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  Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up † N. Colombo 1,2 , S. Carinelli 3 , A. Colombo 4 , C. Marini 5 , D. Rollo 1 & C. Sessa 5,6 , on behalf of theESMO Guidelines Working Group* 1 Department of Gynecologic Oncology, European Institute of Oncology, Milan, Italy;  2 Department of Gynecologic Oncology, Università Milano-Bicocca, Milan, Italy; 3 Department of Pathology, European Institute of Oncology, Milan, Italy;  4 Department of Radiotherapy, Alessandro Manzoni Hospital, Lecco, Italy;  5 Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;  6 Unit of New Drugs and Innovative Therapies, Department of Medical Oncology   – O.U.Medicine, San Raffaele Hospital, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy  incidence Cervical cancer is the third most common cancer inwomen, with an estimated 529 828 new cases and 275 128deaths reported worldwide in 2008. More than 85% of theglobal burden occurs in developing countries, where itaccounts for 13% of all female cancers [1]. In developing countries, the age standardized mortality rate is 10/10 000 — more than three times higher than in developed countries[2].It is common knowledge that the most important cause of cervical cancer is persistent papillomavirus infection. Thehuman papillomavirus (HPV) is detected in 99% of cervicaltumors, in particular the oncogenic subtypes such as HPV16 and 18. While Papanicolau smears are used in theclassical primary screening technique, HPV DNA testing,introduced in 2008, is well diffused in developed countriesand is taking off in developing countries with a potentially signi 󿬁 cant reduction in the numbers of advanced cervicalcancers and deaths [3].In the HPV vaccination era, we expect that the cervicalcancer incidence will be reduced, especially in those developedcountries where large-scale immunization has been introduced.Most developed countries have introduced HPV vaccines intoroutine vaccination programs and more than 60 million doseshave already been distributed in 2010, which could guarantee aprotection rate of   ∼ 70% [4]. However, cervical cancer stillrepresents a major public health problem even in developedcountries: 54 517 new cases of invasive cervical cancer arediagnosed in Europe every year and 24 874 women die of thisdisease [4]. diagnosis and pathology/molecular biology  The WHO recognizes three categories of epithelial tumors of the cervix: squamous, glandular (adenocarcinoma), and otherepithelial tumors including neuroendocrine tumors andundifferentiated carcinoma. Squamous cell carcinomas accountfor  ∼ 70% – 80% of cervical cancers and adenocarcinomas for10% – 15%. Early cervical cancer is often asymptomatic whilelocally advanced disease could cause symptoms including abnormal vaginal bleeding, also after coitus, discharge, pelvicpain, and dyspareunia. Gross appearance is variable.Carcinomas can be exophytic, growing out of the surface, orendophytic with stromal in 󿬁 ltration with minimal surfacegrowth. Some early cancers are not appreciable and evendeeply invasive tumors may be somewhat deceptive on grossexamination. If examination is dif  󿬁 cult or there is uncertainty about vaginal/parametrial involvement, this should be doneunder anesthesia together with a radiotherapist. Papillary tumors are more commonly adenocarcinomas. squamous cell carcinoma Squamous carcinomas are composed of cells that arerecognizably squamous but vary in either growth pattern orcytological morphology. Originally, they were graded using theBroders ’  grading system; subsequently, they were classi 󿬁 ed intokeratinizing, nonkeratinizing, and small-cell squamouscarcinomas. In the more recent WHO classi 󿬁 cation, the termsmall-cell carcinoma was reserved to tumors of neuroendocrinetype. Keratinizing squamous cell carcinomas are characterizedby the presence of keratin pearls. Mitoses are not frequent.Nonkeratinizing squamous cell carcinomas do not form keratinpearls by de 󿬁 nition, but may show individual cell keratinization.Clear-cell change can be prominent in some tumors and shouldnot be misinterpreted as clear-cell carcinoma. adenocarcinoma The arrangement of the invasive glands is highly variable andsome tumors are in part or extensively papillary. About 80% of  †  Approved by the ESMO Guidelines Working Group: January 2008, last update July2012. This publication supersedes the previously published version —  Ann Oncol 2010;21(Suppl 5): v37 – v40.