ESGO/ESTRO/ESP Guidelines for the management of patients with cervical cancer – Update 2023*

In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives. These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined. Supplementary Information The online version contains supplementary material available at 10.1007/s00428-023-03552-3.


Introduction
Cervical cancer is a major public health problem, ranking as the fourth most common cause of cancer incidence and mortality in women worldwide. There are geographical variations in cervical cancer that reflect differences particularly in the prevalence of human papillomavirus (HPV) infection and inequalities in access to adequate screening and treatment [1]. Cervical cancer is uncommon in Europe but still remains the most frequent cause of cancer death in middleaged women in Eastern Europe [2]. Other epidemiologic risk factors associated with cervical cancer are notably a history of smoking, oral contraceptive use, early age of onset of coitus, number of sexual partners, history of sexually transmitted disease, certain autoimmune diseases, and chronic immunosuppression. Squamous cell carcinomas account for approximately 80% of all cervical cancers and adenocarcinoma accounts for approximately 20%. The WHO recently launched a global initiative to scale up preventive, screening, and treatment interventions relying on vaccination against HPVs, screening and treatment of detected cervical preinvasive and invasive lesions, and offering the best possible curative care to women diagnosed with invasive cancer [3].
As part of its mission to improve the quality of care for women with gynecological cancers across Europe, in 2018 the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines to improve the management of patients with cervical cancer within a multidisciplinary setting [4][5][6]. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines and to include new topics in order to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. These guidelines are intended for use by gynecological oncologists, general gynecologists, surgeons, radiation oncologists, pathologists, medical and clinical oncologists, radiologists, general practitioners, palliative care teams, and allied health professionals.

Responsibilities
Even though our aim is to present the highest standard of evidence in an optimal management of patients with cervical cancer, ESGO, ESTRO, and ESP acknowledge that there will be broad variability in practices between the various centers worldwide. Moreover, there will also be significant differences in infrastructure, access to medical and surgical technology, and also training, medicolegal, financial, and cultural aspects that will affect the implementation of any guidelines. These guidelines are a statement of evidence and consensus of the multidisciplinary development group regarding their views and perspective of currently accepted approaches for the management of patients with cervical cancer. Any clinician applying or consulting these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. These guidelines make no representations or warranties of any kind whatsoever regarding their content, use, or application and disclaim any responsibility for their application or use in any way.

Methods
The guidelines were developed using a five-step process defined by the ESGO Guideline Committee (see Figure 1). The strengths of the process include creation of a multidisciplinary international development group, use of scientific evidence and international expert consensus to support the guidelines, and use of an international external review process (physicians and patients). This development process involved three meetings of the international development group, chaired by Professor David Cibula (First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic), Professor Jacob Christian Lindegaard (Aarhus University Hospital, Aarhus, Denmark), and Professor Maria Rosaria Raspollini (University of Florence, Florence, Italy).
To serve on the expert panel, ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement and profile as well as dedication to the topics addressed.The objective was to assemble a multidisciplinary development group and it was therefore essential to include professionals from relevant disciplines (gynecological oncology and gynecology, medical, clinical and radiation oncology, pathology) to contribute to the validity and acceptability of the guidelines. To ensure that the statements were evidence based, the current literature was reviewed and critically appraised. A systematic, unbiased literature review of relevant studies published between January 2017 and March 2022 was carried out using the MEDLINE database (see Online Supplemental File 2). The literature search was limited to publications in English. Priority was given to high-quality systematic reviews, meta-analyses, and randomized controlled trials, but studies of lower levels of evidence were also evaluated. The search strategy excluded editorials, letters, and in vitro studies. The reference list of each identified article was reviewed for other potentially relevant articles. Based on the collected evidence and clinical expertise, the international development group drafted guidelines for all the topics. The updated guidelines were retained if they were supported by a sufficiently high level of scientific evidence and/or when a large consensus among experts was obtained. An adapted version of the "Infectious Diseases Society of America-United States Public Health Service Grading System was used to define the level of evidence and grade of recommendation for each of the recommendations [7] (see Figure 2). In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group.
ESGO/ESTRO/ESP established a large multidisciplinary panel of practicing clinicians who provide care to patients with cervical cancer to act as independent reviewers for the updated guidelines. These reviewers were selected according to their expertise, had to be still involved in clinical practice/research, and were from different European and non-European countries to ensure a global perspective. Patients with cervical cancer were also included. The independent reviewers were asked to evaluate each recommendation according to its relevance and feasibility in clinical practice (only physicians), so that comprehensive quantitative and qualitative evaluations of the updated guidelines were completed. Patients were asked to evaluate qualitatively each recommendation (according to their experience, personal perceptions, etc.). Evaluations of the external reviewers (n=155) were pooled and discussed by the international development group to finalize the guidelines' updating process. The list of the 155 external reviewers is available in Online Supplemental File 2.

