6. Diagnosis – Cervical Carcinoma

Version 2.2 · March 2022 · AWMF 032/033OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

Major changes in the chapter on diagnosis

Some parts of the chapter on diagnosis have been significantly altered. The basis for diagnosis is still the existing TNM classification. In the current FIGO classification dating from 2018, staging on the basis of bimanual examination by the gynecologist has been abandoned and radiological sectional imaging has additionally been taken into account. FIGO regards this as providing benefits for communications within the multidisciplinary team and in improving care for patients with cervical cancer. Although the staging of cervical carcinoma is still clinical, the results of radiologic imaging and biopsies can be included in the assessment of all stages. In patients with cervical carcinoma from at least FIGO IB2 up to and including FIGO III in whom pelvic MRI is not possible for technical reasons, locoregional imaging should be carried out as part of the staging CT of the chest, abdomen, and pelvis. PET-CT is still not recommended in the diagnosis of primary cervical carcinoma, but it can be used in the setting of recurrences to exclude larger lymph-node metastases and distant metastases before planned local procedures.

C.D. Alt, M.C. Koch, F.A. Stübs, E. Merz, J. Menke, M. Reinhardt, B. Zimmer

6.1 Definition of stages — terminology

The 2014 WHO classification [86] is authoritative for characterizing tumors. The 2010 TNM classification [87] applies to the staging of the histological specimen, along with the FIGO 2018 classification optionally (see Table 19). In addition to these clearly defined tumor stages, the literature includes a number of neologisms and unclearly defined terms. These are listed here and an attempt is made to translate them into the authoritative 2010 TNM/UICC classification [87] (Table 9). The guideline group makes a distinction here between microinvasive and macroinvasive carcinomas, but it is clearly shown here that the histological risk factors also have to be stated in order to clearly define the stage, risk, and prognosis, and thus ultimately the treatment indication as well (see section 8.6). The guideline group also regards the distinction between regional and distant metastases as being adequately defined by the 2010 TNM/UICC classification [87]. Otherwise, the guideline group agreed that where possible the precise TNM and/or FIGO stages should be stated for tumor stages and that terms such as “advanced,” “locally (very) advanced,” and “early cervical carcinoma” should be avoided as far as possible, or at least given along with the stage that is meant. In contrast to the above classical definition, the guideline group prefers the view that advanced cervical carcinoma is a disease that cannot be treated unimodally, but requires multimodal therapy due to the histological tumor stage. Due to the tumor biology and extension that are present, this is associated with a poorer prognosis for the patient (mortality) or with more severe treatment side effects (morbidity).

Traditional definitions such as persistent, metastasized, and recurrent also continue to be used. However, a precise distinction must be made between isolated/disseminated metastasis (pM1) and local recurrence including regional metastases (pM0), and these terms must not be confused. The aim is to achieve as precise as possible a description of the tumor characteristics and its extension, in order to allow optimal therapy adapted to the disease stage. The guideline group rejects any distinction between “locally advanced” and “locally very advanced.” Otherwise, the definitions listed in Table 9 apply.

Table 4: Definitions of the nomenclature for cervical carcinoma (checked 2021)

