Invasive cervical cancer: Staging and evaluation of lymph nodes

INTRODUCTION — 

Cervical cancer is diagnosed based on histologic evaluation of a cervical biopsy and staged clinically with physical examination and a limited number of radiographic tests (chest radiograph, intravenous pyelogram [IVP]), basic diagnostic procedures (proctoscopy, cystoscopy, hysteroscopy), advanced radiologic imaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]), or other pathologic findings (eg, lymph node biopsy).

Tumor stage is determined at the time of primary diagnosis of cervical cancer and is not changed 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 "Screening for cervical cancer in resource-limited settings".)

●(See "Cervical intraepithelial neoplasia: Management".)

●(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

●(See "Management of early-stage cervical cancer".)

●(See "Management of locally advanced cervical cancer".)

●(See "Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance" and "Management of recurrent or metastatic cervical cancer".)

●(See "Fertility-sparing surgery for cervical cancer".)

ROUTES OF SPREAD — 

Cervical cancer can spread by direct extension, lymphatic, or hematogenous dissemination.

●Direct extension – Direct extension may involve the uterine corpus, vagina, parametria, peritoneal cavity, bladder, or rectum. A tumor that extends to the bladder, ureter, or lateral pelvic wall may result in hydronephrosis and, ultimately, in a nonfunctioning kidney.

Ovarian involvement by direct extension occurs in approximately 2 percent of squamous cell carcinomas and up to 12 percent of adenocarcinomas; risk also varies based on tumor size, lymphovascular space invasion (LVSI), and nodal status [1].

●Lymphatic spread – 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 [2]. (See "Management of locally advanced cervical cancer", section on 'Prognosis' and "Management of early-stage cervical cancer", section on 'High-risk disease'.)

Historically, it was thought that lymphatic spread advanced in an orderly fashion from the lymph nodes on the pelvic sidewall (eg, obturator, external iliac) to the common iliac and then the paraaortic group (figure 1) [3]. However, subsequent studies (including those utilizing sentinel lymph node mapping) have identified a small proportion of cases where the paraaortic lymph nodes may be the first draining lymph node and, therefore the first site of nodal metastasis [4,5]. In a retrospective study including 120 patients with cervical cancer and solitary (one or two) positive lymph nodes discovered via radical hysterectomy and complete lymphadenectomy, 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) [6].

The risk of pelvic lymph node metastasis increases with:

•Increasing depth of invasion - In a retrospective study of 170 patients with cervical cancer in whom lymph node status was evaluated, those with a depth of invasion of 3 to 5 mm compared with <3 mm had higher rates of lymph node involvement (5/130 patients [3.9 percent] versus 1/48 patients [2.1 percent]) [7].

•Presence of LVSI – In the same retrospective study, 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]) [7].

•Increasing tumor size – 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 [8].

The risk of para-aortic nodal involvement also increases as the extent of local disease increases [9].

●Hematogenous spread – The most common sites for hematogenous spread are the lungs, liver, and bone; the bowel, adrenal glands, spleen, and brain are less frequent sites. (See "Management of recurrent or metastatic cervical cancer", section on 'Diagnostic evaluation'.)

STAGING

Staging systems — The 2018 International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system (which was revised in a 2019 corrigendum) and the American Joint Committee on Cancer tumor, node, metastasis (TNM) staging system are shown in the tables (table 2 and table 3) [10-13]. 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.

Clinical staging — The diagnosis of cervical cancer is made based upon histologic evaluation of a cervical biopsy and staged clinically based on physical examination, utilizing imaging and additional pathologic findings where available [10-13]; invasive surgery is not performed to assign stage.

●Modalities – The following imaging modalities 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 [10,11]:

-Hysteroscopy

-Cystoscopy

-Proctoscopy

-Plain chest radiograph and radiograph of the skeleton

-Computed tomography (CT) or positron emission tomography (PET)-CT

-Magnetic resonance imaging (MRI) or PET-MRI

-Ultrasound

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

●Rational – The context of the 2018 FIGO clinical staging system is multifold:

•The majority of cervical cancers occur in resource-limited countries [14]. As such, the clinical staging system must be able to be performed by practitioners in both resource-limited and abundant settings.

•Cervical cancer outcomes depend greatly on tumor size and lymph node involvement; the utilization of imaging and pathologic assessment improves the ability of staging to predict prognosis and plan treatment.

•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 [15,16]. As a result, the proportion of patients with stage III disease (compared with clinical stage I disease) increases with the use of radiologic (and pathological) testing because of the finding of positive or suspicious lymph nodes.