Guidelines
The guidelines detailed in this article cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy (SH) specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. A summary of evidence supporting the guidelines is included in Online Supplemental File 1, available online.

General Recommendations
• Centralization of care in specialized centers and referral network is encouraged [IV, B]. • Treatment planning should be made on a multidisciplinary basis (generally at a tumor board meeting as defined in the ESGO quality indicators) and based on the comprehensive and precise knowledge of prognostic and predictive factors for oncological outcome, side effects, and quality of life [IV, A].   Figure 3), simple trachelectomy (see Figure 4), radical 1 3 (vaginal) trachelectomy (see Figure 5), abdominal radical trachelectomy (see Figure 6)  ]. • Fertility sparing therapy for patients with tumors greater than 2 cm is significantly associated with a higher risk of recurrence and should not be considered as a standard treatment. The risk of recurrence must be comprehensively discussed with the patient. NACT followed by radical vaginal trachelectomy and abdominal radical trachelectomy or cone has been described for fertility sparing treatment in patients with tumors >2 cm. PLN staging should be performed before starting NACT to confirm tumor-free LN. The optimal number of chemotherapy cycles, chemotherapy regimen as well as extent of cervical resection following NACT, are still a matter of debate [IV, B]. • In more advanced cases, various fertility preservation proposals such as ovarian transposition (see Figure 7), oocyte-, embryo-or ovarian tissue preservation and egg donation should be discussed with the patient. The aim of the fertility preservation should be to offer the most efficient approach in accordance with the legal countryspecific regulations, while not increasing the oncological risk [IV, B].
• Any pregnancy following fertility sparing therapy should be considered as a high-risk pregnancy. Following simple or radical trachelectomy with placement of a permanent cerclage, delivery can only be performed by cesarean section [IV, B]. • Although evidence is limited, several antenatal management tools can be considered following fertility sparing therapy including screening and treatment of asymptomatic bacteriuria, screening for cervical incompetence and progressive cervical shortening by transvaginal ultrasonography, fetal fibronectin testing, screening (and treatment) for asymptomatic vaginal infection, vaginal progesterone application, total cervical closure according to Saling and cervical cerclage, if not placed during trachelectomy [IV, C]. • Routine hysterectomy after completion of childbearing is not mandatory [V, D].

General Recommendations
• Management of disease found after SH should be based on expert pathology review and discussed in a multidisciplinary tumor board. In general, management of occult disease follows the principles of the standard management, and is based on pathologic findings, and clinical staging. Treatment strategy should aim to avoid combining further surgery and radiotherapy because of the high morbidity after combined treatment [III, B]. • Before making further management decisions, optimal imaging is necessary to evaluate the local and regional (nodal) Figure 3 Conization. disease status. Optimal imaging follows the same recommendations as that for the standard management [III, B]. • When surgical staging of nodal disease is indicated (see below for details), it can be considered either as an isolated (preferentially laparoscopic) procedure or as the first step of surgical management in radiologic node negative patients. Surgical staging of nodal disease can also be considered to assess inconclusive nodes at imaging. SLN biopsy cannot be performed in the absence of the uterus. Any suspicious LN should be sent for intraoperative assessment (frozen section) [III, B]. • Para-aortic LN dissection, at least up to inferior mesenteric artery, may be considered for staging purposes in patients with positive pelvic nodes at imaging, or at frozen section [IV, C].