Name	Synonyms	English	TNM	FIGO	UICC	Special characteristics	Definition in the literature
Preinvasive lesion						2014 WHO classification [88] does not correspond to the 2010 TNM/UICC classification (7th edition) [89]	WHO 2014 [88]TNM/UICC 2010 [90]
CIN 1	LSIL*	CIN 1/LSIL	-	-	-	-	WHO 2014 [88]
CIN 2	HSIL*	CIN 2/HSIL	-	-	-	According to WHO [91], HSIL not mentioned in TNM since no pTis.	WHO 2014 [88]
CIN 3*	HSIL*	CIN 3/HSIL	Tis	FIGO does not have a stage 0	0	Is evaluated as CIS	WHO 2014, TNM/UICC 2010 [89]
CIS*	HSIL*	CIS/HSIL	Tis	FIGO does not have a stage 0	0	Is evaluated as CIN 3	WHO 2014, TNM/UICC 2010 [89]
Invasive carcinomas						The tumor entity is classified using the 2014 WHO classification [88]. Staging is carried out according to the 2010 UICC/TNM classification [89]	TNM/UICC 2010 ,[89] WHO classification 2014 [88]
Microinvasive carcinoma*	Early invasive carcinoma, early stromal invasion, microcarcinoma	Microinvasive disease Early (minimal) stromal invasion, - Early stage disease	T1a (T1a1 and T1a2)	IA (IA1 and IA2)	IA (IA1 and IA2)	All macroscopically visible lesions even with superficial invasion are evaluated as T1B/stage IB. NCCN 2014: only IA1 without L1 [92] SIGN Guideline 2008 [93]: „early stage disease” = IA1 and IA2)	No published definition TNM/UICC 2010 distinguishes microscopically and macroscopically visible [89]
Macroinvasive carcinoma*		Macroinvasive disease	≥ Ib	≥ IB	≥ IB		No published definition TNM/UICC 2010 Differentiates microscopically and macroscopically visible [89]
Early cervical carcinoma	Locally limited cervical carcinoma	Early cervical cancer	1A, 1b1, IIa1	IA, IB1, selected IIA1	IA, IB1, selected IIA1	Source: NCCN 2014 [92]	No published definition
Advanced cervical carcinoma		Advanced (stage) disease	≥ 2b and/or pN1 and/or pM1	≥ IIB (up to IVB) Or additionally IB2 and IIA2 with multiple histological risk factors or pN1	≥ IIB (up to IVB) Or also additionally IB2 and IIA2 with multiple histological risk factors or pN1	Locally advanced, recurrent, metastatic, and persistent are often combined as "advanced" in the literature Source: NCCN 2014 [94] For the guideline group definition of this guideline, see Chapter 8.5.1	No published definition
Locally advanced cervical carcinoma		Locally advanced disease	2b to 4 and/or pN1 pM0	IIB to IVA Or additionally IB2 and IIA2 with multiple histological risk factors or pN1 and c/pM0	IIB to IVA Or also additionally IB2 and IIA2 with multiple histological risk factors or pN1 and c/pM0	Source: NCCN 2014 [94]	No published definition
Locally advanced cervical carcinoma.		Disease confined to the pelvis, more advanced disease	3 to 4 and/or pN1 pM0	IIIA to IVA or pN1 and c/pM0	IIIA to IVA or pN1 and c/pM0	With infiltration of the bladder, vagina, or rectum, or extension to the pelvic wall (e.g., urinary stasis) with no distant metastases	No published definition
Incidental cervical carcinoma*	Accidentallly discovered cervical carcinoma	Incidental cervical cancer	-	-	-	Carcinoma detected by chance during a different operation	No published definition
Recurrence		Recurrent disease, relapse	-	-	-	Reappearence of the disease (local or metastatic) after therapy	No published definition
Early recurrence			-	-	-	Instead, a distinction is made between symptomatic and asymptomatic	No published definition
Late relapse			-	-	-	Instead, a distinction is made between symptomatic and asymptomatic	No published definition
Local recurrence*	Locoregional recurrence, central recurrence, pelvic recurrence, vaginal recurrence, isolated pelvic recurrence	Local recurrence, localized recurrence, locoregional recurrence central pelvic recurrence, - isolated central pelvic recurrence	Any T, Any N, M0	-	-	Recurrence in the area of the pelvis or vagina , with no distant metastases.	No published definition
Persistent primary disease*	Tumor persistence	Persistent disease	-	-	-	Continued presence of the disease (local or metastatic) after therapy	No published definition
Metastatic disease*		Metastatic disease	Any T, Any N, M1	IVB	IVB	The primary metastatic situation and recurrences with distant metastases are combined. Para-aortic, inguinal, intraperitoneal, supraclavicular, mediastinal lymph-node metastases, and pulmonary, hepatic, bone, and cerebral metastases are regarded as M1. Metastases in the vagina, pelvic serosa, and adnexa are not included (M0)	TNM/UICC 2010 [89]
Regional metastases*	Locoregional metastases	Regional lymph node metastases	Any T, N1, M0	IIIB, IVa	IIIB, IVA	Regional pelvic lymph-node metastases include: paracervical, parametrial, hypogastric (internal iliac artery, obturator artery region), common iliac artery, external iliac artery, presacral, sacral	TNM/UICC 2010 [89]
Distant metastases*		Distant metastasis	Any T, Any N, M1	IVB	IVB	The primary metastatic situation and recurrences with distant metastases are combined. Para-aortic, inguinal, intraperitoneal, supraclavicular, mediastinal lymph-node metastases, and pulmonary, hepatic, bone, and cerebral metastases are regarded as M1. Metastases in the vagina, pelvic serosa, and adnexa are not included (M0).	TNM/UICC 2010 [89]
Isolated distant metastases*		Isolated distant metastases	Any T, Any N, M1	IVB	IVB	Of questionable treatment relevance	No published definition
Disseminated distant metastases*		Disseminated metastases, oligometastatic disease,	Any T, Any N, M1	IVB	IVB	Of questionable treatment relevance	No published definition
Legend: * = terms used by the guideline group. CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ; HSIL = high-grade squamous intraepithelial lesion; LSIL = low-grade squamous intraepithelial lesion; UICC = Union internationale contre le cancer; NCCN = National Comprehensive Cancer Network; SIGN = Scottish Intercollegiate Guidelines Network; WHO = World Health Organization.

6.2 Diagnosis as the basis for choice of treatment

The new FIGO classification was introduced in 2018 after in-depth consultation. Previously, the FIGO classification of cervical carcinoma was a purely clinical staging classification and was based on the bimanual examination of the patient by the gynecologist. This was due to the fact that the vast majority of cervical carcinomas occur in non-industrialized countries, so that the women affected have limited access to radiological sectional imaging or histological confirmation. This approach has been abandoned in the new FIGO classification. In addition to improving resources in non-industrialized countries, FIGO regards this as providing benefits for communications within the multidisciplinary team and in improving care for patients with cervical cancer. Although the staging of cervical carcinoma is still clinical, the results of radiologic imaging and of biopsies can be included in the assessment of all stages. Unfortunately, however, there is still no recommendation regarding the methods to be used for diagnosis and staging [95]. This of course makes it difficult to compare registries. Some studies have demonstrated the benefits of complementary imaging techniques (e.g., MRI) [96], [97]. Anesthetic examination, cystoscopy, rectosigmoidoscopy, chest X-ray, intravenous pyelography and contrast colonoscopy are reserved for special questions. In particular, intravenous pyelography and contrast colonoscopy are no longer performed in Germany for diagnostic clarification of confirmed cervical carcinoma. The chest X-ray has also been largely replaced by staging CT of the chest and abdomen, which patients receive starting from a localized tumor > 4 cm (FIGO IB2) in accordance with the guideline.

Some of the changes in the current FIGO classification (2018) have fundamental implications for staging and also for stage-based therapy. Since TNM and FIGO are currently not congruent, it is recommended to continue to use the previous TNM classification (see chapter 7.1.2).

This makes the basis for the choice of treatment all the more difficult, since the relevant prospective and randomized studies that are cited in this guideline are in principle based on the imprecise digital FIGO classification system dating from 2009 and the current choice of therapeutic methods is usually not based on surgical or imaging procedures. This lack of clarity in the FIGO classification is also exacerbated by the definition of “macroscopically visible” lesions, and superficial invasion in particular. A cervical lesion that is classified as “microscopic” does not explicitly alter the classification in relation to an increase to stage Ib, but remains in stage IA even in the case of colposcopically visible lesions. The stage is only classified as Ib when there is a pathological T stage after excision or conization, with stromal invasion of more than 5 mm and a superficial size larger than 7 mm.

