World Health Organization (WHO) fifth edition, 2020; classification of tumors of female reproductive organs classifies cervical tumors

Abbreviations: HPV, human papilloma virus; NOS, not otherwise specified.

Clinical Presentation and Workup

The median age at presentation of invasive cervical cancer is in the fifth decade. Early-stage disease is often asymptomatic and detected on screening. Abnormal vaginal bleeding in the form of postcoital, intermenstrual, or postmenopausal bleeding is the most common symptom. Foul smelling, blood-stained vaginal discharge is another common symptom. Constitutional symptoms, back pain, bladder or bowel habit alterations may occur in advanced stages. Rarely lower limb swelling due to deep vein thrombosis may be the presenting symptom. A detailed physical examination should include palpation of the supraclavicular and groin nodes, and liver to exclude metastatic disease. A pelvic examination including speculum, vaginal, and rectal examination is mandatory for the assessment of the cervical lesion as well as local spread to vagina, parametria, rectovaginal septum, and rectum. A punch biopsy should be performed from the visible cervical growth. Colposcopic examination and guided biopsy are required in a patient with grossly normal looking cervix but with an abnormal screening test. After confirmation of diagnosis, a comprehensive pretreatment workup should be done including hematocrit, liver and renal function tests, a chest radiograph, and an abdominopelvic imaging. An examination under anesthesia, cystoscopy, and proctoscopy are recommended only if clinically indicated.

Early detection of cervical cancer and precancer is possible by screening. Various methods available for screening include cytology, visual inspection with acetic acid and HPV DNA testing.

AJCC TNM staging system

Abbreviations: AJCC, American Joint Committee on Cancer; FIGO, International Federation of Gynecology and Obstetrics.

Principles of imaging for initial workup, the NCCN guidelines

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET/CT, positron emission tomography/computed tomography; TH, total hysterectomy.

The NCCN guidelines for imaging on surveillance

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET/CT, positron emission tomography/computed tomography.

Imaging for Diagnosis

A. US: It is often the primary investigation performed for the presenting clinical symptoms, and it may be performed per-abdomen or per-vaginum, or both; the latter depicting a superior resolution. Cervical cancer appears as a hypoechoic lesion, with its epicenter in the cervical lips. Locoregional involvement of the uterine body and parametrium can also be seen. Large, lobulated, irregular pelvic nodes and attenuated hilum are suggestive of metastatic adenopathy. Involvement of extrapelvic organs may also be seen. A larger limitation of US is its subjectivity in assessment, often resting the diagnostic acumen to the hands of the skill of the operating radiologist. The following points should be noted:

• Epicenter and size of the lesion in three dimensions.

• Extent of vaginal involvement

• Involvement of parametrium, rectum or urinary bladder.

• Pelvic lymph nodes.

• Retroperitoneal lymph nodes.

• Renal morphology, and comment on hydroureteronephrosis.

• Any other incidental finding

B. MRI: Carcinoma of the cervix is usually seen as a soft tissue appearing iso to hypointense on T2-weighted (T2W; compared with the normal darker signal intensity), isointense on T1W imaging, higher signal intensity on fat saturated sequences, and restricted diffusion. An important feature often is the differential enhancement between the uninvolved cervix and myometrium compared with cervical lesion, as seen on dynamic subtracted fat-saturated T1 post contrast images. Cervical cancers are usually hypoperfused compared with their endometrial counterparts. Neuroendocrine tumors, however, may show avid enhancement. Parametrial invasion is seen as a loss of distinction of the hypointense T2W signal of the cervical and vaginal outer surface junction with the bright fat containing parametrium, with spiculations, lobulations, or frank invasion ([Fig. 1]).

Imaging for Staging

It can be divided into imaging for locoregional disease and systemic spread.

• A. Evaluation of locoregional disease: Investigation of choice for local staging of cervical cancer is pelvic MRI. Contrast administration is optional, and when administered, a dynamic postcontrast MRI helps in better parametrial assessment, differentiating from the vascular plexus. The cervix is better evaluated when the vaginal cavity is distended by US or lignocaine jelly, opening up and outlining the patent fornices, and superior estimation of parametrial invasion. The following points should be considered while reporting MRI for cancer cervix, which help in determining stage of the lesion and management.

  1. Dimensions of the lesion in orthogonal axes.

  2. The site of the lesion and its extent within the confines of the cervix. Its epicenter, involvement of the fornices, the involvement of the lower uterine segment and vagina.

  3. The extension of the lesion outside the confines of the uterus, for example, the parametrium on either side, involvement of the bladder, and rectum as well as the involvement of pelvic side walls.

  4. Any secondary obstructive collection within the uterus due to stenosed endocervical canal.

  5. Pelvic nodal disease on both sides along with sub sites. Internal, external iliac, obturator and common iliac nodes in their short axis dimension should be measured and mentioned separately. Screening abdomen is suggested, with careful analysis for the presence of supra- and infra renal-hilar retroperitoneal nodes.

