Imaging Recommendations for Diagnosis, Staging, and Management of Cervical Cancer

Abstract Cervical cancer is the fourth most common cancer in women globally and the second most common cancer in Indian women, more common in lower socioeconomic strata. Improvement in survival and decrease in morbidity reflect the earlier detection with screening and imaging, as well as multifactorial multimodality therapy integrating surgery, and concurrent chemoradiation therapy providing superior therapeutic benefits. Imaging plays a vital role in assessing the extent of disease and staging of cervical cancer. The appropriateness criteria of a modality are different from its availability based on infrastructure, medical facilities, and resource status. Although in an ideal situation, magnetic resonance imaging (MRI) would be of greatest value in locoregional assessment of extent of disease and fluorodeoxyglucose positron emission tomography-computed tomography for distant staging; often, an ultrasonography, chest radiograph, and bone scans are utilized, with contrast-enhanced computed tomography representing a fair superior diagnostic accuracy, and can be reported as per the RECIST 1.1 criteria. MRI is also of good utility in the assessment of residual disease, predicting response and detecting small volume recurrence. MRI offers the highest diagnostic accuracy in determining parametrial invasion and hence surgical planning; so also, MRI-guided radiation planning helps in more accurate graded radiation dose planning in radiation therapy. Stage and therapy-based surveillance imaging should be encouraged and recommended.


Introduction
Cervical cancer is the fourth most common cancer in women globally and the second most common cancer in women in India.Annual global and Indian estimates of new cases for the year 2020 were 6,04,127 and 1,23, 907, respectively. 1It is more common in women belonging to lower socioeconomic strata and more than 85% of all cases occur in developing countries.Even in these countries, the incidence is declining that could be attributed to better lifestyle, genital hygiene, and safe sexual practices.Down-staging among the diagnosed cases and earlier stages at presentation alongwith improved treatment protocol with chemoradiation therapy have led to improved survival.Pretreatment imaging plays a critical role in staging the disease as well as planning the appropriate treatment for the patient.

Etiology and Risk Factors
Infection with high-risk human papilloma virus (HPV) is a necessary but not sufficient cause for cervical cancer, with genotypes 16 and 18 being responsible for nearly 70% of cases. 2 HPV is a common sexually transmitted infection.In more than 90% of women, infection is transient and self-limiting; while in less than 10% virus may persist.Incorporation of viral genome into the host nucleus is the key step in HPV carcinogenesis.Factors that increase acquisition and persistence of HPV are also risk factors for cervical cancer and these include infections with other sexually transmitted diseases (human immunodeficiency virus and Chlamydia trachomatis), tobacco use, early onset of sexual activity, multiple sexual partners, multiparity, poor nutrition, personal hygiene, and long-term use of hormonal contraceptives.A minor fraction of cases of cervical cancer is HPV independent.

Classification
►Table 1 shows the World Health Organization fifth edition 2020; classification of cervical tumors.Squamous cell carcinoma is the most common histologic type followed by adenocarcinoma.

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.

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

Imaging in Cervical Cancer
Imaging in cervical cancer is crucial for staging, to determine the extent of disease, in treatment planning and for response assessment.
Imaging findings are used as an adjunct to clinical staging.

Imaging Guidelines
The FIGO (International Federation of Gynecology and Obstetrics) staging system guides management protocol for cervical cancer patients and traditionally, this system was based on clinical evaluation with only limited imaging investigations.However, the most recent update on FIGO cervical cancer staging has allowed imaging findings in stage allocation.Equivalence of the TNM (Tumor Node Metastases) staging system maintained by the AJCC (American Joint Committee on Cancer) and the FIGO classification lay down common imaging and management recommendations.Version 9 update of the 8th edition AJCC TNM staging (►Table 2) highlights the changes of incorporation of imaging and surgical findings, elimination of lateral spread from T1a, addition of a subcategory toT1b (T1b3), and histopathology updated to reflect HPVassociated and independent carcinomas. 3With advancements in technology of computed tomographic (CT) scan and magnetic resonance imaging (MRI), there has been enough evidence to support good accuracy and diagnostic performance of these imaging modalities in determining the extent of disease and staging.In an ideal setting, MRI serves as the modality of choice for local extent of the disease, particularly for endocervical growths that cannot be evaluated on per-speculum or per-vaginal examination.The addition of diffusion weighted imaging has further enhanced the efficacy of MRI for locoregional extension, nodal involvement, and posttherapy tumor recurrence.However, since cervical cancer is more prevalent in women from low socioeconomic strata, MRI may not be accessible and/or affordable to them.Hence, role of ultrasound (US) and CT becomes more crucial in the management algorithm.putting forth MR as a mandatory early investigation modality, with an optional transvaginal/transrectal US -if a skilled radiologist is available.The integration of various modalities of imaging, pathology, and clinical examination has been highlighted in the European guidelines that can be used for staging and treatment planning for the patients. 5Considering heterogeneity of resources in our country, the National Cancer Grid of India has categorized imaging guidelines as optimal and minimal based upon availability of imaging modality. 8MRI has been considered as the optimal imaging modality for disease assessment in early as well as advanced stages, whereas PET-CT is considered optional.On the other hand, in resource constraint setting, a radiograph of the chest and US abdomen should at least be performed for the patients and any indeterminate/suspicious node may be evaluated with fine-needle aspiration cytology sampling.

