Invasive cervical cancer: Staging and evaluation of lymph nodes

INTRODUCTION — Cancer of the uterine cervix has traditionally been staged clinically, but surgical and radiologic evaluation are now part of assigning stage [1-4]. Surgical and radiologic staging provide important information that may impact treatment [5]. However, the International Federation of Gynecology and Obstetrics (FIGO) continues to use clinical staging as an option for several reasons: it is more accessible for low-resource settings, in which cervical cancer remains the most common malignancy among women; it may be better for assessing locally advanced disease (ie, tumor size, vaginal and parametrial involvement); and it avoids surgery in patients who are not candidates for surgical treatment [6].

Tumor stage is determined at the time of primary diagnosis of cervical cancer and is not altered, even upon recurrence. This convention also applies to other gynecologic cancers. Accurate pretreatment staging of cervical cancer is critical, as it determines therapy (ie, surgery, chemoradiation, chemotherapy alone) and prognosis (table 1).

The staging and evaluation of lymph nodes for cervical cancer will be reviewed here. Cervical cancer screening and prevention, epidemiology, risk factors, clinical manifestations, diagnosis, and treatment are discussed separately. (See "Screening for cervical cancer in resource-rich settings" and "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis" and "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer" and "Cervical intraepithelial neoplasia: Management".)

ROUTES OF SPREAD — Cervical cancer can spread by direct extension or by lymphatic or hematogenous dissemination. Direct extension may involve the uterine corpus, vagina, parametria, peritoneal cavity, bladder, or rectum. Ovarian involvement by direct extension of cervical cancer is rare; ovarian metastases occur in approximately 0.5 percent of squamous cell carcinomas and 1.7 percent of adenocarcinomas [7]. The most common sites for hematogenous spread are the lungs, liver, and bone; the bowel, adrenal glands, spleen, and brain are less frequent sites.

Historically, obturator lymph nodes were thought to be the most frequent site of nodal metastases in patients with cervical cancer [8]. It was also thought that lymphatic spread advanced in an orderly fashion from the lymph nodes on the pelvic sidewall, to the common iliac, and then the paraaortic group (figure 1). However, subsequent studies, including those utilizing the sentinel lymph node mapping technique, emphasize that any of the pelvic lymph node groups, and even paraaortic lymph nodes, may contain the first draining lymph node and may be the first site of nodal metastasis [9,10]. This was illustrated in a large retrospective study (n = 619) that evaluated women with cervical cancer who had solitary (one or two) positive lymph nodes discovered via radical hysterectomy and complete lymphadenectomy [11]. The distribution of sites of nodal metastasis were external iliac (43 percent), obturator (26 percent), parametrial (21 percent), common iliac (7 percent), presacral (1 percent), and paraaortic (1 percent).

The risk of pelvic lymph node metastasis increases with increasing depth of invasion [12]:

●Stage IA1 – 2.1 percent

●Stage IA2 – 3.9 percent

However, the presence of lymphovascular space invasion (LVSI) is likely a better predictor of nodal disease. In a retrospective study including 170 patients with cervical cancer and a depth of invasion ≤5 mm, metastatic disease to the lymph nodes was present in more patients with versus without LVSI (4/43 patients [9.3 percent] versus 2/117 patients [1.7 percent]) [12].

Tumor size is also a strong predictor of metastatic disease to lymph nodes. In one retrospective study including over 1400 patients with cervical cancer, the risk of nodal disease in patients with tumors ≤2 cm, 2 to 4 cm, and ≥4 cm in size was 6, 18.4, and 36.4 percent, respectively [13].

The risk of paraaortic nodal involvement also increases as the local disease extent increases; pathologically confirmed paraaortic disease after surgical staging is present as follows [14]:

●Stage IB3 – 21 percent

●Stage IIA – 22 percent

●Stage IIB – 16 percent

●Stage IIIA – 13 percent

●Stage IIIB – 35 percent

Sentinel node biopsy in cervical cancer is discussed in detail separately. (See 'Sentinel lymph node biopsy' below.)