In addition to tumor-related criteria, additional patient-specific aspects also have to be taken into consideration:

(1) In young patients, a possible wish to have children or an existing pregnancy at first diagnosis, depending on the gestational week, has to be included in the choice of diagnosis and therapy.

(2) In addition, the patient’s menopausal status (pre-, peri-, or post-) is important for well-being and life expectancy in patients with cervical carcinoma, from the point of view of ovarian preservation to maintain intrinsic hormonal function.

Due to the structures for providing care described in this guideline, the diagnosis of cervical carcinoma in Germany is subject to different diagnostic algorithms from those proposed by FIGO.

6.2.1 Consensus-agreed diagrams from the guideline group for diagnosing and defining stages as the basis for treatment decision-making

Based on expert consensus, consensus diagnosis and stage definition as the basis for treatment decision-making ≤ FIGO stage IIB

Diagnosis and definition of stages as the basis for treatment decision-making ≤ FIGO stage IIB (2014/2021)

6.2.1.1 Diagnosis and staging as the basis for treatment decisions > FIGO stage IIB

Diagnosis and definition of stages as the basis for treatment decision-making ≤ FIGO stage IIB

6.2.2 Recommendations on diagnostic procedures

6.1 · Consensus-based Recommendation · modified 2021

Vaginal ultrasonography shall be used for clinical imaging to establish the extent of local tumor spread, and renal ultrasonography to exclude urinary transport disturbance.

Consensus: Strong consensus

Change note

Vaginal ultrasound and renal ultrasound should be used to determine the locoregional tumor spread, or MRI if unclear.

6.2 · Evidence-based Recommendation · modified 2021

Patients with histologically confirmed cervical carcinoma from FIGO stage IB2 to III inclusive should undergo pelvic MRI for assessment of locoregional tumor spread. Patients who are unable to undergo pelvic MRI for technical reasons should have a pelvic CT.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 1+
Consensus: Strong consensus
References: [98] [99] [100]

Change note

Patients with histologically confirmed cervical carcinoma FIGO stage IB2 and up to and including III should receive an MRI pelvis to assess locoregional tumour spread. Patients in whom an MRI pelvis cannot be performed for technical reasons should receive a CT pelvis.

6.3 · Consensus-based Recommendation · modified 2021

Starting from FIGO IB2 to III, patients in whom pelvic MRI cannot be carried out for technical reasons should undergo locoregional imaging of the pelvis for staging purposes during staging CT examinations of the chest, abdomen, and pelvis.

Consensus: Strong consensus

Change note

see also 6.2: Patients with histologically confirmed cervical carcinoma FIGO stage IB2 and up to and including III should receive an MRI pelvis to assess locoregional tumour spread. Patients in whom an MRI pelvis cannot be performed for technical reasons should receive a CT pelvis.

In this recommendation on imaging diagnosis in patients with cervical carcinoma, the guideline group has kept quite close to the recommendations given in the 2008 SIGN guideline [101]. This is based above all on consistent evidence that MRI is superior to CT and clinical staging for assessing the primary tumor and invasion of neighboring organs [102]. Data from a systematic review published in 2013 also confirm these data and again show that MRI (with a pooled sensitivity of 84%; 95% CI, 76–90%) is superior to the clinical examination (with a pooled sensitivity of 40%; 95% CI, 25–58%), particularly for detecting parametrial infiltration and cervical carcinomas > stage IIB (and thus potentially inoperable) [103]. For stages below IB2, the guideline group takes a critical view of the role of MRI/CT diagnosis in assessing the primary tumor. For stage IVA, the guideline group — in contrast to the SIGN guideline — also recommends a pelvic MRI for assessment of the primary tumor, due to the potential option of exenteration. For patients in whom MRI is not feasible for technical reasons — for example, due to a pacemaker — CT of the pelvis should no longer be carried out as an equivalent starting from FIGO stage IB2 onwards, but only staging by means of CT of the chest and abdomen, continuing up to and including the symphysis and thus including the pelvis (referred to as CT chest/abdomen/pelvis for precise identification). As early as 2007, the German Medical Association stipulated in its guideline on quality assurance in computed tomography that the abdomen should be imaged in CT scans from the dome of the diaphragm to the pelvic floor in uninterrupted sections and in as similar a respiratory position as possible [104]. This reduces radiation exposure and contrast administration and is therefore less stressful for the patient.

6.4 · Consensus-based Recommendation · new 2021

Patients in FIGO stage IVA who are unable to undergo pelvic MRI for technical reasons should receive locoregional imaging staging of the pelvis as part of staging CT of the chest/abdomen/pelvis.

Consensus: Strong consensus

6.5 · Consensus-based Recommendation · modified 2021

Patients with histologically confirmed cervical carcinoma FIGO stage IB2 or above should undergo chest/abdominal/pelvic CT for assessment of tumor spread.

Consensus: Strong consensus

Change note

Patients with histologically confirmed cervical carcinoma from FIGO stage IB2 should receive a CT thorax/abdomen to assess extrapelvic tumor spread.

The current guideline recommendations are consistent with the 2008 SIGN guideline [101] with regard to the increased use of chest/abdominal CT for staging, and abandonment of hepatic ultrasonography and chest X-ray examinations. The guideline group also follows these recommendations. Despite this, in contrast to the 2008 SIGN guideline, a clear diagnostic emphasis is placed on surgical staging for the choice of treatment. This is above all because precise assessment of lymph-node status (pelvic and para-aortic) for treatment planning appears particularly important to the guideline group, especially in the setting of care in Germany (see also section 8.1.1).