Management of Patients with T1b1 Disease, with Clear Margins and Without Residual Tumor
• Surgical LN staging is recommended in patients with T1b1 tumor with clear margins and absence of residual tumor on    • PALND (at least up to inferior mesenteric artery) may be used to assess the need for elective para-aortic EBRT in patients with negative para-aortic lymph nodes (PALN) and positive PLN on imaging [IV, C]. • If PALND is not performed, risk assessment for microscopic para-aortic nodal involvement and the indication for elective para-aortic irradiation can be based on the number of level 1 positive nodes (external iliac, interiliac, internal iliac) on imaging (e.g. >2 positive nodes). However, elective paraaortic radiation should always be applied in patients who on imaging have even one positive node at level 2 (common iliac) and above. The groin should also be included in the elective target for patients with tumor involvement of the

Follow-up After Definitive CTRT and BT
• Follow-up should be performed/coordinated by a physician experienced with follow-up care after radiotherapy and BT including monitoring of early, and late treatment-

General Recommendations
• Every patient diagnosed with cervical cancer in pregnancy must be counseled by a multidisciplinary team. This team should consist of experts in the fields of gynecological oncology, neonatology, obstetrics, pathology, anesthesiology, radiation oncology, medical oncology, psycho-oncology, and, spiritual and ethical coun- tiate cancer-specific treatment immediately after delivery by cesarean section. This option might be considered if the term or fetal maturity is approaching. • Conization or simple trachelectomy in order to completely remove the tumor, obtain free margins and perform nodal staging if needed, with the intention to preserve the pregnancy. • Radical surgery or definitive CTRT according to the disease stage as recommended outside pregnancy, if the woman decides not to preserve the pregnancy. Pregnancy termination is recommended before any treatment after the first trimester, and fetus evacuation before CTRT, if possible. • Chemotherapy until term of pregnancy (37 weeks of gestation) and initiation of definitive cancerspecific treatment immediately after delivery by cesarean section. At least a 2 week interval between chemotherapy and surgery is recommended. In patients with locally advanced disease or residual tumor after surgical procedure that cannot be completely removed (risk of premature rupture of amniotic membranes and/or cervical insufficiency), chemotherapy based on cisplatin or carboplatin can be considered starting after 14 weeks of pregnancy. Combination with taxanes is an option. Bevacizumab and checkpoint inhibitors are contraindicated.
• Before starting each cycle of chemotherapy, an assessment of treatment response should be made by clinical examination and transvaginal or transrectal ultrasound. If no response is achieved after 2 cycles of chemotherapy during pregnancy, treatment strategy should be re-evaluated.

Pregnancy Management
• Spontaneous delivery appears to have negative prognostic impact in patients with cervical cancer in pregnancy. Thus, cesarean section is the recommended mode of delivery [IV, B]. • At the time of cesarean section, definitive cancer specific treatment should be performed corresponding to that of non-pregnant women, taking into account the treatment that has already been given during pregnancy [IV, A].

Rare Tumors
• Histopathological diagnosis of rare cervical tumors needs confirmation (second opinion) by an expert pathologist [IV, A]. • Treatment and care of rare cervical tumors needs to be centralized at referral centers and discussed in a multidisciplinary tumor board [IV, A].

Management of T1a Disease
Fertility Sparing Treatment -Selection of Candidates 1 3

Definitive CTRT and BT -General Aspects
Definitive management (ie, without tumor related surgery) consists of EBRT with concomitant platinum-based chemotherapy and BT. Delay of treatment and/or treatment interruptions have to be prevented to avoid tumor progression and accelerated repopulation. The overall treatment time including both EBRT and BT should therefore not exceed 7 weeks. chemotherapy, preferably cisplatin (weekly 40 mg/m 2 ). If cisplatin is not applicable, alternative treatment options are weekly carboplatin (area under the curve (AUC) =2) or hyperthermia (if available). EBRT may also be applied without concomitant chemotherapy or hyperthermia according to patient selection (ie, patients unfit for any chemotherapy).