* Correspondence to:  ESMO Guidelines Working Group, ESMO Head Of  󿬁 ce,ViaL. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalguidelines@esmo.org       c       l       i      n       i      c      a       l      p     r      a      c       t       i      c      e      g     u       i       d      e       l       i      n      e      s clinical practice guidelines  Annals of Oncology   23 (Supplement 7): vii27 – vii32, 2012doi:10.1093/annonc/mds268© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.   b  y g u e  s  t   on O c  t   o b  e r 1 4  ,2  0 1 4 h  t   t   p :  /   /   a nn on c  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   adenocarcinomas of the cervix are of endocervical or usualtype; unlike normal endocervical mucinous epithelium, tumorcells are not obviously mucinous and show a rathercharacteristic appearance having eosinophilic cytoplasm. Thegreat majority of endocervical-type adenocarcinomas arearchitecturally well differentiated, but they are cytologically grade 2 or 3. Only a subset of papillary or villoglandularadenocarcinoma is considered well differentiated for their goodprognosis when in pure form; tumors with an underlying component of conventional adenocarcinoma behave asadenocarcinomas of the usual type. Unlike cervical squamouscell carcinomas, differential diagnosis of early invasiveadenocarcinoma from adenocarcinoma  in situ  showing somewhat complex architecture can be dif  󿬁 cult. In mucinousadenocarcinoma mucin-rich cells predominate; some show gastric-type features and some are of the minimal deviationtype (or adenoma malignum). Rare tumors are mixedadenosquamous carcinomas and include so-called glassy cellcarcinoma. The other more rare types of cervicaladenocarcinoma include clear-cell carcinoma and mesonephricadenocarcinoma.Neuroendocrine tumors include carcinoids, atypicalcarcinoids, and neuroendocrine carcinomas. Diagnosis ishistological and can be con 󿬁 rmed by neuroendocrine markers. pathogenesis — molecular biology  HPV has been recognized as the most important etiologicfactor in cervical cancer. HPV16/18 account for at least two-thirds of cervical carcinomas in all continents; HPV 31, 33, 35,45, 52, and 58 are the next most common types in cancersglobally. A prophylactic vaccine against HPV16/18 has thepotential to prevent more than two-thirds of worldwidecervical carcinomas and half of high-grade squamousintraepithelial lesions. These proportions may be even higherdue to cross-protection against other high-risk HPV-typeinfections.Squamous cell carcinomas and their precursor,intraepithelial squamous lesions, are related to HPV infectionin almost all the cases and the presence of HPV 18 DNA isassociated with poor prognosis. Adenocarcinomas encompass aheterogeneous group of tumors. Endocervical adenocarcinomaof usual type and its precursor, the adenocarcinoma  in situ ,have been shown to be positive for HPV in nearly 90% and100% of cases. HPV 18 is more common in adenocarcinomasand adenosquamous carcinomas than in squamous cellcarcinomas.Unlike endocervical adenocarcinoma of usual type, the othermore rare types including clear-cell and mesonephricadenocarcinoma seem to be unrelated to HPV.Several markers identi 󿬁 ed along the carcinogenetic pathwayshave been studied. P53 RAS mutations are rare in cervicalcarcinomas. EGFR, HER2, VEGS, COX-2, and c-myc weretested as prognostic or predictive factors, but the results werenot conclusive. Similarly, estrogen and progesterone receptorsdo not play a signi 󿬁 cant role; however, they can be useful indifferential diagnosis between endocervival type andendometrioid adenocarcinomas, together with vimentine, CEA,and p16. staging and risk assessment The cervical cancer Féderation Internationale de Gynécologieet d ’ Obstétrique (FIGO) classi 󿬁 cation is based on clinicalexamination [5]. A comparison between TNM classi 󿬁 cation(The American Joint Committee on Cancer) and FIGO staging is shown in Table 1.The FIGO classi 󿬁 cation is based on tumor size, vaginal orparametrial involvement, bladder/rectum extension, anddistant metastases. It requires radiological imaging such aschest X-ray and intravenous pyelogram. Other imaging studies Table 1.  