6.6 · Consensus-based Recommendation · checked 2021

If a tumor of the vaginal part of the cervix cannot be clearly assessed macroscopically, a differential colposcopy and targeted biopsy shall be carried out.

Consensus: Strong consensus

6.7 · Consensus-based Recommendation · checked 2021

The histologically confirmed tumor stage should be the basis for interdisciplinary treatment decision-making at the tumor conference.

Consensus: Strong consensus

In the framework of statutory early cancer detection guidelines, a gynecological examination and cytology are the initial components of the diagnostic process, along with HPV testing starting from age 35. In the case of higher-grade cytological abnormalities, differential colposcopy with targeted biopsy sampling, or diagnostic/therapeutic conization or excision if the lesion is easily localized colposcopically, should be carried out.

These measures lead to the histological diagnosis, which by defining the FIGO stage after the digital examination points the way to the algorithm for further diagnostic procedures and treatment. The diagnostic measures listed by FIGO are reserved, if used at all, for carcinomas ≥ FIGO stage IIb or suspected distant metastases (e.g., inguinal, para-aortic lymph-node metastases, scalene lymph-node metastases). Data on the routine use of imaging procedures such as abdominal CT or MRI for classification and thus to provide the basis for treatment decisions are heterogeneous. While CT provides better information in the area of the lateral borders (osseous structures) to the pelvic wall, MRI provides better differentiation of the primary tumor size and infiltration relative to the parametria and the soft-tissue organs of the bladder and bowel, as well as in the lymph nodes [101] [96] [102] [105]. Using MRI with a field strength of at least 1.5 Tesla, diffusion imaging in combination with high-resolution T2 weighting and administration of Buscopan (hyoscine butylbromide) or glucagon to provide drug-produced intestinal atony significantly improves the detection of parametrial infiltration [97]. Studies on the use of vaginal ultrasound have shown that it has good validity, particularly for assessing the tumor size in the cervical region (kappa 0.81; 95% CI, 0.73 to 0.90) [106]. With regard to the parametrial infiltration depth, ultrasound examination underestimates the findings in up to one-third of patients [106] [107] [108]. Research to assess the value of PET or PET-CT continues to provide very heterogeneous results. Overall, in the view of the guideline group, PET-CT still does not have any value for routine diagnosis, due to its lack of differentiation between superinfection and infiltrating tumor in the cervical region and a lack of sensitivity and specificity for micrometastases and small metastases in the area of the lymph nodes [109] [110] [111]. On the basis of recent research data, however, pretherapeutic PET-CT may be advocated in individual cases — e.g., if histological clarification of the para-aortic lymph nodes is not possible, or to select patients for histological clarification of the para-aortic lymph nodes [112] [113]. With regard to lymph-node detection, a meta-analysis has shown that MRI with diffusion imaging had the best sensitivity at 88%, PET or PET-CT had the best specificity at 94%, and the AUC of DWI and PET-CT were both more than 90% in comparison with the histopathological results [114].

Due to the problems involved in the clinical FIGO classification, there are unclear aspects in the choice of treatment options, both with regard to surgical treatment and also radio(chemo)therapy. Particularly when there are unclear imaging findings in the area of the para-aortic lymph nodes, for example, or when the extent of the tumor is unclear during a digital examination, obtaining histological information from these areas is thus the best option for determining the histological tumor stage. Surgical staging makes it possible to assess the lymph nodes, the peritoneum, and local tumor spread. This leads to more precise staging. It allows more precise treatment planning and discrimination of the therapeutic options, with the goal of reducing the effects of the disease and treatment on morbidity and mortality as much as possible. Surgical staging has thus gained in importance in recent years. Surgical staging should allow precise classification. When there are bilateral negative sentinel lymph nodes, no further lymphadenectomy needs to be carried out for completeness. When there are positive para-aortic or pelvic lymph nodes, radical hysterectomy with subsequent radio(chemo)therapy needs to be critically considered as a treatment measure, and expansion of the radiation field is certainly necessary. If the lymph nodes are negative on quick-section diagnosis, radical hysterectomy is justified with lower tumor stages. The aim of surgical staging is therefore to achieve a precise definition of the tumor stage and thus in particular to provide the basis for the relevant stage-appropriate treatment in the primary situation. In premenopausal women, simultaneous repositioning of the ovaries should be carried out to preserve hormonal production.

In the recurrent setting, when symptoms develop, or when there is a suspicion of metastases, imaging procedures are used — particularly vaginal ultrasound and pelvic MRI, and chest/abdomen/pelvis CT when there is a suspicion of metastases. If there are unclear findings, PET-CT has advantages for clear identification of lymph-node metastases and distant metastases, which is particularly relevant in case of planned exenteration or radio(chemo)therapy. Surgical measures using minimally invasive techniques can also influence the choice of therapy, particularly when there is evidence of peritoneal metastases or tumor spread extending into other organs.

6.8 · Evidence-based Recommendation · modified 2021

PET-CT should not be used for treatment planning in primary cervical carcinoma.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 2+
Consensus: Strong consensus
References: [115] [109] [116] [117] [118]

Change note

PET-CT has no place in the treatment planning of primary cervical carcinoma.

The 2008 SIGN guideline already recommends PET-CT in the primary situation (recommendation grade C) only as an option in patients who are not candidates for surgery and who due to their high tumor stage have a statistically high probability of lymph-node metastases. The negative predictive value in lower tumor stages is not sufficient, and micrometastases are often not detected [101]. A meta-analysis in 2010 showed that PET/PET-CT had a better diagnostic performance than CT or MRI, but only with very heterogeneous data. In addition, no distinctions were made between the various CT and MRI developmental stages [119]. Another 2010 meta-analysis investigated the diagnostic quality of PET-CT for diagnosing para-aortic lymph-node metastases in patients with cervical carcinoma. The authors concluded that PET-CT only detects para-aortic lymph-node metastases with sufficient certainty in patient groups in which there is a high probability of metastases [115]. Another study including 237 patients (stages IB2 to IVa) compared laparoscopic staging of the para-aortic lymph nodes with the results of PET-CT imaging. It was found that survival in patients with para-aortic lymph-node metastases > 5 mm was markedly poorer and that these metastases were not detected using PET-CT [120].