Brachytherapy
IGABT is recommended, preferably using MRI with applicator in place. Repeated gynaecologic examination is mandatory, and alternative imaging modalities such as CT scan and ultrasound may be used. The tumour-related targets for BT include: 1) the residual gross tumor volume (GTV-T res ) after CTRT; 2) the adaptive high-risk clinical target volume (CTV-T HR ) including the whole cervix and residual adjacent pathologic tissue; and 3) the intermediate-risk clinical target volume (CTV-T IR ) taking the initial tumor extent into consideration. The BT applicator should consist of a uterine tandem and a vaginal component (ovoids/ ring/mold/combined ring/ovoid). A combined intracavitary/interstitial implant is recommended in advanced cases to achieve the dose planning aim (see below), in particular in case of residual disease in the parametrium. Ultrasound (transabdominal and/or transrectal) maybe used to intraoperatively support applicator insertion (avoidance of uterine perforation by the tandem, guidance of interstitial needles). In IGABT, the planning aim should be to deliver a BT dose of 40 to 45 Gy EQD2 to reach a total EBRT+BT dose of 85 to 95 Gy EQD2 (D90) (assuming 45 Gy through EBRT) to the CTV-T HR , equal to or greater than 60 Gy (D98) to the CTV-T IR , and equal to or greater than 90 Gy (D98) to the GTV-T res . The use of three dimensional and 2D dose volume and point constraints for rectum, bladder, vagina, sigmoid, and bowel are recommended, and they have to be based on the published clinical evidence. Even though point A dose reporting and prescription have been surpassed by the volumetric approach, a point A dose standard plan should be used as a starting point for stepwise treatment plan optimization to retain the pear shaped iso-dose pattern with a high central dose. This is especially important for the combined intracavitary/interstitial technique to avoid overloading of the interstitial needles.
BT should be delivered in several fractions as high dose rate (usually 3-4) with at least 6-8 hours interval or pulse dose rate delivered in one fraction (50-60 hourly pulses) or 2-3 fractions (15-24 hourly pulses) to respect the limitations of current radiobiological models for speed and capacity of radiation damage repair. In large tumors, BT should be delivered within 1 to 2 weeks toward the end of or after CTRT. In

Definitive CTRT and BT
CTRT Target contouring for EBRT should be based on 3D imaging (preferably fused MRI and PET-CT) performed in the supine treatment position. Controlled bladder filling is recommended to minimize uterus movements and to push the intestines away. The result of the gynecological examination (ie, clinical drawing and description) as well as diagnostic imaging should be available during the contouring phase. A contouring protocol including a margin strategy for handling of internal movement (ITV) should be used to minimize irradiation of organs at risk. The EMBRACE II protocol may serve as a template. The tumor related target volume for EBRT (CTV-T-LR) includes the primary cervical tumor (GTV-T), the uterus, parametria and upper vagina (or minimal 2 cm tumour-free margin below any vaginal infiltration respectively) and is optimally defined on MRI with assistance of the clinical findings.
The elective target (CTV-E) includes the obturator, internal, external and common iliac and presacral regions. The inguinal nodes should be included if the primary tumor involves the distal third of the vagina. A reduced elective target volume for EBRT without the common iliac nodes may be considered in low-and intermediate-risk T1b1 patients with negative LN and no LVSI. In case of PLN involvement indicating an increased risk of PALN spread (i.e.>2 pathological LN or involvement of common iliac region) and absence of surgical para-aortic staging, the elective target for EBRT should include the para-aortic region up to the renal vessels. In case of PALN involvement, the target volume includes at a minimum the region up to the renal vessels. Pathological macroscopic LN (GTV-N) are optimally localized with PET-CT and contoured on MRI.
The planning aim for EBRT is 45 Gy/25 fractions or 46 Gy/23 fractions using intensity-modulated radiotherapy/ volumetric modulated arc therapy (IMRT/VMAT). A homogeneous dose from EBRT is needed in the central pelvis to ensure a safe platform for planning of BT. The use of an EBRT boost to the primary tumor and/or the parametria for complete or partial replacement of BT is not recommended.
Pathological macroscopic LN (GTV-N) should receive an EBRT boost. Simultaneous integrated boosting using coverage probability planning is recommended. Depending on nodal size and the expected dose contribution from BT a total dose of approximately 60 Gy EQD2 should be the aim of treatment. An alternative treatment option is surgical removal of enlarged nodes.
Image-guided radiotherapy with daily on-board 3D imaging is recommended for IMRT/VMAT to ensure safe dose application with limited PTV margins. Concomitant chemotherapy should be based on single-agent radiosensitizing 1 3 limited-size tumors, BT may start earlier during CTRT. For the tumour-related targets (GTV-T res , CTV-T HR , CTV-T IR ), the use of external beam therapy for giving an extra dose (eg, parametrial boost, cervix boost) is not recommended, even when using advanced EBRT technology such as stereotactic radiotherapy or particle therapy. The use of a midline block for boosting the parametrium is not recommended when applying advanced image-guided radiotherapy and IGABT. Care should be taken to optimize patient comfort during (fractionated) BT. Preferably this includes a multidisciplinary approach. Intracavitary and combined intracavitary/interstitial BT implants should be performed under anesthesia.