Comparison of TNM categories and FIGO staging TNMcategoriesFIGOstagesTX Primary tumor cannot be assessed.T0 No evidence of primary tumor.Tisb Carcinoma  in situ  (preinvasive carcinoma).T1 I Cervical carcinoma con 󿬁 ned to uterus (extension tocorpus should be disregarded).T1ac IA Invasive carcinoma diagnosed only by microscopy.Stromal invasion with a maximum depth of 5.0mm measured from the base of the epitheliumand a horizontal spread of   ≤ 7.0 mm. Vascularspace involvement, venous or lymphatic, does notaffect classi 󿬁 cation.T1a1 IA1 Measured stromal invasion ≤ 3.0 mm in depth and ≤ 7.0 mm in horizontal spread.T1a2 IA2 Measured stromal invasion >3.0 mm and  ≤ 5.0 mmwith a horizontal spread of   ≤ 7.0 mm.T1b IB Clinically visible lesion con 󿬁 ned to the cervix ormicroscopic lesion >T1a/IA2.T1b1 IB1 Clinically visible lesion ≤ 4.0 cm in greatestdimension.T1b2 IB2 Clinically visible lesion >4.0 cm in greatestdimension.T2 II Cervical carcinoma invades beyond uterus but notto pelvic wall or to lower third of vagina.T2a IIA Tumor without parametrial invasion.T2a1 IIA Clinically visible lesion ≤ 4.0 cm in greatestdimension.T2a2 IIA2 Clinically visible lesion >4.0 cm in greatestdimension.T2b IIB Tumor with parametrial invasion.T3 III Tumor extends to pelvic wall and/or involves lowerthird of vagina, and/or causes hydronephrosis ornonfunctioning kidney.T3a IIIA Tumor involves lower third of vagina, no extensionto pelvic wall.T3b IIIB Tumor extends to pelvic wall and/or causeshydronephrosis or nonfunctioning kidney.T4 IV The carcinoma has extended beyond the true pelvisor has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such,does not permit a case to be allotted to stage IV.T4a IVA Spread of the growth to adjacent organs.T4b IVB Spread to distant organs. clinical practice guidelines  Annals of Oncology  vii   | Colombo et al. Volume 23 | Supplement 7 | October 2012   b  y g u e  s  t   on O c  t   o b  e r 1 4  ,2  0 1 4 h  t   t   p :  /   /   a nn on c  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   have been used to more accurately de 󿬁 ne the extent of disease.Computed tomography (CT) can detect pathologic lymphnodes, while magnetic resonance imaging can determinetumor size, degree of stromal penetrations, vaginal extension,and corpus extension with high accuracy [6]. More recently,positron emission tomography (PET) has been seen to havethe potential to accurately delineate the extent of disease,particularly in lymph nodes that are not macroscopically enlarged and in distant sites, with high sensitivity andspeci 󿬁 city. In early-stage disease, PET/CT has a sensitivity of 53% – 73% and speci 󿬁 city of 90% – 97% for the detection of lymph node involvement, while in more advanced stages thesensitivity for detecting the involvement of para-aortic nodesincreases to 75% with 95% speci 󿬁 city [7]. Several investigatorshave reported on the evaluation of sentinel lymph node inearly stages to avoid complete lymphadenectomy or to increaseaccuracy, but no de 󿬁 nitive conclusions can be drawn. Similarly,the need for pretreatment surgical para-aortic lymph nodeassessment in locally advanced cervical cancer is still a matterof debate [8].Tumor risk assessment includes tumor size, stage, depth of tumor invasion, lymph node status, lymphovascular spaceinvolvement (LVSI), and histological subtype. Lymph nodestatus and number of lymph nodes involved are the mostimportant prognostic factors. In stages IB-IIA, the 5-yearsurvival rate without lymph node metastasis and with lymphnode metastasis is 88% – 95% and 51% – 78%, respectively [9]. management of local/locoregionaldisease primary treatment Depending on stage, primary treatment consists of surgery,radiotherapy, or a combination of radiotherapy andchemotherapy. De 󿬁 nitive radiation therapy should consist of pelvic external beam radiation with high-energy photons