In more recent studies published in 2015 and 2018, some research groups advocate the use of PET in the primary therapeutic setting when suspicious pelvic lymph nodes are visible on CT, in order to reduce the likelihood of side effects due to extended combined radiochemotherapy [121] [122] [123]. Others have concluded that although PET-CT can be recommended to increase diagnostic accuracy, it is not justified due to its low sensitivity for abdominal lymph-node detection in locally advanced carcinoma [124]. Other studies have defined volume-based FDG-PET-CT parameters as prognostic factors for event-free survival and overall survival [125] aand recommend performing PET-CT pretherapeutically before planned radio(chemo)therapy and 3 weeks after the start of treatment for monitoring and adjusting therapy if necessary, as this improves the overall survival [126]. Overall, however, in the opinion of the guideline group, PET-CT still has no value for routine diagnosis, also due to its well-known lack of differentiation between superinfection and infiltrating tumor in the cervical region and lack of sensitivity and specificity for micrometastases and small metastases in the area of the lymph nodes [109] [110] [111]. Data from a meta-analysis show that MRI with diffusion imaging had the best sensitivity for lymph-node detection, at 88%, while PET or PET-CT had the best specificity at 94%, and the AUC of DWI and PET-CT were both greater than 90% [114]. Martinez et al. reported that four of 78 patients (5.1%) had para-aortic lymph-node metastases in FDG-negative pelvic lymph-node sites [113]. De Cuypere et al. reported a high specificity with FDG-PET-CT, at 93.3%, with a low sensitivity of 23.5% [112]. Seven of nine false-positive findings were in region of the common iliac artery. Ultimately, the results of FDG-PET-CT in the primary setting are still too inconsistent for the guideline group to justify a general recommendation for PET-CT diagnosis in this setting.

6.9 · Evidence-based Recommendation · modified 2021

When a local procedure (radiochemotherapy or exenteration) is being considered for treatment of a recurrence, PET-CT should be carried out to exclude lymph-node metastases and distant metastases.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 2+
Consensus: Strong consensus
References: [127] [128] [98] [129]

Change note

PET-CT should be reserved for special questions in the recurrence situation.

Evidence tables (2)

Ding et al. 2014; Xiao et al. 2014

The 2008 SIGN guideline recommends whole-body PET-CT only for patients in whom a recurrence or persistent cervical carcinoma has been identified on MRI or CT, in whom a salvage operation is planned [101]. Several research groups also recommend FDG-PET-CT in patients with suspected recurrences and rising SCC-Ag levels but with negative or equivocal results on conventional imaging with CT or MRI. They report a sensitivity of 91% and a specificity of 92% [127] [128]. On the other hand, however, Meads et al. 2014 complained that although the recommendation of PET-CT in patients with recurrences before planned exenteration or even generally 9 months after completion of chemotherapy is anchored in the guidelines, but is not evidence-based [130] [131] [132] [133]. Particularly in patients who have local recurrences in whom exenteration or radio(chemo)therapy are options, distant metastases must be reliably ruled out. When there are unclear imaging findings on CT and MRI, the guideline group therefore advocates carrying out PET-CT before renewed therapy in order to reliably exclude metastases. For imaging when there are suspected recurrences or metastases, see also sections 16.5, 16.6, 17.2 and 18.2.

6.3 Transvaginal ultrasound (TVU) in the diagnosis of cervical carcinoma

In addition to gynecological palpation and speculum examination, transvaginal ultrasound (supplemented in selected cases with transrectal ultrasound) is part of the primary gynecological diagnostic approach in cervical carcinoma. In adenocarcinoma, cervical carcinoma tissue typically appears as a hyperechoic or isoechoic mass in contrast to the surrounding tissue. In squamous cell carcinoma, it is hypoechoic. The detection rate achievable for tumor extension > 4 cm is 78%, with a specificity of 99% [134]. In cases of deep stromal infiltration (more than two-thirds of the wall thickness (see Chapter 7.2.4), TVU has a sensitivity of 88–91% (specificity 93–97%), while for parametrial infiltration it has a sensitivity of 60–83% (specificity 89–100%). In specialized centers, diagnostic results achievable to those with MRI can be achieved [106] [134]. TVU has been reported to be advantageous in the search for residual tumor after conization. However, this observation does not appear to be transferable to the assessment of residual tumor size during or after neoadjuvant treatment [106], [135]. TVU is still suitable in connection with options for fertility-preserving surgery, since the distance between the tumor and the isthmus of the uterus and the expected length of the functional residual cervix can be accurately estimated due to the technique’s high spatial resolution. Due to its limited depth of penetration, limited angle of view, and overlying bowel, TVU has limitations for assessing pelvic and/or para-aortic lymph-node metastases [136] [137].

Increased angiogenesis and neovascularization are risk factors and can be investigated using Doppler ultrasonography [134]. In addition to color Doppler ultrasound visualization of the vessels, attention should be paid to tumor vessels with low resistance indices (cut-off PI < 0.73). The state of the data on perfusion assessment using 3D (power) Doppler ultrasound is currently divergent. In a larger prospective study (PRICE), it was considered to be an insufficiently predictive response criterion in connection with neoadjuvant radiochemotherapy [138], [139]. However, newer techniques such as the inclusion of the glass-body mode, may significantly improve the assessment of the vascular architecture here. Additional prospects for extending the diagnostic value of ultrasound include tomographic 3D ultrasound and elastography, the value of which has yet to be evaluated in larger prospective a and controlled studies [140], [141].