•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 [17]. Based on international data from over 13,000 patients with cervical cancer, the correlation between clinical staging and surgicopathologic findings reached 90 percent or higher only for patients with microscopic disease and those with a tumor extending to pelvic sidewall, hydronephrosis, or bladder/rectal invasion) [18]. For other stages, the correlation between clinical and surgical stages ranged from 66 to 83 percent.

STAGING PROCEDURE

All patients: Physical examination and biopsy — The following are performed on all patients:

●Pelvic examination – Physical examination, including speculum and bimanual examinations, are performed; the cervix and entire vagina are inspected and palpated to identify overt tumors or subepithelial vaginal extension. Tumor size and parametrial involvement are best assessed by rectovaginal examination.

As the FIGO staging system is largely based on physical examination findings, it is critical that the pelvic examination be performed by an experienced examiner. Examination under anesthesia is needed only in uncommon circumstances (eg, severe physical limitations, patient intolerance due to pain or anxiety).

●Examination for distant metastases – The groin and supraclavicular lymph nodes are palpated, and the right upper quadrant is examined for signs of distant metastases.

●Biopsy – Cervical biopsy may have been performed as part of the initial evaluation or along with the staging procedure, depending on the level of suspicion of malignancy. The approach to cervical biopsy (eg, colposcopy with or without directed biopsy, conization, loop electrosurgical excision) differs depending on the patient's presentation, findings on pelvic examination, and the patient's access to health care. This is discussed in detail separately. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Cervical biopsy and colposcopy'.)

Usually, once a biopsy confirms invasive disease (>5 mm) or the clinical tumor is greater than stage IA, 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 [with or without lymph node assessment]) (see "Management of early-stage cervical cancer", section on 'Type of surgery'). Some investigators feel that removing the entire lesion by cone biopsy prior to a minimally invasive surgical procedure can reduce the purported increased recurrence rate [19].

Lesions with vaginal extension are diagnosed with visual inspection; vaginal biopsy is not typically required. (See 'Routes of spread' above.)

Subsequent evaluation for patients in whom surgery is planned

Imaging — For patients with early-stage disease (ie, FIGO stages IA, IB1, and IB2) in whom surgery is planned, evaluation of tumor size and vaginal parametrial involvement may be based on physical examination and biopsy alone (see 'All patients: Physical examination and biopsy' above); imaging does not need to be performed in all such patients as part of clinical staging.

However, for patients in whom there is uncertainty about tumor size and/or local spread following the clinical examination (eg, those with prior pelvic surgery or radiation, vaginal bleeding), imaging is performed.

●MRI – Pelvic MRI with contrast, if available, is the preferred imaging modality to measure tumor size and detect invasion into the parametria, adjacent organs (eg, bladder or rectum), or the pelvic sidewall [20]. For patients with a contraindication to gadolinium due to renal insufficiency, pelvic MRI without contrast can be performed.

•Evaluation of tumor size – Some data suggest that tumor size can be determined more accurately with MRI than with clinical examination. In a prospective study including 208 patients with invasive cervical cancer (the majority with tumor confined to the cervix), MRI prior to surgery compared with physical examination or CT correlated more closely with surgicopathologic findings [21]. All three modalities, however, 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 could potentially triage a patient to surgical excision when chemoradiation might be the best option. In a subsequent prospective study of 60 patients with cervical cancer, MRI findings also correlated better with histopathology than clinically detected tumor size with a sensitivity and specificity for vaginal extension of 100 and 95 percent, respectively [22]. Both the sensitivity and specificity of MRI evaluation of parametrial invasion were 100 percent.

•Evaluation for local spread – Determining the presence of parametrial spread is also critical 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 [17,21,23-25]. This is discussed in more detail below. (See 'Subsequent evaluation for patients in whom chemoradiation is planned' below.)

Newer MRI techniques, such as diffusion-weighted imaging (DWI), texture analysis, and dynamic contrast-enhanced (DCE) MRI, have been shown to improve the diagnostic performance of imaging in selected patients [26-30]. In one prospective study evaluating 65 patients with cervical cancer, the positive predictive value of parametrial invasion was higher for those evaluated with T2-weighted MRI fused with DWI sequences compared with T2-weighted MRI alone (50 versus 23 to 29 percent) [31].

●CT - Preoperative abdominopelvic CT with intravenous contrast may be used to exclude obvious lymph nodes and distant metastases. 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 [32,33].