Imaging for Diagnosis
A. US: It is often the primary investigation performed for the presenting clinical symptoms, and it may be performed perabdomen 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: a. Epicenter and size of the lesion in three dimensions.b.Extent of vaginal involvement c.Involvement of parametrium, rectum or urinary bladder.d.Pelvic lymph nodes.e. Retroperitoneal lymph nodes.f.Renal morphology, and comment on hydroureteronephrosis.g.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.
a. Retroperitoneal nodes, mention above or below the level of renal vein.Involvement of the major vessels by the nodes should be recorded.b.Liver or other organ metastasis.c.Peritoneal involvement.d.Mediastinal adenopathy.e. Supraclavicular nodes.f.Kidneys and ureters for any dilatation.g.Any pelvic arterial or venous and/or pulmonary embolus h.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: a. Standardized uptake value of all the metabolically active lesions.b.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. 9MR-based radiomics also allow discrimination of responders versus non responders prior to onset of chemoradiation therapy. 10Dynamic contrast-enhanced MRI identifies hypoxic fraction and allows identification of patients who are expected to have unfavorable outcome. 11Blood oxygen level-dependent hypoxia imaging characterizes tumor biology at the cellular level. 12or 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. 13,14As 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. 15Adjuvant 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. 16Adjuvant chemoradiotherapy with concurrent cisplatin is recommended in patients with any highrisk features including positive surgical margins, positive lymph nodes, or parametrial involvement. 17eoadjuvant chemotherapy followed by surgery is not superior to concomitant chemoradiotherapy (CTRT) in stages IB2, IIA, and IIB. 18CTRT 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. 19A phase III randomized study comparing concurrent chemoradiation versus radiation alone, in patients with

Fig. 1
Fig. 1 A young 34-year-old lady with a history of postcoital pervaginal bleeding.Magnetic resonance imaging shows early-stage cervical lesion, pathologically proven as squamous cell carcinoma.(A) Small field of view sagittal T2-weighted image shows a polypoid exophytic lesion (marked by arrowhead) arising from the posterior lip of the cervix.Arrow shows superior delineation of the posterior vaginal forniceal space, due to intravaginal instillation of lignocaine, distending the vaginal space.In this case, the posterior fornix and vaginal wall are clearly seen as uninvolved by the disease.(B) Postcontrast imaging shows differential poor enhancement of the lesion (marked by Ã ).(C) Small field of view axial T2-weighted image shows lignocaine jelly surrounding the cervical lips and vaginal wall, also helping in ruling out lateral parametrial invasion.(D) Diffusion weighted imaging shows restricted diffusion seen as a high signal intensity (marked by Ã ).

Table 1
World Health Organization (WHO) fifth edition, 2020; classification of tumors of female reproductive organs classifies cervical tumors

Table 2
AJCC TNM staging system T3III Carcinoma involves the lower one-third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney; note: the pelvic wall is defined as the muscle, fascia, neurovascular structures, and skeletal portions of the bony pelvis; cases with no cancer-free space between the tumor and pelvic wall by rectal examination are FIGO stage III T3a IIIA Carcinoma involves the lower one-third of the vagina, with no extension to the pelvic wall T3b IIIB Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause) T4 IVA Carcinoma has involved (biopsy-proven) the mucosa of the bladder or rectum or has spread to adjacent organs (bullous edema, as such, does not permit a case to be assigned to stage IVA) cM1 IVB Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone; excludes metastasis to pelvic or para-aortic lymph nodes or vagina) pM1 IVB Microscopic confirmation of distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone; excludes metastasis to pelvic or para-aortic lymph nodes or vagina) Abbreviations: AJCC, American Joint Committee on Cancer; FIGO, International Federation of Gynecology and Obstetrics.