STAGING SYSTEM — The diagnosis of cervical cancer is made clinically based upon histologic evaluation of a cervical biopsy. For centers that have limited resources, staging may be determined clinically based upon physical examination and a limited number of endoscopic diagnostic procedures and imaging studies. However, in 2018, the International Federation of Gynecology and Obstetrics (FIGO) expanded the list of tests and procedures that may be used in assigning stage to include imaging and pathologic findings where available (table 2) [1,2]. In addition, stage definitions also changed; tumor size categories have shifted and lymph node metastases are now included. Cervical cancer outcomes depend greatly on tumor size and lymph node involvement, and these changes aim to improve the ability of stage to predict prognosis and plan treatment.

The context of the changes is that, as the majority of cervical cancer occurs in low-resource countries, FIGO had established a clinical staging system that could be performed by practitioners in both the developing and developed worlds. These included physical examination, inexpensive radiographic tests (chest radiograph and intravenous pyelogram [IVP]), and basic diagnostic procedures (examination under anesthesia, proctoscopy, cystoscopy, hysteroscopy). However, many clinicians were utilizing advanced radiologic imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), to develop treatment plans, even though these did not change the assigned stage. For example, patients with a clinical stage IB1 cervical cancer with multiple positive pelvic nodes detected on CT scan would not have had their stage changed, but their treatment would have changed from probable surgery to chemoradiation. In an effort to account for the wide array of evaluation methods that clinicians use to determine the optimal treatment for patients with cervical cancer, the FIGO 2018 staging allows for advanced radiologic imaging and confirmatory pathology. This staging system is still considered clinical staging as invasive surgery is not required to assign stage.

The American Joint Committee on Cancer tumor, node, metastasis (TNM) staging system is shown in the table (table 3) [15,16]. While both systems are acceptable staging systems and widely used, this topic will utilize the 2018 FIGO staging system except when describing studies that used the TNM staging system.

2018 FIGO staging — The 2018 FIGO cervical cancer staging system (which was revised in a 2019 corrigendum) is as follows (table 2) [1,2]:

●Stage I – Carcinoma strictly confined to the cervix

•IA – Diagnosed by microscopy only, with maximum depth of invasion <5 mm

-IA1: ≤3 mm in depth

-IA2: >3 mm and ≤5 mm in depth

•IB – Deepest invasion >5 mm but limited to the cervix

-IB1: >5 mm in depth and ≤2 cm in greatest dimension

-IB2: >2 cm and ≤4 cm in greatest dimension

-IB3: >4 cm in greatest dimension

●II – Invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall

•IIA – Involvement limited to upper two-thirds of vagina without parametrial involvement

-IIA1: ≤4 cm in greatest dimension

-IIA2: >4 cm in greatest dimension

•IIB – Parametrial involvement but not up to the pelvic wall

●III – Involves lower third of vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes

•IIIA – Involves lower third of vagina, with no extension to the pelvic wall

•IIIB – Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause)

•IIIC – Involves pelvic/para-aortic lymph nodes, irrespective of tumor size and extent

-IIIC1: Pelvic lymph node metastasis only

-IIIC2: Paraaortic node metastasis

●IV – Extends beyond the true pelvis or involves the mucosa of the bladder or rectum

•IVA – Spread to adjacent pelvic organs

•IVB – Spread to distant organs

STAGING PROCEDURE — Standard staging procedure International Federation of Gynecology and Obstetrics (FIGO) guidelines allow the following examinations for establishing the stage of cervical cancer, but it is not mandatory to perform all of these tests on every patient [3,5].

In resource-limited settings, it may only be feasible to do physical examination, biopsy, and limited endoscopy or imaging studies, and this is an appropriate option. If resources are available, more advanced imaging examinations may be performed and, if findings suggest lymph node metastasis, lymph node sampling may be done. Any of the modalities below may be used in assigning stage, but none are required. The combination of modalities utilized is left to the clinician's discretion and available resources.