Adjuvant Radiotherapy or CTRT
Adjuvant radiotherapy or CTRT follows analog principles for target contouring, dose and fractionation as outlined for definitive treatment. Different concomitant and/or sequential chemotherapy schedules have been established including cisplatin alone or combinations of cisplatin with other agents such as 5-FU or paclitaxel. Carboplatin should be considered for patients unfit for cisplatin. The application of IMRT/VMAT and image-guided radiotherapy is recommended as treatment-related morbidity is reduced. Additional BT as part of adjuvant radiotherapy or CTRT should be considered only if a well-defined limited area accessible through a BT technique is at high risk of local recurrence (eg, positive resection margins in vagina or parametrium). Such adjuvant BT should follow the major principles outlined above for IGBT.

Definitive 3D Conformal EBRT or CTRT and Radiography-based BT
Three-dimensional conformal radiotherapy alone or as definitive concomitant CTRT (platinum based) ± para-aortic radiotherapy and/or 2D radiography based BT is recommended, if intensity modulated radiotherapy and/or IGABT are not available. In case of 3D conformal radiotherapy and/ or radiography based BT, the recommendations for EBRT and IGABT as outlined above in regard to target, dose, fractionation, and overall treatment time have to be respected as much as possible. A sequential LN boost is applied as appropriate after completion of 3D EBRT. Planning aim for BT should be based on point A. Dose to point A should be equal to or greater than 75 Gy (EQD2) in limited width adaptive CTV-T HR (≤3 cm) and should aim at higher doses in large width adaptive CTV-T HR (>4 cm). In addition, dose for the maximum width of the adaptive CTV-T HR should be reported. Radiography based dose point constraints -plus 3D dose volume constraints as available -for rectum, bladder, vagina, sigmoid, and bowel are recommended, and must be based on published clinical evidence.

Requirements for Specimen Submitted for Pathological Evaluation
Patient information, previous cervical cytology, histological specimens, clinical and radiological data, colposcopic findings and information on previous treatment (eg, surgery, radiotherapy) need to be included on the specimen request form. Details of cytology, biopsy, and surgical specimen (cone/loop specimen, trachelectomy, type of hysterectomy, presence of ovaries and fallopian tubes, presence of LN and designation of the LN sites, presence of vaginal cuff, and presence of parametria) need to be itemized in the specimen request form. Biopsies and surgical specimens should be sent to the pathology department in a container with liquid fixative (''clamping'' of surgical specimens on a surface may be useful). If the local situation requires biobanking of fresh tissue, surgical specimens should be submitted fresh with minimum ischemia time. Cytology specimens should be sent to the pathology department preferentially as liquid-based cytology. Smear preparations are not recommended. The former is necessary when an HPV test is requested. Immunocytochemistry is possible on LBC but of limited extent (eg, CPS score for PD-L1 cannot be assessed). Cone/loop specimen should ideally be sent intact with a suture to identify the 12-o'clock position.

Biopsy/Cone/Loop
Small biopsy specimens should be enumerated. The cone/loop specimens should be measured in three dimensions according to the recent ESGO/ESP recommendations. If the cone can be oriented properly, the anterior and the posterior half should be inked with separate colors. It should further be recorded if the specimen is complete or fragmented. If more than one piece of tissue is received, every piece should be measured in three dimensions. All specimens should be entirely submitted for microscopic examination. Inking of the surgical margins of cone/loop specimens is recommended. Dissection of cone/loop specimens should be performed in a standardized procedure. All the pieces submitted should be in consecutive numerical order. This is important because if tumor is present in more than one piece, it needs to be known whether these pieces are consecutive and, thus, a single tumor is present or whether the tumor is multifocal. It is recommended to place only one piece of tissue in each cassette. There are also techniques that allow embedding of more than one piece in a cassette if they are small enough. In cases that do not comprise intact cone/loops, serial radial sectioning and placing of each slice of tissue in a single cassette should be performed.

Trachelectomy
The upper (proximal) surgical margin of a trachelectomy specimen should be inked. The upper margin of a trachelectomy specimen should be sampled in its entirety in a way that allows to measure the distance of the tumor to the margin. The vaginal margin should also be inked and examined totally as radial sections if no tumor is seen grossly.

