–N0–M0IIA Extension and/or implants on the uterus and/or fallopian tubes and/or ovaries T2a–N0–M0 IIB Extension to other pelvic intraperitoneal tissues/organs T2b–N0–M0 Comments:Stage II ovarian cancer remains controversial and ill defined.It comprises a small group of ovarian cancer patients that have direct extension of their tumors to otherpelvic organs without evidence of metastatic disease.However,it also includes a group of patients that has metastases to the pelvic peritoneum.In this secondgroup of patients,disease is similar to that of stage III patients.Disease invading through the bowel wall and into the mucosa increases the stage to IVB.Stage IIIStage III Cancer involves1or both ovaries,fallopian tubes,or is primarily from the peritoneum with histologically confirmed spread outside of the pelvis and/ormetastases to the retroperitoneal nodes.T1/T2–N1–MO IIIA1Positive retroperitoneal nodes only.This can be confirmed histologically or cytologically.lllA(i)Metastases up to and including10mm in greatest dimensionIIIA(ii)Metastases more than10mm in greatest dimensionStage IIIA2:Microscopic extrapelvic(above the boney pelvic brim)peritoneal involvement with or without metastases to the retroperitoneal lymph nodes T3a2–N0/N1–M0IIIB:Macroscopic peritoneal metastases beyond the pelvis up to and including2cm in greatest dimension,with or without metastases to the retroperitoneal lymph nodes.T3b–N0/N1–M0IIIC:Macroscopic peritoneal disease beyond the pelvis more than2cm in greatest diameter,with or without metastases to the retroperitoneal lymph nodes(includes tumor extension to the capsule of the liver and spleen but no parenchymal metastases).CommentsApproximately,85%of ovarian cancers present as stage III tumors and the vast majority are high-grade serous carcinomas[12].A little less than10%of patients with ovarian cancer that appear to have stage I disease will have isolated lymph node metastases.The likelihood of having nodal metastasis in other stages are:III,55% and IV,88%[13].There is some evidence that exclusive retroperitoneal disease portends a better prognosis and for this reason the new staging system addresses this issue in the IIIA category[14–19].It should be noted that the size separating the IIIA tumors applies to the tumor size and not the lymph node size.Stage IV:Distant metastases excluding peritoneal or retroperitoneal nodal disease below the diaphragm.IVA:Pleural effusion with positive cytologyIVB:Metastases to extra abdominal sites including inguinal lymph nodes and parenchymal involvement of visceral organs including liver and spleen.Transmural involvement of a visceral structure also represents stage IVB disease.403Clinical Commentary[11]Bakkum-Gamez JN,Richardson DL,Seamon LG,Aletti GD,Powless CA,Keeney GL,et al.Influence of intraoperative capsule rupture on outcomes in stage I epithelial ovarian cancer.Obstet Gynecol2009;113(1):11–7.[12]Heintz AP,Odicino F,Maisonneuve P,Quinn MA,Benedet JL,Creasman WT,et al.Carcinoma of the ovary.FIGO26th annual report on the results of treatment in gy-necologic cancer.Int J Gynecol Obstet2006(95Suppl.1):S161-92.[13]Ayhan A,Gultekin M,Dursun P,Dogan NU,Aksan G,Guven S,et al.Metastaticlymphnode number in epithelial ovarian carcinoma:does it have any clinical signif-icance?Gynecol Oncol2008;108(2):428–32.[14]Onda T,Yokishikawa H,Yasugi T,Mishima M,Nakagawa S,Yamada M,et al.Patientswith ovarian carcinoma upstaged to stage III after systemic lymphadenectomy have similar survival to Stage I/II patients and superior survival to other stage III patients.Cancer1998;83(8):1555–60.[15]Kanazawa K,Suzuki T,Tokashika M.The validity and significance of substage IIIC bynode involvement in ovarian cancer:impact of nodal metastasis on patient survival.Gynecol Oncol1999;73(2):237–41.[16]Panici PB,Maggioni A,Hacker N,Landoni F,Ackerman S,Campagnutta E,et al.Sys-tematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer:a randomized clinical trial.J Natl Can-cer Inst2005;97(8):560–6.[17]Cliby WA,Aletti GD,Wilson TO,Podratz KC.Is it justified to classify patients to stageIIIC epithelial ovarian cancer based on nodal involvement only?Gynecol Oncol 2006;103(3):797–801.[18]Ferrandina G,Scambia G,Legge F,Petrillo M,Salutari V.Ovarian cancer patients with“node positive-only”Stage IIIC disease have a more favorable outcome than Sage IIIA/B.Gynecol Oncol2007;107(1):154–6.[19]Baek SJ,Park JY,Kim DY,Kim JH,Kim YM,Kim YT,et al.Stage IIIC epithelial ovariancancer classified soley by lymph node metastasis has a more favorable prognosis than other types of stage IIIC epithelial ovarian cancer.J Gynecol Oncol 2008;19(4):223–8.David G.Mutch Department of Obstetrics and Gynecology,Washington University School of Medicine,4911Barnes Hospital Plaza,St.Louis,MO63110,United StatesJaime Prat Department of Pathology,Hospital de la Santa Creu i Sant Pau,Autonomous University of Barcelona,Sant Quinti,87-89,08041Barcelona,Spain404Clinical Commentary。