Clinical staging

●Physical examination

•Pelvic examination – Speculum, bimanual, and rectovaginal examination for palpation and inspection of the primary tumor, uterus, vagina, and parametria.

•Examination for distant metastases – Palpation of groin and supraclavicular lymph nodes, examination of the right upper quadrant.

●Cervical biopsy

•Colposcopy with directed cervical biopsy or cervical biopsy without colposcopy if visible lesion

•Endocervical curettage

•Conization

●Endoscopy

•Hysteroscopy

•Cystoscopy

•Proctoscopy

●Imaging studies

•Intravenous pyelogram (IVP) – Evaluation for urinary tract obstruction; in many centers, computed tomography (CT) or magnetic resonance imaging (MRI) is used instead.

•Imaging with a plain chest radiograph and radiograph of the skeleton – Evaluation for metastases.

•In settings in which these imaging studies are readily available and accessible:

-CT scan or positron emission tomography (PET)-CT – This is typically used to assess involvement of pelvic and paraaortic lymph node involvement.

-MRI – To assess tumor size and local extent of disease, including lymph node assessment.

-Ultrasound – This may also be used to assess tumor size and local extent of disease.

If imaging shows sites suspicious for metastatic disease, image-guided biopsy may be obtained and the results incorporated into stage assignment.

The FIGO staging system remains largely based upon physical examination. Thus, a good pelvic examination by an experienced examiner is of critical importance. Rarely does it need to be performed under anesthesia.

Cervical cancer spreads locally by extension to the uterine corpus, vagina, and parametria. Thus, the cervix and entire vagina should be inspected and palpated to identify overt tumors or subepithelial vaginal extension. Vaginal extension is diagnosed with visual inspection; biopsy is not typically required. Tumor size and parametrial involvement are best assessed by rectovaginal examination. (See 'Routes of spread' above.)

Cervical biopsy may have been performed as part of an initial evaluation or along with the staging procedure, depending on the level of suspicion of malignancy. The approach to cervical biopsy (eg, colposcopy with directed biopsy or conization) differs depending upon the patient’s presentation, findings on pelvic examination, and the patient’s access to health care. Usually, once a biopsy confirms invasive disease, repeat biopsy or cervical conization procedure is not necessary unless the conization is part of treatment (eg, a stage IA1 cancer being treated definitively with cone biopsy). Approaches to cervical biopsy for varying presentations (ie, visible lesion, abnormal cytology) are discussed separately. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Cervical biopsy and colposcopy'.)

Hysteroscopy, cystoscopy, and proctoscopy can be used to assess adjacent areas. Suspicious lesions should be confirmed by biopsy.

The limitations of clinical staging are well appreciated and have been accounted for in the new FIGO staging system. Parametrial and sidewall invasion, as well as metastases to lymph nodes, can be difficult to assess accurately using physical examination alone and can lead to understaging of some patients [17,18]. Clinical staging appears to perform best for microscopic or late-stage disease but less well for the stages that depend largely upon assessment of tumor size or local spread [19]. Based on international data from over 13,000 women with cervical cancer, the correlation between clinical staging and surgicopathologic findings reached 90 percent or higher only for stage IA1 (microscopic disease) and stages IIIB and IVA (tumor extends to pelvic sidewall, hydronephrosis, or bladder/rectal invasion) [20]. For other stages, the correlation between clinical and surgical stages ranged from 66 to 83 percent. For these reasons, radiologic and pathologic assessment are now allowable (but not required) modalities for assigning stage.

Imaging — Practice patterns vary regarding the choice of staging imaging studies and are subject to the availability of the scanner hardware and radiologist expertise.