  6. Assessment of inguinal nodes.

• B. Evaluation of systemic spread: Investigation of choice for systemic staging is CT with contrast (only portal venous phase may suffice). Both the abdomen (upper abdomen) and thorax should be covered. PET-CT has been used for both locoregional and systemic staging in clinically advanced stages. Depending on the available resources, technetium 99 m methylene diphosphonate bone scan may be used for detecting predominantly sclerotic skeletal metastases. Chest radiographs have been used for detecting or following up on lung metastasis as well as pleural effusion, and US may be used to rule out organ metastases or adenopathy.

The following points should be considered for systemic staging.

• Retroperitoneal nodes, mention above or below the level of renal vein. Involvement of the major vessels by the nodes should be recorded.

• Liver or other organ metastasis.

• Peritoneal involvement.

• Mediastinal adenopathy.

• Supraclavicular nodes.

• Kidneys and ureters for any dilatation.

• Any pelvic arterial or venous and/or pulmonary embolus

• Apart from the above, an attempt for locoregional assessment in terms of size, parametrial invasion, and bowel/bladder wall involvement should be made.

Fluorodeoxyglucose (FDG) PET-CT: It has been a useful tool in pre-treatment evaluation to rule out distant nodal involvement or other metastatic disease. It is essential to rule out metastases, in early-stage cancer for definitive curative therapy, and hence PET-CT is recommended by the NCCN guidelines for workup of cervical cancers clinically considered as stage IB. Metastatic workup of clinical stage IIB and III who are planned for multimodality treatment include a FDG PET-CT if available. The ability to reliably identify and characterize retroperitoneal nodal metastases may help in altering the radiotherapy (RT) field. Another nuclear medicine procedure proven to be helpful prior to surgical excision is the sentinel node scintigraphy. A radionuclide colloid, commonly Technetium (TcO4) nano colloidal filtered sulfur colloid, is injected in the peritumoral region and scan obtained. Identification of the echelon node and frozen section examination of the sentinel node helps in intraoperative decision making. Radical surgery is abandoned in favor of definitive chemoradiation if sentinel lymph node shows metastatic disease. A check-list for PET-CT should include the following:

• Standardized uptake value of all the metabolically active lesions.

• Bone lesions.

Imaging for Planning Therapy

Based on the locoregional extent of disease and clinical status of patient, radical surgery or definitive radiation therapy (RT) with or without concurrent chemotherapy is planned. For RT planning contouring, contrast-enhanced CT (CECT) is the primary modality of imaging. MRI and CT fusion as well as PET-CT have been used as well. An advantage of MR over CT is its better soft tissue resolution that helps in planning graded radiation doses. Hypoxic imaging also serves as a surrogate for prediction of response to RT. Traditionally, brachytherapy prescription from last many decades has been performed using anatomical surrogates that represent boundaries of medial parametrium (referred as point A, representing the crossing of ureter and uterine artery). In the last two decades, MR has also been integrated for brachytherapy treatment planning in cervix cancer.

Imaging in Prediction of Pretreatment and Post-Treatment Response

MRI is a reliable modality for the assessment of post-therapy (especially post radiation) response, with remarkable reduction in size of the lesion, cicatrizing appearance of the cervical lips; accompanied with the tumor-related isointense T2W signal intensity changing to T2 dark signal intensity as the neoplasm undergoes fibrosis and the restricted diffusion moving towards near normal facilitation. Smaller areas of residual disease may be detected by remnant areas of signal intensity lacking these features and mimicking the index lesion. MRI has also been integrated in response and outcome prediction. Tumor necrosis identified on T2W MRI is known to clearly impact outcomes after chemoradiation.[9] MR-based radiomics also allow discrimination of responders versus non responders prior to onset of chemoradiation therapy.[10] Dynamic contrast-enhanced MRI identifies hypoxic fraction and allows identification of patients who are expected to have unfavorable outcome.[11] Blood oxygen level-dependent hypoxia imaging characterizes tumor biology at the cellular level.[12]

For response assessment in metastatic lymph nodes and other distant sites, either CECT or PET-CT or PET-CECT is useful. It is also imperative to note that in cervical cancer chemoradiotherapy studies, traditional radiological response evaluation has been sparingly utilized. Multiple ongoing studies especially that combine RT and drugs (targeted agents or immunotherapy) now utilize RECIST 1.1 for determining progression-free survival.[13] [14] As chemoradiotherapy studies have traditionally not utilized RECIST 1.1, studies are underway within multi-institutional collaboration to understand the impact of such a transition on assessment of various disease outcome endpoints.

The NCCN guidelines recommend the use of CECT/PET-CT/MRI modality for response assessment and surveillance, varying over 6 months to 2 to 3 yearly, depending on the stage of presentation and the therapy received ([Table 4] [Table 5] and [Table 6]).

Synoptic reporting formats have been attached for reference of the salient features essential for appropriate imaging ([Table 7] and [Table 8]).