•If the lymph nodes do not appear enlarged or suspicious, surgery is performed. The type of surgery (eg, simple versus radical hysterectomy) is described separately. (See "Management of early-stage cervical cancer", section on 'Type of surgery'.)

•If the lymph nodes are suspicious for metastases, options for further evaluation and/or management include the following:

-CT- or ultrasound-guided lymph node biopsy or

-Whole-body fluorodeoxyglucose (FDG) PET/CT (see 'Subsequent evaluation for patients in whom chemoradiation is planned' below), or

-Administer chemoradiation; the role of lymph node sampling in such patients is discussed separately. (See "Management of locally advanced cervical cancer".)

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 'Lymphadenectomy procedure' below.)

Imaging for patients undergoing fertility-sparing procedures is described separately. (See "Fertility-sparing surgery for cervical cancer", section on 'Preoperative assessment and counseling'.)

Sentinel lymph node biopsy — For most patients with early-stage cervical cancer, further assessment of the pelvic and para-aortic lymph nodes (with sentinel lymph node biopsy [SLNB] or lymphadenectomy) is also performed. The exception is patients with stage IA disease, in whom the incidence of lymph node spread is very low. Patient selection for lymph node assessment is reviewed separately. (See "Management of early-stage cervical cancer", section on 'Type of surgery'.)

While surgery with lymphadenectomy has historically been used to evaluate for lymph node metastases, SLNB has become the standard of care in most resource-abundant countries [34,35]. Early techniques included the use of blue dye with or without technetium 99, but indocyanine green (with a near-infrared camera) has become the predominant tracer [36].

Four criteria are widely accepted as necessary for determining which patients should undergo SLNB and include [37]:

●Tumors <4 (ideally <2) 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).

SLNB accurately predicts the absence or presence of lymph node metastases, allowing many patients to avoid the morbidity of a pelvic lymphadenectomy procedure. 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 [38]. In one study included in the meta-analysis, SLNB increased the sensitivity of identifying lymph node metastases by approximately 2.5-fold [39]. In another study included in the meta-analysis, two patients had false-negative findings, one of which had a positive lymph node found in a non-mapping hemipelvis; this highlights the importance of complete lymphadenectomy if the mapping procedure fails to detect an SLN in one hemipelvis [35].

SLNB also appears to perform better than imaging studies [40]. In a meta-analysis of 72 studies including 5042 patients with cervical cancer, the sensitivity and specificity for the detection of lymph node metastases 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) [41].

Pathology evaluation with ultrastaging may result in increased identification of metastatic lymph nodes [42]. While an abundance of high-quality data are lacking, micrometastatic disease, compared with node-negative disease, appears to be associated with a higher risk of recurrence; by contrast, isolated tumor cells (ITC) do not appear to increase the risk of recurrence [43]. 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 [44].

Subsequent evaluation for patients in whom chemoradiation is planned — For patients with locally advanced disease (ie, FIGO stages IB3, II, III, and IVA) in whom primary chemoradiation is planned, imaging is routinely performed as part of clinical staging (where available). Imaging may also be performed after chemoradiation to assess treatment response. (See "Management of locally advanced cervical cancer", section on 'Post-treatment imaging and surveillance'.)

●FDG PET/CT – Whole-body fluorodeoxyglucose (FDG) PET/CT, in which both PET and CT are performed in an integrated PET/CT scanner, is the preferred imaging modality in such patients to detect lymph node metastases and provide information to determine radiation fields [45]. If PET/CT detects distant metastases, treatment is usually with chemotherapy (with or without immunotherapy) rather than chemoradiation. (See "Management of recurrent or metastatic cervical cancer" and "Management of recurrent or metastatic cervical cancer", section on 'Initial treatment'.)

If FDG PET/CT is not available, abdominopelvic CT (with contrast to improve diagnostic accuracy) can be used. Pelvic MRI without or with contrast represents another valuable modality and is comparable to CT in diagnostic performance. Lymphangiography is rarely used as it has been largely replaced by these noninvasive imaging modalities [41,46,47].

The superiority of FDG PET/CT to other imaging modalities was illustrated in a meta-analysis of 11 cohort studies that showed PET/CT, compared with MRI, had a higher sensitivity and specificity for the detection of lymph node metastases (PET/CT: 65 and 93 percent; MRI: 58 and 91 percent, respectively) [48]. The added value of PET/CT compared with CT alone is in the improved sensitivity for abdominal lymph node metastases, a feature that helps determine radiotherapy fields and estimates patient prognosis [47]. In a subsequent retrospective study evaluating the detection of lymph nodes in patients with early-stage cervical cancer, PET/CT, compared with MRI and CT, was also superior in detecting nodal metastases [49].

