Castiglione, M.

Colombo, N.

Peiretti, M.

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Annals of Oncology 20 (Supplement 4): iv24–iv26, 2009doi:10.1093/annonc/mdp118clinical recommendationsNon-epithelial ovarian cancer: ESMO ClinicalRecommendations for diagnosis, treatment andfollow-upN. Colombo1, M. Peiretti1 & M. Castiglione2On behalf of the ESMO Guidelines Working Group*1Department of Gynecologic Oncology, European Institute of Oncology, Milan, Italy; 2Institute of Social and Preventive Medicine (ISPM), University of Geneva, Geneva,SwitzerlandincidenceNon-epithelial malignancies of the ovary account for 10% ofall ovarian cancers. Germ cell tumors (GCTs) are diagnosedprincipally in young subjects whereas sex cord stromal tumors(SCSTs) are more common in adult women. GCTs represent5% of all ovarian neoplasms and 80% of preadolescentmalignant ovarian tumors. Sex cord stromal tumors are rareneoplasms that account for 3–5 % of ovarian malignanciesand for the majority are functioning tumors with clinicalmanifestations. The yearly adjusted incidence rate is 3.7/1000000 and 2.1/1000 000 women for GCTs and SCSTs,respectively.diagnosisThe initial symptoms and signs of non-epithelial ovariancancers are usually characterized by subacute pelvic pain,feeling of pelvic pressure due to the presence of a pelvic massand menstrual irregularities. Diagnostic work-up shouldinclude pelvic ultrasound, abdomino-pelvic computedtomography (CT scan), chest X-ray and PET scan for selectedcases. In young patients serum human chrorionic gonadotropin(hCG), a-fetoprotein (AFP) titer and lactate dehydrogenase(LDH), a complete blood count, and liver and renal functiontests should be determined. Inhibin is secreted by granulosa celltumors and is a useful marker for the disease. In case ofsuspected gonadoblastomas a preoperative karyotype should beobtained on all pre-menarche girls because of the propensity ofthese tumors to arise in dysgenetic gonads.The definitive diagnosis of non-epithelial ovarian cancerrequires a surgical specimen. Pathological diagnosis should bemade by a gynaecologic pathologist trained in ovarian cancer,according to the World Health Organization classification.The histologic subtypes are listed in Tables 1 and 2.staging and risk assessmentThe staging system for non-epithelial ovarian cancers isgenerally adopted from that used for epithelial ovarian canceras originally defined by the Fe´de´ration Internationale deGyne´cologie et d’Obste´trique (FIGO). Surgery can beperformed through the open route or, in selected cases, bylaparoscopy. A careful examination of the abdominal cavity isrequired. The staging procedure includes infracolicomentectomy, biopsy of the diaphragmatic peritoneum,paracolic gutters, pelvic peritoneum and peritoneal washings.Systematic lymphadenectomy is not required; there is noconsensus about it. Only in cases of evidence of nodalabnormality is node dissection required. A thorough surgicalstaging for endodermal sinus tumor is not indicated because allpatients need chemotherapy. For SCSTs the retroperitonealevaluation is not mandatory because of the very low incidenceof retroperitoneal metastases in early stage [III, A]. Endometrialcurettage must be performed to rule out concomitantuterine cancers in patient with granulosa cell tumor. Sertoli–Leydig cell tumors are most frequently low-grade malignancies,although occasionally a poorly differentiated variety may behavemore aggressively. The tumors typically produce androgens, andclinical virilization is noted in 70–85% of patients.Unilateral salpingo-oophorectomy with preservation of thecontralateral ovary and the uterus is now considered adequatesurgical treatment for patients with GCTs, even in cases ofadvanced disease, because of the sensitivity of the tumor tochemotherapy, and no systematic ovarian biopsy need beperformed where the contralateral ovary is macroscopicallynormal. Conservative surgery also seems to be the appropriateapproach in young patients with SCSTs at stage I disease. Forpostmenopausal women and in patients with advanced stagedisease or with bilateral ovarian involvement, abdominalhysterectomy and bilateral salpingo-oophorectomy should beperformed with careful surgical staging.Stage is the most important prognostic factor established todate for SCSTs, in fact several article have reported that patientswith advanced disease have a significantly poorer survival rate.For GCTs stage is an important prognostic factor as well,though given their sensitivity to chemotherapy treatment evenmore advanced stage disease can have a good prognosis.