The evidence regarding the performance of specific imaging modalities is reviewed in detail in the sections that follow. In our practice, we use the following approach:

●For patients who are candidates for radical hysterectomy (stages IA2 to IB2):

•We assess the tumor size and vaginal and parametrial involvement by clinical examination alone. If there is uncertainty about tumor size and/or local spread following the clinical examination (eg, prior pelvic surgery or radiation, vaginal bleeding), some clinicians evaluate the patient with pelvic MRI without and with intravenous contrast.

•We use preoperative abdominopelvic CT with intravenous contrast to exclude obvious lymph node and distant metastases. If the nodes appear benign, we proceed with surgery. If the CT findings are suspicious for lymph node metastases, there are two commonly used options for further evaluation: (1) in our practice, we refer for a CT- or ultrasound-guided node biopsy, or (2) other clinicians commonly use whole body fluorodeoxyglucose (FDG) PET/CT for further evaluation.

•For patients with lymph node metastases on imaging-guided biopsy or PET/CT, some clinicians treat based upon these findings and others perform laparoscopic pelvic and paraaortic lymph node dissection to debulk enlarged nodes and provide further information to determine the radiation fields. (See 'Surgical evaluation of lymph nodes' below.)

●For patients with locally advanced disease (stages IB3 to IVA) for whom primary chemoradiation is planned:

•Prior to treatment, we obtain a whole body FDG PET/CT to evaluate extent of disease with particular attention to lymph node metastases to provide information to design radiation fields [21]. If PET/CT detects distant metastases, we treat with full-dose chemotherapy rather than chemoradiation.

•Some radiation oncologists will add pelvic MRI without and with contrast for treatment planning, particularly if there is concern for rectum or bladder involvement.

Tumor size and local spread — If imaging is needed to evaluate tumor spread in the central pelvis, pelvic MRI without and with contrast is the preferred modality [22]. It can be used to measure tumor size, detect invasion into the parametria, adjacent organs (eg, bladder or rectum) or the pelvic sidewall.

●Tumor size – For patients who are surgical candidates based upon clinical staging, some data suggest that tumor size can be determined more accurately with MRI than clinical examination. As an example, a prospective study included 208 women, most with stage IB disease, who underwent MRI and CT prior to surgery [23]. MRI correlated more closely with surgicopathologic findings than CT or physical examination. All three modalities overestimated tumor size compared with the fixed surgical specimen. This is an important observation, as overestimation of tumor size in surgical candidates likely would not change treatment or prognosis, while underestimation of size would potentially triage a patient to surgical excision when chemoradiation would be the best option.

●Local spread – Determining the presence of parametrial spread is also of critical importance for determining whether patients are candidates for surgical treatment. Whether imaging is more accurate than physical examination is unclear, as significant variability exists in the reported accuracy of clinical staging [19,23-26]. Imaging performed better than clinical staging in a prospective multicenter study in which 172 women with cervical cancer who were clinically staged as IB or higher underwent CT and MRI prior to surgery [19]. Detection of stage IIB or higher was poor for all approaches, but imaging performed better than clinical staging: clinical staging (sensitivity: 29 percent and specificity: 99 percent), CT (42 and 82 percent), and MRI (53 and 74 percent). By contrast, a retrospective single-center study found clinical staging to be superior to CT and MRI [26]. In that study, the sensitivity and specificity for detection of parametrial involvement (stage IIB) was: clinical staging (sensitivity: 66 percent and specificity: 81 percent), CT (43 and 71 percent), and MRI (52 and 63 percent).

If imaging is to be used for parametrial assessment, we suggest MRI. However, when MRI is not available, ultrasound may be of similar value. In a meta-analysis of 115 studies including almost 14,000 patients with newly diagnosed cervical cancer, the pooled estimates for sensitivity and specificity of pelvic MRI and ultrasound were comparable and better than CT [27].

We usually do not use PET or PET/CT to assess tumor size or local spread in cervical cancer as accumulation of the tracer in the bladder may obscure visualization of the uterine cervix.