andintracavitary brachytherapy, and must be administered at highdoses (>80 – 90 Gy) and in a short time (<55 days), with thebest technological resources available. stage IA1 Stage IA1 cervical cancer can be managed conservatively topreserve fertility, with conization without lymphadenectomy,because the risk of nodes metastasis is <1%. The cone ’ smargins must be free of disease. If a nonfertility-preserving therapy hysterectomy is performed, ovaries need not beremoved. In the presence of LVSI, lymphadenectomy isrecommended (Table 2). stage IA2 Stage IA2 with no LVSI can be treated by conization (if fertility is to be preserved) or extrafascial hysterectomy. In case of LVSIpelvic lymphadenectomy is indicated with radicaltrachelectomy or radical hysterectomy. In patients with surgicalcontraindication, brachytherapy may represent an alternativeoption. stages IB1 to IIA1 Stages IB and IIA cervical carcinoma can be cured by radicalsurgery including pelvic lymphadenectomy or radiotherapy.The two procedures are equally effective, but differ in terms of morbidity and type of complications.In the only randomized trial directly comparing radicalhysterectomy and radiation therapy only in 343 women withstage IB-IIA disease, overall and disease-free survivals at 5years were similar for the two groups (83% and 74%,respectively), and 66% of the patients in the surgical armhad adjuvant radiation for the presence of risk factors. Therate of severe morbidity was 28% in the surgery group and12% in the radiotherapy group (level of evidence I) [10].There is no published evidence that concurrentchemoradiation would be useful in patients with early cervicalcancer (stages IB1 and IIA <4 cm).Fertility-preserving surgery consisting of radicaltrachelectomy or conization with/without chemotherapy can beoffered to young patients with early-stage cervical cancerwishing to preserve their fertility (level of evidence IV)[11, 12]. stages IB2 to IVA  chemoradiation Historically, radiotherapy has been the mainstay in thetreatment of locally advanced cervical cancer, with a localcontrol rate ranging between 88% and 95% for stage IB, 70% – 80% for stage IIB, and 30% – 40% for stage III and 5-yearsurvival >80% for stage IB, 65% for stage IIB, and 40% forstage III [13, 14]. Table 2.  Cervical cancer treatment according to stageStage Treatment IssueIA1 Conization or simple hysterectomy± salpingo-ophorectomy andPLND if LVSIConservative surgery IA2 Conization/radical trachelectomy or modi 󿬁 ed radical hysterectomy and PLNDAdjuvant CT/RT if risk factors (LVSI, G3, positive resection margins,multiple nodes)IB1, IIA Radical hysterectomy and PLND Adjuvant CT/RT if risk factors (LVSI, G3, positive resection margins,multiple nodes)IB2, IIB – IV Combination CT/RT with cisplatin NACT to large bulky tumors prior CT/RTPLND, pelvic lymphadenectomy; LVSI, lymphovascular space invasion; CT, computed tomography; NACT, neoadjuvant chemotherapy; RT, radiationtherapy.  Annals of Oncology clinical practice guidelines  Volume 23 | Supplement 7 | October 2012 doi:10.1093/annonc/mds268 |  vii    b  y g u e  s  t   on O c  t   o b  e r 1 4  ,2  0 1 4 h  t   t   p :  /   /   a nn on c  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   In February 1999, the NCI published a ClinicalAnnouncement strongly recommending the use of concurrentplatinum based chemoradiation in patients with locally advanced disease based on the results of   󿬁  ve randomizedclinical trials [15 – 19]. These data were con 󿬁 rmed in furtherreviews and meta-analysis, the most recent of which, based onindividual patient data from 18 randomized trials,demonstrated an absolute 5-year survival bene 󿬁 t of 8% foroverall disease-free survival, 9% for locoregional disease-freesurvival, and 7% for metastases-free survival in all stages. Theadvantage is also shown for nonplatinum-based chemotherapy [I, A] [20].Optimal radiation therapy, consisting of high doses (80 – 90Gy to the target) administered over a short time (<50 – 55 days),signi 󿬁 cantly impacts on outcome [21].The optimal regimen for chemotherapy has yet to bede 󿬁 ned, but weekly single-agent cisplatin at 40 mg/m 2 /week during external beam therapy is widely