*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.Taddei 4, CH-6962 Viganello-Lugano, Switzerland;E-mail: clinicalrecommendations@esmo.orgApproved by the ESMO Guidelines Working Group: October 2008.Conflict of interest: the authors have reported no conflicts of interest.ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.orgtreatment planearly stage disease, FIGO stage I–IIagerm cell tumors. The majority of GCTs (60–70%) arediagnosed at an early stage. Stage I patients have an excellentprognosis (long-term disease-free status is 90%) and, afteradequate surgical staging, very often further adjuvant treatmentis not required. Therefore patients with stage Ia immatureteratoma or stage I pure dysgerminoma can be treated withsurgery only. All patients with stage I endodermal sinus aretreated with adjuvant chemotherapy. Data from theEnglish literature show that the most employedcombination therapy is bleomycin, etoposide and cisplatin(BEP) [III, A].sex cord stromal tumors. The majority of SCSTs (60–95%) areat stage I at the time of diagnosis. Patients with stage I have anexcellent prognosis (long-term disease-free status is 90% ofthe cases). The selection of early stage SCSTs patients for anypostoperative treatment is controversial. At present the relativebenefit of adjuvant chemotherapy has yet to bedemonstrated. Some authors would suggest adjuvant therapyfor stage Ic patients with high mitotic index SCST. In thiscase platinum-based chemotherapy is the treatment of choice[II–III].advanced stage disease, FIGO stage IIb–IVgerm cell tumors. Patients with advanced stage disease shouldundergo debulking surgery to remove as much gross tumor aspossible, but without major extensive procedures given the highchemosensitivity of these tumors. Platinum-based regimenshave been the treatment of choice over the past decade forGCTs, with the BEP regimen becoming the most widely used.The optimal duration of therapy is still under debate, butgenerally many investigators believe that three cycles of BEPwith completely resected disease and four cycles for patientswith macroscopic residual disease seem appropriate [III, A].Even though dysgerminomas are very sensitive to radiationtherapy there is no evidence to support the use of adjuvantradiation therapy for advanced stage GCTs.sex cord stromal tumors. Debulking surgery, whenever feasible,remains the most effective treatment for metastatic or recurrentgranulosa cell tumors. Platinum-based chemotherapy iscurrently used for patients with advanced stage SCSTs orrecurrent disease, with an overall response rate of 63–80%.There are limited data regarding the utility of chemotherapy inpatients with persistent Sertoli–Leydig tumor, but responses inpatients with measurable disease have been reported. TheBEP regimen for 3–6 cycles is currently recommended foradjuvant postoperative chemotherapy and for patients withrecurrent SCSTs. Taxanes demonstrated an interesting activityin SCSTs with a favorable toxicity profile [III, A]. Taxaneand platinum combination chemotherapy seems to be areasonable candidate for future trials. Little evidence exists forthe use of hormonal therapy or radiation therapy and thesemodalities should be restricted to selected cases.response evaluationSerum tumor markers (hCG, AFP, LDH, CA125 and inhibin)can accurately correlate with tumor response duringchemotherapy. CT scan of the abdomen, pelvis and chest (incase of suspected lung metastases) and pelvic ultrasound are themost common and useful imaging methods to evaluate theresponse to chemotherapy in patients with measurable disease.follow-upApproximately 75% of GCT recurrences occur within the firstyear after initial treatment; the most common site is theperitoneal cavity and more rarely the retroperitoneal lymphnodes.In contrast, the indolent nature of SCSTs with a tendency tolate recurrence (median time to relapse is 4–6 years), requireslong-term