In locally advanced cervical cancer (stages IB3 to IVA), correlation of tumor size by physical examination with imaging is difficult to estimate since those patients typically undergo definitive chemoradiation therapy, making pathologic examination and measurement of true tumor size impossible.

Lymph node metastases — Cervical cancer may spread to the pelvic or paraaortic lymph nodes, as well as more distal nodes. The presence of lymph node involvement is associated with a worse prognosis and impacts decisions regarding the radiotherapy field [28]. (See 'Routes of spread' above and "Management of locally advanced cervical cancer", section on 'Prognosis' and "Management of early-stage cervical cancer", section on 'High-risk disease'.)

Historically, surgery with lymphadenectomy was required to evaluate for lymph node metastases. Currently, options for evaluating for lymph node metastases include lymph node dissection, imaging examinations, or both.

Whole body FDG PET/CT, in which both PET and CT are performed in an integrated PET/CT scanner, is the preferred imaging modality for detecting lymph node metastases. If the technology is not available, evaluation of lymph nodes is performed with abdominopelvic CT. Intravenous contrast administration with CT is suggested as it may improve diagnostic accuracy. Pelvic MRI without or with contrast represents another second-line alternative, as it is comparable to CT in diagnostic performance. Lymphangiography has been largely replaced by these noninvasive imaging modalities [29-31].

The superiority of FDG PET to other imaging modalities was illustrated in a meta-analysis of 72 studies including 5042 women with cervical cancer that found the following sensitivities and specificities for the detection of lymph node metastases: PET (sensitivity: 75 percent and specificity: 98 percent), MRI (56 and 93 percent), and CT (58 and 92 percent) [30]. The added value of PET/CT compared with CT alone is in the improved sensitivity for abdominal lymph node metastases, a feature that impacts on the radiotherapy fields and estimates of patient prognosis [31].

While FDG PET/CT is the most accurate imaging examination for lymph node evaluation, it nevertheless results in false negative diagnoses [32,33]. As an example, a study in 60 patients with stage IB2 to IVA disease found that 12 percent of those with no finding of positive paraaortic nodes on PET/CT had pathologically positive paraaortic nodes [32]. A subset of patients with PET/CT findings of positive pelvic and negative paraaortic nodes had an even higher rate of pathologically positive paraaortic disease (22 percent). In a separate study of PET/CT and pathologic analysis of paraaortic nodes, patients with PET-positive pelvic nodes were more likely than those with PET-negative pelvic nodes to have paraaortic lymph node metastases confirmed at surgery (24 versus 3 percent) [34].

Upper urinary tract involvement — Tumor extension to the bladder and ureter may result in hydronephrosis and, ultimately, in a nonfunctioning kidney in patients with cervical cancer. The urinary tract is imaged in all patients with more than a microscopic tumor.

IVP is the examination included in the guidelines for clinical staging [3]. IVP or ultrasound of the kidneys is used in low-resource settings to evaluate for hydronephrosis. In settings where advanced imaging technologies are available, urinary tract obstruction is usually detected on the whole body FDG PET/CT, abdominopelvic CT, or pelvic MRI used for treatment planning and lymph node evaluation.

Evaluation of ureteral obstruction is discussed in detail separately. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)

Surgical evaluation of lymph nodes — Patients treated with radical hysterectomy for cervical cancer should also undergo assessment of pelvic and paraaortic lymph nodes. In addition, lymph node sampling may be performed in some patients treated with primary chemoradiation. In the FIGO staging system, positive lymph nodes alter disease staging (table 2), and surgicopathologic results impact treatment planning in up to 43 percent of cases compared with clinical staging alone [35,36].

Lymph node dissection — Lymph node dissection debulks enlarged nodes, which may have a therapeutic benefit and provides information for treatment planning (to individualize the radiotherapy field) [37]. (See "Management of early-stage cervical cancer", section on 'Indications'.)