Evidence tables

Ding et al. 2014

Ding XP, Feng L, Ma L. Diagnosis of recurrent uterine cervical cancer: PET versus PET/CT: a systematic review and meta-analysis. Arch Gynecol Obstet. 2014;290(4):741-7.
Studiendesign	Population	Interventionen	Endpunkte
Systemtaischer Review / Meta-Analyse	Patienten mit Zervixkarzinom Keine Einschränkungen bzgl. Krankheitsstadium 18 Publikationen eingeschlossen: 10 PET alleine, 7 PET-CT, 1 PET und PET-CT Insgesamt 1.624 Patienten	Positronenemissionstomografie alleine vs. Positronenemissionstomografie / Computertomografie jeweils zur Detektion des Rezidivs	Angaben Testgenauigkeit mit Rate an richtig positiven und falsch positiven Ergebnissen durch PET-CT vs. Referenzstandard (histopathologische Analyse)
Evidenzgrad
1-
Vertrauen in Effekte
moderat bis gering
Ergebniszusammenfassung Sowohl PET als auch PET-CT verfügen über eine gute diagnostische Genauigkeit zur Detektion von Zervixkarzinomen. Die Autoren schlussfolgern zudem, dass PET-CT mehr zu einer richtigen Behandlung des rezidivierenden Zervixkarzinoms im Sinne einer anatomischen und funktionellen Lokalisierung des Rezidivs beitragen könne. Diese Aussage wird jedoch nicht durch die Ergebnisse der Studie gestützt. Anmerkungen zum Vertrauen in die Effektschätzer z.T. hohe Heterogenität zwischen den Gruppen
CT: Computertomografie; PET: Positronenemissionstomografie

Verfahren	N [Studien]	N [Tests]	Sensitivität [95% KI]		Spezifität [95% KI]		Anmerkungen
PET	11	1.461	91% [87; 94]; p=0,22, I²=23,2%	p>0,05 ¹	92% [91; 94]; p<0,001; I²=92,4%	p>0,05 ¹	Geringe bis hohe Heterogenität
PET-CT	8	236	94% [89; 97]; p=0,54; I²=0%	p>0,05 ¹	84% [74; 91]; p=0,15; I²=34,4%	p>0,05 ¹	Keine bis geringe Heterogenität
1: Vergleich der Area under the Curve KI: Konfidenzintervall; PET: Positronenemmisionstomografie; CT: Computertomografie

Xiao et al. 2014

Xiao Y, Wei J, Zhang Y, Xiong W. Positron emission tomography alone, positron emission tomography-computed tomography and computed tomography in diagnosing recurrent cervical carcinoma: a systematic review and meta-analysis. Arch Med Sci. 2014;10(2):222‐231. doi:10.5114/aoms.2014.42572
Studiendesign	Population	Interventionen	Endpunkte
Systematischer Review / Meta-Analyse	Patientinnen mit rezidiviertem Zervixkarzinom, diagnostiziert mittels Computertomografie (CT), Positronenemissionstomografie (PET) oder PET-CT Keine Einschränkungen bezüglich des Krankheitsstadiums 23 Studien eingeschlossen: 1 prospektive Studie, 15 retrospektive Registerstudien, 7 ohne Angabe	Computertomografie (CT) vs. Positronenemissionstomografie (PET) oder PET-CT	2x2-Tafeln zur Testgenauigkeit mit Rate an richtig positiven, richtig negativen, falsch positiven und falsch negativen Ergebnissen durch PET-CT vs. Referenzstandard
Evidenzgrad
2++
Vertrauen in Effekte
sehr gering
Ergebniszusammenfassung: PET hatte die höchste Spezifität (92%) PET-CT hatte die höchste Sensitivität (94%) Paarweise Vergleiche zeigten, dass die Spezifität von PET signifikant höher war als diejenige der PET-CT (p<0,05) Es wurden keine statistisch signifikanten Unterschiede der Sensitivität zwischen den Verfahren ermittelt. Anmerkungen zum Vertrauen in die Effektschätzer Laut den Autoren wurde kein Publikationsbias identifiziert. Die Heterogenität zwischen den Studien war hoch.

Verfahren	Studien	Sensitivität [95% KI]	Vergleich gegenüber… [p-Wert]			Spezifität [95% KI]	Vergleich gegenüber… [p-Wert]			DOR	AUC
Verfahren	Studien	Sensitivität [95% KI]	PET	PET-CT	CT	Spezifität [95% KI]	PET	PET-CT	CT	DOR	AUC
PET	12	91% [88; 94]	-	≥0,5	≥0,5	92% [90; 94]	-	<0,05	≥0,5	74.15 (27.04–203.32	0.9594
PET-CT	9	94% [90; 97]	≥0,5	-	≥0,5	84% [75; 91]	<0,05	-	≥0,5	62.74 (27.82–141.47)	0.9508
CT	4	89% (81–95%)	≥0,5	≥0,5	-	87% (76–94%)	≥0,5	≥0,5	-	29.31 (5.46–157.31)	0.9363
AUC: area under the curve; CT: Computertomografie; DOR: diagnostisches Odds Ratio; KI: Konfidenzintervall; PET: Positronenemissionstomografie

References

[86] Kurman, R. J., Carcangiu, M. L., Herrington, C. S., WHO Classification of Tumours of the Female Genital TractIARC Press, 2014. p. 169-206.

[87] Wittekind, C, Meyer, HJ, TNM-Klassifikation maligner TumorenViley-VCH Verlag, 2010.

[88] Kurman, R. J., Carcangiu, M. L., Herrington, C. S., WHO Classification of Tumours of the Female Genital TractIARC Press, 2014. p. 169-206.