Nevertheless, FDG PET/CT can result in false negative diagnoses [50,51], which tends to occur due to poor metabolic activity or small-volume metastatic deposits in the node. In a prospective study of 60 patients with advanced-stage cervical cancer, among the 26 patients with no findings of positive pelvic or para-aortic nodes on PET/CT, three (12 percent) had pathologically positive para-aortic nodes [50]. The rate was even higher (22 percent) among the subset of patients with PET/CT findings of positive pelvic but negative paraaortic nodes. 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) [52].

●MRI – Some radiation oncologists add pelvic MRI with and without contrast for treatment planning, particularly if there is a concern for rectal or bladder involvement. PET or PET/CT are not used to evaluate tumor spread for such patients as accumulation of the tracer in the bladder obscures visualization of the uterine cervix, nor does it appear to add utility to MRI in the evaluation of local staging [53].

However, in patients with locally advanced cervical cancer, 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. In a prospective multicenter study of 172 patients with cervical cancer (the majority with tumors >7 mm in width and >5 mm in depth but without parametrial involvement) undergoing CT and MRI prior to surgery, detection of parametrial involvement (or more advanced disease) 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) [17]. By contrast, in a retrospective single-center 255 with cervical cancer undergoing surgical treatment, clinical staging was superior to CT and MRI for the detection of parametrial involvement: clinical staging (sensitivity: 66 percent and specificity: 81 percent), CT (43 and 71 percent), and MRI (52 and 63 percent) [25].

●PET-MRI – PET-MRI, in which PET and MRI are performed in an integrated PET-MRI scanner, has higher contrast resolution compared with CT and appears to have higher diagnostic accuracy than CT or MRI alone for pretreatment staging of cervical cancer [54]. However, data on this modality are limited, and future studies on this technique for such patients are necessary.

●Lymph node sampling – Lymph node sampling may also be performed in some patients treated with primary chemoradiation. (See 'Lymphadenectomy procedure' below.)

Alternative imaging in selected patients — Other imaging modalities (eg, ultrasound, cystoscopy, intravenous pyelogram [IVP]) may be used in selected patients (eg, those with suspected tumor extension to the bladder and ureter) or in settings in which MRI, CT, PET/CT are not available. The choice of modality varies based on patient symptoms, availability of the resource, and radiology expertise.

For example, cystoscopy may be performed in patients with urinary symptoms (eg, hematuria) or in cases of a barrel-shaped endocervical growth or where the growth has extended to the anterior vaginal wall. Similarly, ultrasound may be used to assess tumor size, local extent of disease, and identify urinary tract obstruction in patients with kidney failure. Ultrasound appears to perform similarly to MRI for the detection of parametrial invasion. In a meta-analysis of 115 studies, including almost 14,000 patients with newly diagnosed cervical cancer, pooled estimates for sensitivity and specificity of pelvic MRI and ultrasound were comparable and better than CT [55].

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

LYMPHADENECTOMY PROCEDURE

●Patient selection – Lymphadenectomy is performed in cases of failed sentinel lymph node (SLN) mapping or in those with suspicious or grossly enlarged lymph nodes (regardless of SLN mapping) [37]. Debulking enlarged lymph nodes may have a therapeutic benefit and provide information for treatment planning (to individualize the radiotherapy field) [56]. (See "Management of early-stage cervical cancer", section on 'Indications' and "Management of locally advanced cervical cancer", section on 'Pretreatment evaluation'.)

Para-aortic lymphadenectomy can be 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 is positive, and metastases are confirmed.

This is also discussed in more detail elsewhere. (See "Radical hysterectomy", section on 'Examination of lymph nodes'.)

●Procedure – According to the Gynecologic Oncology Group Surgical Procedures Manual, pelvic lymph node dissection (LND) includes the 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) [57]. Removal of the circumflex iliac nodes is not performed as isolated involvement of the circumflex iliac nodes is infrequent [58], and some data suggest that removal of the circumflex iliac nodes to the distal external iliac nodes increases the risk of lymphedema [59].

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 [60]. Some experts extend the paraaortic LND superiorly to the level of the renal veins [61].

The operative technique of pelvic and para-aortic lymphadenectomy is described separately. (See "Radical hysterectomy", section on 'Examination of lymph nodes'.)