The necessity for and extent of lymphadenectomy (pelvic, paraaortic) depends upon disease stage and imaging findings:

●The risk of lymph node metastases with stage IA1 squamous cell cervical cancer is so small (1 percent or less) that lymphadenectomy is not performed unless there is lymphovascular space invasion (LVSI), which is also rare at this early stage [38]. This is true for both squamous cell carcinoma and adenocarcinoma [39].

●For stage IA2 to IIA1 disease, the risk of lymph node metastases is higher (2 to 8 percent with stage IA2 and microscopic IB1 disease, and up 12 percent with macroscopic stage IB1, IB2, and IIA1 disease), and pelvic lymphadenectomy or sentinel lymph node biopsy (SLNB) is generally performed in these patients [17,38,40-45]. Paraaortic lymphadenectomy is performed at the surgeon's discretion or when:

•Pretreatment imaging demonstrates paraaortic nodes suspicious for metastatic disease.

•Enlarged or fixed pelvic lymph nodes are encountered at surgery.

•Frozen section of the pelvic nodes are positive, and metastases are confirmed.

This is discussed in more detail elsewhere. (See 'Sentinel lymph node biopsy' below and "Radical hysterectomy", section on 'Pelvic lymphadenectomy' and "Radical hysterectomy", section on 'Paraaortic node sampling'.)

According to the Gynecologic Oncology Surgical Procedures Manual, pelvic node dissection includes removal of nodal tissue from the distal one-half of each common iliac artery, the anterior and medial aspect of the proximal half of the external iliac artery and vein, and the distal half of the obturator fat pad anterior to the obturator nerve (figure 2 and figure 3) [46]. Isolated involvement of the circumflex iliac nodes is infrequent [47], and some data suggest that removal of the circumflex iliac nodes to the distal external iliac nodes increases the risk of lymphedema [48].

Paraaortic node dissection consists of resection of nodal tissue over the distal vena cava from the level of the inferior mesenteric artery to the mid right common iliac artery and between the aorta and the left ureter from the inferior mesenteric artery to the left mid common iliac artery [49]. Some experts extend the paraaortic lymph node dissection (LND) superiorly to the level of the renal veins [50].

The evaluation procedure can be performed via laparotomy or laparoscopy through a transperitoneal or extraperitoneal approach [51-54]. Extraperitoneal and laparoscopic approaches to staging (including extraperitoneal laparoscopic [53]) are associated with reduced morbidity.

The best available data regarding this issue are from a classic Gynecologic Oncology Group retrospective study in which 284 women with cervical carcinoma (most with stage IIB or IIIB) planned for pelvic irradiation with or without paraaortic irradiation underwent pretreatment selective paraaortic lymphadenectomy using either an extraperitoneal or transperitoneal approach [55]. The rate of vascular injury was lower in the extraperitoneal group (2 versus 8 percent), but this did not reach statistical significance; the rates of postoperative infection were similar (3 percent in both groups). The rates of postradiation enteric and urinary tract injury below the pelvic peritoneal reflection (eg, vesicovaginal fistula) were similar for both groups. However, some postradiation complications above the pelvic peritoneal reflection were significantly lower in the extraperitoneal group, including bowel obstruction (4 versus 12 percent) and other regional enteric injury, including large and small bowel necrosis, enteritis, cecal and sigmoid colonic perforation, and persistent nausea, vomiting, and diarrhea (4 versus 12 percent).

Potential surgical complications of pelvic and paraaortic lymphadenectomy include vascular damage, ureteral injury, infection, fistula formation, lymphocyst/lymphedema, bowel obstruction, and thrombophlebitis. (See "Pelvic and paraaortic lymphadenectomy in gynecologic cancers", section on 'Lymphadenectomy procedure'.)