[89] Wittekind, C, Meyer, HJ, TNM-Klassifikation maligner TumorenViley-VCH Verlag, 2010.

[90] Wittekind, C, Meyer, HJ, TNM-Klassifikation maligner TumorenViley-VCH Verlag, 2010.

[91] Kurman, R. J., Carcangiu, M. L., Herrington, C. S., WHO Classification of Tumours of the Female Genital TractIARC Press, 2014. p. 169-206.

[92] NCCN Clinical Practice Guideline in Oncology (NCCN Guidelines) 1.2014 Cervical Cancer.pdf, 2014., http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf

[93] SIGN, Management of cervical cancer - A national clinical guideline, 2008., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174776/

[94] NCCN Clinical Practice Guideline in Oncology (NCCN Guidelines) 1.2014 Cervical Cancer.pdf, 2014., http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf

[95] Horn, L. C., Brambs, C. E., Opitz, S., Ulrich, U. A., Hohn, A. K., [The 2019 FIGO classification for cervical carcinoma-what's new?], Pathologe, 2019. 40(6): p. 629-635., https://www.ncbi.nlm.nih.gov/pubmed/31612260

[96] Dappa, E., Elger, T., Hasenburg, A., Duber, C., Battista, M. J., Hotker, A. M., The value of advanced MRI techniques in the assessment of cervical cancer: a review, Insights Imaging, 2017. 8(5): p. 471-481., https://www.ncbi.nlm.nih.gov/pubmed/28828723

[97] Woo, S., Suh, C. H., Kim, S. Y., Cho, J. Y., Kim, S. H., Magnetic resonance imaging for detection of parametrial invasion in cervical cancer: An updated systematic review and meta-analysis of the literature between 2012 and 2016, Eur Radiol, 2018. 28(2): p. 530-541., https://www.ncbi.nlm.nih.gov/pubmed/28726120

[98] SIGN, SIGN: Management of Cervical Cancer, 2008.

[99] Bipat, S., Glas, A. S., van der Velden, J., Zwinderman, A. H., Bossuyt, P. M., Stoker, J., Computed tomography and magnetic resonance imaging in staging of uterine cervical carcinoma: a systematic review, Gynecol Oncol, 2003. 91(1): p. 59-66.

[100] Thomeer, M. G., Gerestein, C., Spronk, S., van Doorn, H. C., van der Ham, E., Hunink, M. G., Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis, Eur Radiol, 2013. 23(7): p. 2005-18., http://download.springer.com/static/pdf/254/art%253A10.1007%252Fs00330-013-2783-4.pdf?auth66=1392375236_9bca73cd15ec7d965b9126f42a2a136c&ext=.pdf

[101] SIGN, SIGN: Management of Cervical Cancer, 2008.

[102] Bipat, S., Glas, A. S., van der Velden, J., Zwinderman, A. H., Bossuyt, P. M., Stoker, J., Computed tomography and magnetic resonance imaging in staging of uterine cervical carcinoma: a systematic review, Gynecol Oncol, 2003. 91: p. 59-66., https://www.ncbi.nlm.nih.gov/pubmed/14529663

[103] Thomeer, M. G., Gerestein, C., Spronk, S., van Doorn, H. C., van der Ham, E., Hunink, M. G., Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis, Eur Radiol, 2013. 23(7): p. 2005-18., https://www.ncbi.nlm.nih.gov/pubmed/23455762

[104] , 2007., https://www.bundesaerztekammer.de/aerzte/qualitaetssicherung/richtlinien-leitlinien-empfehlungen-stellungnahmen/richtlinien-leitlinien-empfehlungen-zur-qualitaetssicherung/bildgebende-verfahren/computertomographie/

[105] Choi, H. J., Ju, W., Myung, S. K., Kim, Y., Diagnostic performance of computer tomography, magnetic resonance imaging, and positron emission tomography or positron emission tomography/computer tomography for detection of metastatic lymph nodes in patients with cervical cancer: meta-analysis (Structured abstract), Cancer Science, 2010. 101: p. 1471-1479., https://www.ncbi.nlm.nih.gov/pubmed/20298252

[106] Epstein, E., Testa, A., Gaurilcikas, A., Di Legge, A., Ameye, L., Atstupenaite, V., et.al. Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial, Gynecol Oncol, 2013. 128(3): p. 449-53., https://www.ncbi.nlm.nih.gov/pubmed/23022593

[107] Delgado, G., Bundy, B., Zaino, R., Sevin, B. U., Creasman, W. T., Major, F., Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, Gynecol Oncol, 1990. 38: p. 352-7., https://www.ncbi.nlm.nih.gov/pubmed/2227547

[108] Lagasse, L. D., Creasman, W. T., Shingleton, H. M., Ford, J. H., Blessing, J. A., Results and complications of operative staging in cervical cancer: experience of the Gynecologic Oncology Group, Gynecol Oncol, 1980. 9(1): p. 90-8.

[109] Gouy, S., Morice, P., Narducci, F., Uzan, C., Martinez, A., Rey, A., et.al. Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging, J Clin Oncol, 2013. 31(24): p. 3026-33., https://www.ncbi.nlm.nih.gov/pubmed/23857967

[110] Tsai, C. S., Lai, C. H., Chang, T. C., Yen, T. C., Ng, K. K., Hsueh, S., et.al. A prospective randomized trial to study the impact of pretreatment FDG-PET for cervical cancer patients with MRI-detected positive pelvic but negative para-aortic lymphadenopathy, Int J Radiat Oncol Biol Phys, 2010. 76: p. 477-84., https://www.ncbi.nlm.nih.gov/pubmed/19464824