●Mode of surgery – The evaluation procedure can be performed via laparotomy or minimally invasive surgery (MIS; laparoscopic or robotic) through a transperitoneal or extraperitoneal approach [62-65]. Extraperitoneal and MIS approaches to staging are associated with reduced morbidity.

The best available data regarding this issue are from a classic Gynecologic Oncology Group retrospective study in which 284 patients with cervical carcinoma (most with parametrial spread) planned for pelvic irradiation with or without para-aortic irradiation underwent pretreatment selective para-aortic lymphadenectomy using either an extraperitoneal or transperitoneal approach [66]. 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 injuries, including large and small bowel necrosis, enteritis, cecal and sigmoid colonic perforation, and persistent nausea, vomiting, and diarrhea (4 versus 12 percent).

●Complications – Potential surgical complications of pelvic and para-aortic lymphadenectomy include vascular injury, ureteral injury, infection, fistula formation, lymphocyst/lymphedema, bowel injury/obstruction, and thrombophlebitis. This is discussed in detail separately. (See "Pelvic and paraaortic lymphadenectomy in gynecologic cancers", section on 'Lymphadenectomy procedure'.)

LIMITED ROLE OF LABORATORY EVALUATION — 

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

Routine laboratories — Patients with cervical cancer should have a complete blood count and renal function tests; liver function tests are also obtained if advanced disease is suspected. Urinalysis is obtained to evaluate for potential metastatic disease. Other preoperative or pretreatment testing is discussed separately. (See "Preoperative testing for noncardiac surgery".)

Tumor markers — The use of tumor markers for monitoring therapy or detecting recurrence in cervical cancer is investigational and not considered standard of care.

A number of serum markers have been investigated for their utility in assessing prognosis, monitoring response to therapy, and detecting recurrence; none have achieved widespread acceptance. The most commonly used serum markers are [67-82]:

●Squamous cell carcinoma (SCC) antigen – 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 ["Sedlis criteria"] [83]) in patients who undergo surgery for stage IB/IIA disease.

In a cohort study of 337 patients with surgically treated cervical cancer, elevated (>1.9 ng/mL) compared with normal preoperative SCC antigen levels was associated with a higher likelihood of needing postoperative radiation therapy both for tumors <4 cm (57 versus 16 percent) and tumors >4 cm or with vaginal spread (74 versus 29 percent) [84]. The potential clinical utility of this finding is in the ability to identify preoperatively most patients who would likely require trimodality treatment (ie, surgery and chemoradiotherapy) so that they could be considered for primary chemoradiotherapy rather than include surgery. The drawback is that almost half (43 percent) of patients 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'.)

By contrast, in other mostly small reports using varying cut-off levels, serum SCC antigen level did not accurately predict lymph node or parametrial involvement, and there are conflicting reports as to its independent prognostic significance [69,71,72,78].

●Tissue polypeptide antigen

●Carcinoembryonic antigen (CEA)

●Cancer antigen 125 (CA 125)

●Cytokeratin 19 fragment (CYFRA 21-1)

Many of these markers are elevated in a significant proportion of patients with more advanced-stage disease and correlate with disease activity. However, it is important to note that tumor markers generally have low sensitivity and specificity, are not consistently produced by different histology subtypes (eg, CA 125 levels may be a better tumor marker for those with adenocarcinoma compared with SCC [75,76]), and may also be associated with benign conditions (eg, CA-125 is associated with fibroids, endometriosis, and functional ovarian cysts) which are common in reproductive-age patients.

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

SPECIAL CONSIDERATIONS FOR INVASIVE CERVICAL ADENOCARCINOMA — 

Depth of invasion is a criterion for staging stage IA and IB cervical cancers, but accurately measuring the depth of invasion in adenocarcinomas is more challenging than with squamous cell carcinomas in such patients.

The Silva pattern-based classification system (A, B, C) (table 4) helps to further categorize stage IA and IB HPV-dependent cervical adenocarcinomas and predict the risk of lymph node metastases, ovarian metastases, and recurrence [37,85-87]. In a review of 1319 patients with invasive endocervical adenocarcinoma, patterns A, B, and C occurred in 20, 20, and 60 percent of patients, respectively [85]. Of those with pattern A tumors, none had lymph node metastases, almost all (99 percent) had stage I disease, and no patients experienced disease recurrence. For those with pattern B and C tumors, lymph node metastases occurred in 5 and 22 percent of patients, respectively. Most patients with patterns B and C also had stage I disease (97 and 83 percent, respectively), but disease recurrence occurred in 3 and 19 percent of patients, respectively.