Sentinel lymph node biopsy — SLNB for patients with cervical cancer appears promising and is a National Comprehensive Cancer Network-approved option for those surgeons experienced with the procedure [56,57]. The usual technique includes the use of blue dye with or without technetium 99, but indocyanine green may be used if a near-infrared camera is available for detection [58].

Four criteria are widely accepted as necessary for determining which patients should undergo SLNB and include:

●Tumors <4 cm.

●No suspicious lymph nodes identified during preoperative imaging.

●Bilateral sentinel lymph node (SLN) detection.

●Ultrastaging (ie, enhanced pathologic review, including additional sectioning and staining of the SLN).

In a meta-analysis of over 3900 patients from 44 studies, the sensitivity of SLNB for identifying nodal metastases was 81 percent; however, the sensitivity increased to 99 percent (95% CI 98-100 percent) with a negative predictive value of 97 to 100 percent when the analysis included only patients with tumors <4 cm in size, negative preoperative imaging, and in whom bilateral SLNs were detected intraoperatively with ultrastaging performed on sentinel node specimens [59]. In one study included in the meta-analysis, two patients had false-negative findings, one of which had a positive lymph node found in a nonmapping hemipelvis; this highlights the importance of complete lymphadenectomy if the mapping procedure fails to detect an SLN in one hemipelvis [57].

Pathology evaluation with ultrastaging may result in increased identification of metastatic lymph nodes [60]. However, the prognostic implications of micrometastatic disease or isolated tumor cells in sentinel nodes remains to be established [61]. Most institutions have developed their own ultrastaging protocols. For example, one protocol involves bivalving SLNs and then sectioning and staining with hematoxylin and eosin (H&E). If no metastatic disease is detected by this initial H&E staining, two adjacent 5 micrometer sections are cut and sectioned at each of the two levels, 50 micrometers apart from each paraffin block. Sections at each level are then stained with H&E and with immunohistochemistry using anticytokeratin AE1:AE3 [62].

SLNB appears to perform better than imaging studies [63]. This was illustrated in a meta-analysis of 72 studies, including 5042 women with cervical cancer that evaluated several approaches, and found that the sensitivity and specificity for the detection of lymph node metastases for various approaches were: SLNB (sensitivity: 91 percent and specificity: 100 percent), PET (75 and 98 percent), MRI (56 and 93 percent), and CT (58 and 92 percent) [30].

LABORATORY EVALUATION — Laboratory evaluation is not part of staging but may be part of the pretreatment evaluation.

Routine evaluation — Patients with cervical cancer should have a complete blood count, liver and renal function tests, and urinalysis to determine systemic effects and the impact of potential metastatic disease. In addition, they should have routine preoperative or pretreatment testing. (See "Preoperative medical evaluation of the healthy adult patient", section on 'Laboratory evaluation'.)

Tumor markers — The use of tumor markers for monitoring therapy or detecting recurrence in cervical cancer is investigational.

A number of serum markers have been investigated for their utility in assessing prognosis, monitoring response to therapy, and detecting recurrence; none has achieved widespread acceptance. The most commonly used are serum squamous cell carcinoma (SCC) antigen, tissue polypeptide antigen, carcinoembryonic antigen (CEA), cancer antigen 125 (CA 125), and CYFRA 21-1 [64-79]. Many of these markers are elevated in a significant proportion of patients with more advanced-stage disease, and they correlate with disease activity. CA 125 levels are elevated in only 13 to 21 percent of patients with cervical squamous cell cancer, but may be a better tumor marker for those with adenocarcinoma [72,73].