Table 3
Principles of imaging for initial workup, the NCCN guidelines Consider pelvic MRI with contrast to assess local disease extent (preferred for FIGO stage IB1-IB3) } Neck/chest/abdomen/pelvis/groin PET/CT (preferred) or chest/abdomen/pelvis CT or PET/MRI for FIGO stage IB1-IB3 } For patients who underwent TH with incidental finding of cervical cancer, consider neck/chest/abdomen/pelvis/groin PET/ CT or chest/abdomen/pelvis CT to evaluate for metastatic disease and pelvic MRI to assess pelvic residual disease Neck/chest/abdomen/pelvis/groin PET/CT (preferred) or chest/abdomen/pelvis CT to evaluate for metastatic disease Other initial imaging should be based on symptomatology and clinical concern for metastatic disease For patients who underwent TH with incidental finding of cervical cancer, consider neck/chest/abdomen/pelvis/groin PET/CT or chest/ abdomen/pelvis CT to evaluate for metastatic disease and pelvic MRI with contrast to assess pelvic residual disease a. MRI and CT are performed with contrast throughout the guidelines unless contraindicated.Contrast is not required for screening chest CT b These factors may include abnormal physical exam findings or pelvic, abdominal, or pulmonary symptoms c These factors may include abnormal physical exam findings, bulky pelvic tumor (>4 cm), delay in presentation or treatment, and pelvic abdominal or pulmonary symptoms 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.

Table 4
The NCCN guidelines for imaging on surveillance Imaging should be based on symptomatology and clinical concern for recurrent/metastatic disease b b.For patients with FIGO stage IB3 or patients who required postoperative adjuvant radiation or chemoradiation due to high-risk Imaging as appropriate (CT, MRI, or PET/CT) to assess response or determine further therapy a. MRI and CT are performed with contrast throughout the guidelines unless contraindicated.Contrast is not required for screening chest CT b.These factors may include abnormal physical exam findings or pelvic, abdominal, or pulmonary symptoms c.Risk factors may include positive nodes, positive parametria, positive margins, or local cervical factors d.These factors may include abnormal physical exam findings such as palpable mass or adenopathy, or new pelvic, abdominal, or pulmonary symptoms Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET/CT, positron emission tomography/computed tomography.

Table 5
The NCCN guidelines on imaging for recurrence

Table 6
The NCCN guidelines on imaging in small cell neuroendocrine carcinoma of the cervix

Table 7
Synoptic reporting CT for cervical cancerPatient instructions:Patient is asked to void 30 minutes prior to the scan Serum creatinine to be in check, ideally <1.2 mg/dL, above which the eGFR is calculated.If it is >30 mL/min, full dose contrast can be safely injected.If <30 mL/min, decide on IV contrast injection on case-by-case basis Abbreviations: eGFR, estimated glomerular filtration rate; IV, intravenous; CT, computed tomography.

Table 8
Synoptic reporting MRI for cervical cancer Protocol Patient instructions: 4 hours fasting, but water intake is encouraged prior to the scan Patient is asked to void 30 minutes prior to the scan Serum creatinine to be in check, ideally <1.2 mg/dL, above which the eGFR is calculated.Contrast enhanced scan can be safely performed for eGFR >30mL/min.Antiperistaltic medication (e.g., Buscopan) is recommended Preparation: For optimal reporting, instillation of per-vaginum sterile jelly is necessary Sequences: Dedicated oblique axial small FOV high-resolution T2W sequence.Dedicated oblique sagittal small FOV 24 cm high-resolution T2W sequence.Coronal T2W sequence, optional for small versus large FOV, but small FOV is preferred Large FOV T2W image in coronal plane to include kidneys for hydronephrosis Fat-saturated sequence for lower abdomen and pelvis Axial T1W sequence for screening upper abdomen.Diffusion-weighted imaging, with b value 600-800, optional FOV, but preferably small FOV Dynamic postcontrast screening is recommended in cases of uncertain diagnosis or equivocal parametrial extension.Precontrast followed by 4 to 5 runs of postcontrast imaging.(may be avoided in obviously large infiltrating diseases of advanced stage) Multiplanar postcontrast fat sat sequence Anterior cervical lip /posterior cervical lip /circumferential Dimension: Percentage involvement of stroma, i.e., >50% or <50% Signal intensity description: T2W, restricted diffusion, dynamic postcontrast enhancement characteristics Circumferential cervical hypointense stromal ring: Whether intact or involved, focally or circumferentially