Hysterectomy
The description of the specimen (hysterectomy, trachelectomy, presence of ovaries and fallopian tubes, presence of LN and indication of the LN sites, presence of vaginal cuff and presence of parametria) should be recorded and checked for consistency with the description given in the specimen request form. The presence of any gross abnormality in any organ should be documented. The dimensions of the uterus for a hysterectomy specimen and the cervix for a trachelectomy specimen should be documented. The minimum and maximal length of the vaginal cuff should be documented. The size of the parametria should be documented in two dimensions (vertical and horizontal). Gross tumor involvement of the parametrium, vagina, uterine corpus, or other organs should be documented. The relationship of the cervical tumor to the vaginal and parametrial margins (and upper margin in case of a trachelectomy specimen) should be measured and appropriate sections taken to demonstrate this. Radial/circumferential and vaginal margins should be inked. The gross appearance of the cervix should be documented and any gross tumor mass measured. If visible, the site of a previous cone biopsy should be documented. Gross tumors should be measured in three dimensions, namely, the horizontal extent and the depth of invasion.
The tumor site within the cervix should be documented. The cervical tumor should be sampled to demonstrate the maximum depth of invasion, the relationship of the tumor with the surgical borders, and the extension to other organs. When the tumor is small (or with tumors that cannot be identified macroscopically), the cervix should be separated from the corpus, opened and processed as for a cone/ loop specimen. In the case of a large tumor, the hysterectomy or trachelectomy specimen should be opened in the sagittal plane. At least one block per centimeter of the greatest tumor dimension should be taken for large tumors.
Additional blocks including the cervix adjacent to the tumor should be taken to identify precursor lesions. The whole cervix should be sampled in the case of a small tumor or where no macroscopic tumor is identified. The uterine corpus, vagina, and adnexa should be sampled according to standard protocols if not involved by tumor. If the uterine corpus and/or adnexa are grossly involved, additional blocks should be sampled. The entire vaginal margin should be blocked. The parametria should be submitted totally for histological examination to assess tumor invasion and surgical margins. The use of large sections is optional and provides good information on tumor size and marginal status.

Lymph nodes
All the LN should be submitted for histological examination. If the LN are grossly involved, representative samples are sufficient. If grossly uninvolved, each node should be sliced at 2 mm interval (eg, perpendicular to its longitudinal axis) and totally embedded. From each block, hematoxylin-eosin (H&E) sections should be taken. LN should be submitted in separate cassettes according to the site recorded on the specimen request form.

Pathological Analysis of SLN
Intraoperative assessment of sentinel nodes is a reliable procedure but may miss micrometastases and isolated tumor cells. Intraoperative assessment should be performed on a grossly suspicious sentinel node and may be performed on a "non-suspicious" SLN because the confirmation of tumor involvement will result in abandoning a hysterectomy or trachelectomy. For intraoperative evaluation, the SLN should be sent to the pathology department in a container without liquid fixative. Intraoperative analysis requires gross dissection of the resected adipose tissue by the pathologist and selection of LN. It is important to leave some peri-nodal tissue allowing proper diagnosis of extranodal tumor spread. For a LN with obvious gross tumor, a single section is adequate for frozen section.
Frozen section may be combined with imprint cytology. The use of one step nucleic acid amplification is not recommended particularly due to the interference with benign epithelial inclusions in PLN. Any nonsuspicious sentinel node should be bisected (if small) or sliced at (approximately) 2 mm thickness and entirely frozen. From each sample, histological sections should be cut and stained by H&E. After frozen section analysis, the tissue should be put into a cassette, fixed in liquid fixative (preferably 4% buffered formalin) and subsequently processed and embedded in paraffin. If no metastases are present in the first section, SLN should undergo ultrastaging in definitive paraffin sections, including immunohistochemistry. A minimum procedure should include five serial sections at 200 µm. At least, at two levels an additional section must be cut and stained with a broad-spectrum cytokeratin antibody (eg, AE1/AE3). If the resources of the pathology lab allow, it is recommended to cut serial sections through the whole block (eg, at 100-200 µm) and to perform about additional cytokeratin immunostainings. Cytokeratin-positive cells should always be correlated with the morphology. Müllerian inclusions (endosalpingiosis, endometriosis) and mesothelial cells may rarely be present in pelvic and PALN and are cytokeratin positive.

Language English
Study design Priority was given to high-quality systematic reviews and meta-analyses but lower levels of evidence were also evaluated. The search strategy excluded editorials, letters, case reports and in vitro studies