At least some data suggest that elevated preoperative serum levels of SCC antigen may be a helpful predictor of the need for postoperative radiation therapy (which is typically reserved for positive or close resection margins, positive lymph nodes, microscopic parametrial involvement, or large tumors with deep cervical stromal invasion and/or lymphovascular space involvement) in patients who undergo surgery for stage IB/IIA disease. This was illustrated in a cohort study of 337 women with surgically treated stage IB/IIA cervical cancer [80]. Compared with women with a normal preoperative marker level, elevated SCC antigen levels (>1.9 ng/mL) were associated with a significantly higher likelihood of needing postoperative radiation therapy both for stage IB1 (57 versus 16 percent) and IB2/IIA disease (74 versus 29 percent). The potential clinical utility of this finding is in the ability to identify preoperatively most women who would likely require trimodality treatment (ie, surgery and chemoradiotherapy) so that they could be considered for primary chemoradiotherapy rather than surgery. The disadvantage is that 43 percent of women identified for primary chemoradiotherapy might have been treated by surgery alone and avoided the long-term morbidity of radiation therapy. (See "Management of locally advanced cervical cancer", section on 'Definition of locally advanced-stage cervical cancer'.)

However, in other mostly small reports using varying cut-off levels, the serum SCC antigen level did not accurately predict lymph node or parametrial involvement, and there are conflicting reports as to its independent prognostic significance [66,68,69,75].

It is also unclear whether routine serial monitoring of any of these markers adds significantly to postoperative clinical or radiographic monitoring for recurrence.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of cervical cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cervical cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Fertility preservation in early-stage cervical cancer (Beyond the Basics)" and "Patient education: Cervical cancer treatment; early-stage cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Cervical cancer staging in the International Federation of Gynecology and Obstetrics (FIGO) 2018 system allows the use of readily available techniques, such as physical examination, biopsy, chest radiography, cystoscopy, proctoscopy, as well as advanced radiologic (computed tomography [CT], positron emission tomography [PET], magnetic resonance imaging [MRI]) and biopsy or surgical lymph node evaluation. The radiologic and pathologic assessments are allowable but not required. (See 'Staging procedure' above.)

●The FIGO 2018 staging system (which was revised in a 2019 corrigendum) (table 2) also includes information about tumor size categories and involvement of lymph nodes that are important prognostic factors in cervical cancer. (See '2018 FIGO staging' above.)

●Tumor size and local spread are important factors in planning cervical cancer treatment, particularly in determining which patients are candidates for primary surgical treatment. Understaging may result in unnecessary surgery in a patient who is better treated with primary chemoradiation. Imaging studies may be used if the clinical examination findings are not definitive. To assess tumor size and local spread, we suggest pelvic MRI without and with contrast rather than pelvic CT or fluorodeoxyglucose (FDG) PET/CT. (See 'Tumor size and local spread' above.)

●Cervical cancer may spread to the pelvic or paraaortic lymph nodes, as well as more distant nodes. Options for evaluating for lymph node metastases include imaging examination, lymph node dissection, and sentinel lymph node biopsy (SLNB). (See 'Lymph node metastases' above and 'Surgical evaluation of lymph nodes' above and 'Sentinel lymph node biopsy' above.)

•For patients who are candidates for radical hysterectomy, we suggest evaluation of the lymph nodes with imaging examinations prior to surgery. We use abdominopelvic CT without or with contrast for evaluation of nodes in preoperative patients. Suspicious findings can be further evaluated with an imaging-guided biopsy, lymphadenectomy, or FDG PET/CT. (See 'Imaging' above.)

•For patients with locally advanced disease for whom primary chemoradiation is planned, we suggest evaluation of the lymph nodes with FDG PET/CT rather than CT alone or MRI. Information regarding lymph node involvement is used to design radiation fields. (See 'Imaging' above and 'Lymph node metastases' above.)

•For patients with stage IA2 to IIA1 disease, pelvic lymphadenectomy or SLNB is generally performed at the time of surgery. Paraaortic lymphadenectomy is performed at the surgeon's discretion or in those patients with pretreatment imaging demonstrating paraaortic nodes suspicious for metastatic disease, enlarged or fixed lymph nodes encountered at surgery, or in whom frozen section of the pelvic nodes are positive and metastases are confirmed. (See 'Surgical evaluation of lymph nodes' above and 'Sentinel lymph node biopsy' above.)