Principles of Management

Management guidelines are broadly dependent on the stage of disease, and its presence as an in-situ versus invasive component. The choice of treatment depends upon stage of the disease, patient's performance status, and preference. In patients up to FIGO stage IB2 disease (with disease confined to cervix) radical surgery is the preferred modality of treatment, although definitive RT gives equivalent survival in these patients. In stage IA disease (with microscopic invasive carcinoma with less than 5 mm depth of invasion), cervical conization or extrafascial hysterectomy with or without pelvic lymphadenectomy is recommended. For stages IB1 and IB2, more radical surgery in the form of radical hysterectomy with bilateral pelvic lymphadenectomy is considered.[15] Adjuvant RT is indicated in patients with any two intermediate risk factors including deep cervical stromal invasion, lymphovascular stromal invasion, and tumor size more than 4 cm.[16] Adjuvant chemoradiotherapy with concurrent cisplatin is recommended in patients with any high-risk features including positive surgical margins, positive lymph nodes, or parametrial involvement.[17]

Neoadjuvant chemotherapy followed by surgery is not superior to concomitant chemoradiotherapy (CTRT) in stages IB2, IIA, and IIB.[18] CTRT is the standard of care for bulky IB-IVA. Individual patient data meta-analysis from 13 trials confirmed benefit of CTRT in comparison to RT alone. Hazard ratio for overall survival (OS) and disease-free survival (DFS) was 0.81 and 0.78, respectively, which translates into absolute survival benefit of 10%-in FIGO stage I/II and 3%-in stage III/IVA.[19] A phase III randomized study comparing concurrent chemoradiation versus radiation alone, in patients with stage III B disease showed improvement in both DFS (44% to 52%) and OS (46–54%) in favor of concurrent chemoradiation.[18] Thus, CTRT remains the standard of care even in stage III disease. The most commonly used chemotherapy regimen is weekly cisplatin[19] 40 mg/m2.

Integration of MRI in last two decades facilitated development of brachytherapy “adaptive target concept” that was based on response of tumor to external radiation.[20] Integration of target concept, simultaneous development of MRI compatible brachytherapy applicators for intracavitary–interstitial implants, and accurate tumor identification at brachytherapy has led to upward of 90%-local control in patients with even very advanced cervical cancer. The results of multicentric international study of MR based brachytherapy (EMBRACE) have been recently reported and represent benchmark for cervical cancer brachytherapy.[21] Further adaptations of brachytherapy dose were performed in EMBRACE II.[21] Taken together these studies have recruited more than 2,800 patients worldwide. Though these were single arm large registration studies, a recent meta-analysis of more than 5,000 patients reported close to 11%-improvement in 3-year DFS with integration of MR-based brachytherapy.[22] This highlights the role of RT as curative therapy for early cervical cancer with marked improvement in DFS in advanced disease.

For patients with metastatic or recurrent disease who are not candidates for surgical resection or RT, platinum and paclitaxel with or without bevacizumab are the preferred treatment. Cisplatin-based doublets demonstrate superiority over cisplatin monotherapy in terms of response rates and PFS, whereas addition of bevacizumab to doublet shows prolongation of OS (GOG240).[23] [24] Japan Clinical Oncology Group(JCOG) demonstrated noninferiority with substitution of carboplatin AUC5 for cisplatin in JCOG0505(27).[9] Addition of pembrolizumab with first-line chemotherapy with or without bevacizumab improves both PFS and OS with similar benefit between overall population and in those with programmed death ligand 1 (PD-L1) combined positive score more than 1 or more than 10.[25]

There is little evidence to suggest that treatment in second line or later line setting improves OS compared with palliation alone. Single-agent carboplatin, paclitaxel, and topotecan are the most active agents in second-line setting. In PD-L1-positive cancers, single-agent pembrolizumab has shown favorable response rates in second-line setting.

An integrated multidisciplinary oncology team working towards increasing awareness and screening, improving accuracy of imaging and multimodal therapy for management of cervical cancers, bears a positive impact towards improvement in survival and quality of life.

Summary of Recommendations

• ⋄ Imaging plays a vital role in assessing the extent of disease and staging of cervical cancer.

• ⋄ In clinically early-stage disease, MRI, on the basis of estimation of tumor size, cervical stromal invasion, parametrial invasion, and nodal involvement can help triage patients for surgery versus RT.

• ⋄ While hypoxic imaging can predict response, MR is fairly reliable in post-RT locoregional response assessment and detect early recurrence

• ⋄ CECT or PET CECT-based RECIST 1.1 may be followed for distant metastatic response assessment.

• ⋄ Stage and therapy-based surveillance imaging should be recommended.

The NCCN guidelines on imaging for recurrence

Abbreviations: MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET/CT, positron emission tomography/computed tomography.

The NCCN guidelines on imaging in small cell neuroendocrine carcinoma of the cervix

Abbreviations: MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET/CT, positron emission tomography/computed tomography.

Synoptic reporting CT for cervical cancer

Abbreviations: eGFR, estimated glomerular filtration rate; IV, intravenous; CT, computed tomography.

Synoptic reporting MRI for cervical cancer

Abbreviations: eGFR, estimated glomerular filtration rate; FOV, field of view; MRI, magnetic resonance imaging; T1W, T1-weighted.

Conflict of Interest

None.