surveillance. Several reports describe relapsesoccurring >20 years (up to 37 years) after diagnosis. Commonsites of recurrence are the upper abdomen (55–70%) and thepelvis (30–45%).The follow-up visit must include history, physicalexamination with pelvic examination and tumor markers every3 months for the first 2 years, and every 6 months during years3–5 or until progression is documented. Pelvic ultrasoundshould be performed every 6 months in those patients whoTable 1. Classification of germ cell ovarian tumorsDysgerminomaTeratomaImmatureMatureMonodermal and highly specializedEndodermal sinus tumorEmbryonal carcinomaPolyembryomaChoriocarcinomaMixed formsTable 2. Classification of sex cord stromal ovarian tumorsGranulosa-stromal cell tumorsGranulosa cell tumorsAdult typeJuvenile typeTumors in the thecoma–fibroma groupThecomaFibroma–fibrosarcomaSclerosing stromal tumorSertoli–Leydig cell tumors (androblastomas)Sertoli cell tumorsLeydig cell tumorSertoli–Leydig cell tumorsGynandroblastomaSex cord tumor with anular tubulesUnclassifiedAnnals of Oncology clinical recommendationsVolume 20 | Supplement 4 | May 2009 doi:10.1093/annonc/mdp118 | iv25underwent fertility sparing surgery, whereas CT scan of theabdomen and pelvic is usually performed yearly.noteLevels of evidence [I–V] and grades of recommendation [A–D]as used by the American Society of Clinical Oncology aregiven in square brackets. Statements without grading wereconsidered justified standard clinical practice by the experts andthe ESMO Faculty.literature1. Young RC, Knapp RC et al. Cap 33 ca´ncer de ovario: ca´ncer, principios ypra´ctica de oncologı´a. In Vincent T (ed.), Devita, 2nd edition. Barcelona: Salvat1988; 1008–1018.2. Merino MJ, Jaffe G. Age contrast in ovarian pathology. Cancer 1993; 71 (Suppl):537–544.3. Horn-Ross PL, Whittemore AS et al. Collaborative Ovarian Cancer Group, 1992characteristics relating to ovarian cancer risk. Collaborative analysis of 12 UScase–control studies. VI. Nonepithelial cancers among adults. Epidemiology1992; 3: 490–495.4. Evans AT, Gaffey TA, Malkasian GD et al. Clinicopathologic review of 118granulosa and 82 theca cells tumors. Obstet Gynecol 1980; 55: 231–238.5. Bjorkholm E, Silfversward C. Prognostic factors in granulosa-cell tumors. GynecolOncol 1981; 11: 261–274.6. Gershenson DM. Update on malignant ovarian germ cell tumors. Cancer 1993;71: 1581–1590.7. Zhang M, Cheung MK, Shin JY et al. Prognostic factors responsible for survival insex cord stromal tumors of the ovary—an analysis of 376 women. GynecolOncol 2007; 104: 396–400.8. Kurman RJ, Scardino PT, Waldmann TA et al. Malignant germ cell tumors of theovary and testis: an immunohistologic study of 69 cases. Ann Clin Lab Sci 1979;9: 462–466.9. Obata NH, Nakashima N, Kawai M et al. Gonadoblastoma with dysgerminoma inone ovary and gonadoblastoma with dysgerminoma and yolk sac tumor in thecontralateral ovary in a girl with 46XX karyotype. Gynecol Oncol 1995; 58:124–128.10. Hildebrandt RH, Rouse RV, Longacre TA. Value of inhibin in the identification ofgranulosa cell tumors of the ovary. Hum Pathol 1997; 28: 1387–1395.11. Malmstrom H, Hogberg T, Risberg B et al. Granulosa cell tumor of the ovary:prognostic factors and outcome. Gynecol Oncol 1994; 52: 50–55.12. Gershenson DM. Management of early ovarian cancer: germ cell and sex-cordstromal tumors. Gynecol Oncol 1994; 55: S62–S72.13. Bajorin DF, Sarosdy MF, Pfister GD et al. Randomized trial of etoposide andcisplatin versus etoposide and carboplatin in patients with good-risk germ celltumors: a multi-institutional study. J Clin Oncol 1993; 11: 598–606.14. Homesley HD, Bundy BN, Hurteau JA et al. Bleomycin, etoposide, and cisplatincombination therapy of ovarian granulosa cell tumors and other stromalmalignancies: a Gynecologic Oncology Group study. Gynecol Oncol 1999; 72:131–137.15. Williams SD, Blessing JA, Hatch KHomesley HD. Chemotherapy of advancedovarian dysgerminoma: trials of the Gynecologic Oncology Group. J Clin Oncol1991; 9: 1950–1955.clinical recommendations Annals of Oncologyiv26 | Colombo et al. Volume 20 | Supplement 4 | May 2009

Non-epithelial ovarian cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

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