As such, some experts avoid lymph node assessment and radical surgery in patients with Silva pattern A, stage IA (and IB) HPV-associated adenocarcinomas where the entire lesion has been removed with an excisional procedure (ie, cold knife conization, loop electrosurgical excision procedure [LEEP]) and in whom margins are negative. While no ovarian metastases have been reported in such patients, there have been reports of ovarian metastases with adenocarcinoma in situ, therefore some caution must be utilized with respect to ovarian spread.

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

●Staging systems – The 2018 International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging system and the American Joint Committee on Cancer tumor, node, metastasis (TNM) staging system are shown in the tables (table 2 and table 3). (See 'Staging systems' above.)

●Clinical staging – Cervical cancer is diagnosed based on histologic evaluation of a cervical biopsy and staged clinically with physical examination and a limited number of radiographic tests (chest radiograph, intravenous pyelogram [IVP]), basic diagnostic procedures (proctoscopy, cystoscopy, hysteroscopy), advanced radiologic imaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]), or other pathologic findings (eg, lymph node biopsy). The radiologic and pathologic assessments may be used to assign stage, but none are required; the combination of modalities utilized is left to the clinician's discretion and available resources. (See 'Clinical staging' above.)

●Staging procedure

•All patients – Physical examination, including speculum, bimanual, and rectovaginal examinations are performed to assess tumor size and parametrial involvement. Cervical biopsy may have been performed as part of the initial evaluation or along with the staging procedure, depending on the level of suspicion of malignancy. (See 'All patients: Physical examination and biopsy' above and "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Cervical biopsy and colposcopy'.)

•Patients in whom surgery is planned

-For patients with early-stage disease (ie, FIGO stages IA, IB1, and IB2) in whom surgery is planned, evaluation of tumor size and vaginal parametrial involvement may be based on physical examination and biopsy alone; imaging does not need to be performed in all such patients as part of clinical staging. (See 'Imaging' above.)

-For patients in whom there is uncertainty about tumor size and/or local spread following the clinical examination (eg, those with prior pelvic surgery or radiation, vaginal bleeding), imaging (with pelvic MRI, abdominopelvic CT) is performed. (See 'Imaging' above.)

-For most patients with early-stage disease, further assessment of the pelvic and para-aortic lymph nodes (with sentinel lymph node biopsy [SLNB] or lymphadenectomy) is also performed. SLNB has become the standard of care in most resource-abundant countries. (See 'Sentinel lymph node biopsy' above.)

•Patients in whom chemoradiation is planned – For patients with locally advanced disease (ie, FIGO stages IB3, II, III, and IVA) in whom primary chemoradiation is planned, imaging (with whole-body fluorodeoxyglucose (FDG) PET/CT) is routinely performed as part of clinical staging (where available). Some radiation oncologists add pelvic MRI with and without contrast for treatment planning, particularly if there is a concern for rectal or bladder involvement. (See 'Subsequent evaluation for patients in whom chemoradiation is planned' above.)

•Alternative imaging – Other imaging modalities (eg, ultrasound, cystoscopy, intravenous pyelogram [IVP]) may be used in selected patients (eg, those with suspected tumor extension to the bladder and ureter) or in settings in which MRI, CT, PET/CT are not available.

●Lymphadenectomy

•Lymphadenectomy is performed in cases of failed sentinel lymph node (SLN) mapping or in those with suspicious or grossly enlarged lymph nodes (regardless of SLN mapping). Debulking enlarged lymph nodes may have a therapeutic benefit and provide information for treatment planning (to individualize the radiotherapy field). (See 'Lymphadenectomy procedure' above.)

•Para-aortic lymphadenectomy is performed at the surgeon's discretion or in those patients with pretreatment imaging demonstrating para-aortic 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 'Lymphadenectomy procedure' above.)

●Role of Silva classification – The Silva pattern-based classification system (A, B, C) (table 4) helps to further categorize stage IA and IB HPV-dependent cervical adenocarcinomas and predict the risk of lymph node metastases, ovarian metastases, and recurrence in such patients. (See 'Special considerations for invasive cervical adenocarcinoma' above.)

ACKNOWLEDGMENT — We are saddened by the death of Michael Frumovitz, MD, MPH, who passed away in July 2024. UpToDate acknowledges Dr. Frumovitz's past work as an author for this topic.