used; concurrentcarboplatin or nonplatinum chemoradiation regimens areoptions for patients who may not tolerate cisplatin-containing schedules.One recent study seems to indicate a signi 󿬁 cant bene 󿬁 t forthe use of adjuvant chemotherapy following chemoradiation.Patients with locally advanced cervical cancer (stages IIB to IV)treated with cisplatin – gemcitabine, both during and afterradiation therapy, demonstrated great improvement inprogression-free survival and overall survival. Despite theseencouraging results, systemic consolidation should only beused in clinical trials [II, C] [22]. neoadjuvant chemotherapy to radiation A systematic review from 18 trials and 2074 patients publishedin 2006 demonstrated that the timing and dose intensity of cisplatin-based neoadjuvant chemotherapy before radiationcould affect outcome. However, the data are heterogeneous anddeserve further con 󿬁 rmation [II, B] [23]. neoadjuvant chemotherapy to surgery  A meta-analysis of neoadjuvant chemotherapy followed by radical hysterectomy showed an absolute improvement of 14%in 5-year survival compared with radiotherapy [23]. However,there are several objections because patients in the control armreceived radiation therapy not in combination withchemotherapy. Moreover, in a separate analysis by stagesubgroups, patients with stage III did not show any signi 󿬁 cantbene 󿬁 t. Neoadjuvant chemotherapy followed by radical surgery could have an important role in the treatment of locally advanced cervical cancer, but the appropriate indications stillneed to be established. The ongoing trial EORTC 55994 willclarify whether neoadjuvant chemotherapy followed by surgery will result into a better outcome compared withchemoradiotherapy in patients with stages IB2 to IIB cervicalcancer. adjuvant treatment Women with risk factors on the pathology specimen shouldreceive adjuvant therapy following hysterectomy (Table 3).Two classes of risk are de 󿬁 ned: intermediate and high-risk patients. intermediate-risk disease A Gynecologic Oncology Group (GOG) trial that randomly assigned 277 women to receive pelvic RT (withoutchemotherapy) or no further treatment demonstrated a bene 󿬁 tfor postoperative RT in women with the following features:deep cervical stromal invasion (to the middle or one-thirddepth), lymphovascular space invasion, and large tumor size(>4 cm).With a median follow-up of 10 years, a signi 󿬁 cant bene 󿬁 thas been shown for progression-free survival, but not foroverall survival [24] [II, B]. high-risk disease Women with one or more worse prognostic factors such aspositive or close surgical margins, positive lymph nodes, ormicroscopic parametrial involvement are considered to be athigh risk of relapse. In this setting of patients, adjuvantchemoradiation is indicated on the basis of a clinical trialthat randomly assigned 268 women IA2, IB, and IIA toadjuvant radiotherapy with or without chemotherapy (cisplatin – 5- 󿬂 uorouracil) for four courses [19]. The use of chemotherapy was associated with a substantially better 4-year overall survival (81% versus 71%) and progression-freesurvival (80% versus 63%), and the outcome was better forpatients who completed three to four cycles of chemotherapy [I, A]. management of advanced/metastaticdisease Patients with metastatic or recurrent cervical cancer arecommonly symptomatic. The role of chemotherapy in suchpatients is palliative, with the primary objective to relievesymptoms and improve quality of life. The response rates afterprevious chemotherapy are worse compared with Table 3.  Necessary histopathologic parameters for assessment of cervicalcancerHistopathologic evaluationDimensions of the tumorStromal invasion/depth of the wall involvedTumor differentiationLVSIStatus of resection marginsStatus of parametria and vaginal cuff Number and status of lymph nodesLVSI, lymphovascular space invasion. clinical practice guidelines  Annals of Oncology  vii   | Colombo et al. Volume 23 | Supplement 7 | October 2012   b  y g u e  s  t   on O c  t   o b  e r 1 4  ,2  0 1 4 h  t   t   p :  /   /   a nn on c  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om 
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