[111] Kang, S., Kim, S. K., Chung, D. C., Seo, S. S., Kim, J. Y., Nam, B. H., et.al. Diagnostic value of 18F-FDG PET for evaluation of paraaortic nodal metastasis in patients with cervical carcinoma: a meta-analysis (Structured abstract), Journal of Nuclear Medicine, 2010. 51: p. 360-367., https://www.ncbi.nlm.nih.gov/pubmed/20150275

[112] De Cuypere, M., Lovinfosse, P., Goffin, F., Gennigens, C., Rovira, R., Duch, J., et.al. Added value of para-aortic surgical staging compared to (18)F-FDG PET/CT on the external beam radiation field for patients with locally advanced cervical cancer: An ONCO-GF study, Eur J Surg Oncol, 2020. 46(5): p. 883-887., https://www.ncbi.nlm.nih.gov/pubmed/31784203

[113] Martinez, A., Voglimacci, M., Lusque, A., Ducassou, A., Gladieff, L., Dupuis, N., et.al. Tumour and pelvic lymph node metabolic activity on FDG-PET/CT to stratify patients for para-aortic surgical staging in locally advanced cervical cancer, Eur J Nucl Med Mol Imaging, 2020. 47(5): p. 1252-1260., https://www.ncbi.nlm.nih.gov/pubmed/31915897

[114] Liu, B., Gao, S., Li, S., A Comprehensive Comparison of CT, MRI, Positron Emission Tomography or Positron Emission Tomography/CT, and Diffusion Weighted Imaging-MRI for Detecting the Lymph Nodes Metastases in Patients with Cervical Cancer: A Meta-Analysis Based on 67 Studies, Gynecol Obstet Invest, 2017. 82(3): p. 209-222., https://www.ncbi.nlm.nih.gov/pubmed/28183074

[115] Kang, S., Kim, S. K., Chung, D. C., Seo, S. S., Kim, J. Y., Nam, B. H., et.al. Diagnostic value of 18F-FDG PET for evaluation of paraaortic nodal metastasis in patients with cervical carcinoma: a meta-analysis (Structured abstract), Journal of Nuclear Medicine, 2010. 51: p. 360-367.

[116] Choi, H. J., Ju, W., Myung, S. K., Kim, Y., Diagnostic performance of computer tomography, magnetic resonance imaging, and positron emission tomography or positron emission tomography/computer tomography for detection of metastatic lymph nodes in patients with cervical cancer: meta-analysis (Structured abstract), Cancer Science, 2010. 101(6): p. 1471-1479., http://onlinelibrary.wiley.com/o/cochrane/cldare/articles/DARE-12010005302/frame.html

[117] Tsai, C. S., Lai, C. H., Chang, T. C., Yen, T. C., Ng, K. K., Hsueh, S., et.al. A prospective randomized trial to study the impact of pretreatment FDG-PET for cervical cancer patients with MRI-detected positive pelvic but negative para-aortic lymphadenopathy, Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 477-84., http://www.ncbi.nlm.nih.gov/pubmed/19464824

[118] Kang, S., Kim, S. K., Chung, D. C., Seo, S. S., Kim, J. Y., Nam, B. H., et.al. Diagnostic value of 18F-FDG PET for evaluation of paraaortic nodal metastasis in patients with cervical carcinoma: a meta-analysis (Structured abstract), Journal of Nuclear Medicine, 2010. 51(3): p. 360-367., http://jnm.snmjournals.org/content/51/3/360.full.pdf

[119] Choi, H. J., Ju, W., Myung, S. K., Kim, Y., Diagnostic performance of computer tomography, magnetic resonance imaging, and positron emission tomography or positron emission tomography/computer tomography for detection of metastatic lymph nodes in patients with cervical cancer: meta-analysis (Structured abstract), Cancer Science, 2010. 101: p. 1471-1479.

[120] Gouy, S., Morice, P., Narducci, F., Uzan, C., Martinez, A., Rey, A., et.al. Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging, J Clin Oncol, 2013. 31: p. 3026-33.

[121] Elit, L. M., Fyles, A. W., Gu, C. S., Pond, G. R., D'Souza, D., Samant, R., et.al. Effect of Positron Emission Tomography Imaging in Women With Locally Advanced Cervical Cancer: A Randomized Clinical Trial, JAMA Netw Open, 2018. 1(5): p. e182081., https://www.ncbi.nlm.nih.gov/pubmed/30646153

[122] Lin, S. Y., Tsai, C. S., Chang, Y. C., Ng, K. K., Chang, T. C., Kao, W. H., et.al. The Role of Pretreatment FDG-PET in Treating Cervical Cancer Patients With Enlarged Pelvic Lymph Node(s) Shown on MRI: A Phase 3 Randomized Trial With Long-Term Follow-Up, International journal of radiation oncology, biology, physics, 2015. 92(3): p. 577-85., http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/013/CN-01084013/frame.html

[123] Small, W., Jr., Winter, K., Levenback, C., Iyer, R., Gaffney, D., Asbell, S., et.al. Extended-field irradiation and intracavitary brachytherapy combined with cisplatin chemotherapy for cervical cancer with positive para-aortic or high common iliac lymph nodes: results of ARM 1 of RTOG 0116, Int J Radiat Oncol Biol Phys, 2007. 68(4): p. 1081-7.

[124] Atri, M., Zhang, Z., Dehdashti, F., Lee, S. I., Ali, S., Marques, H., et.al. Utility of PET-CT to evaluate retroperitoneal lymph node metastasis in advanced cervical cancer: Results of ACRIN6671/GOG0233 trial, Gynecol Oncol, 2016. 142(3): p. 413-9., https://www.ncbi.nlm.nih.gov/pubmed/27178725

[125] Han, S., Kim, H., Kim, Y. J., Suh, C. H., Woo, S., Prognostic Value of Volume-Based Metabolic Parameters of (18)F-FDG PET/CT in Uterine Cervical Cancer: A Systematic Review and Meta-Analysis, AJR Am J Roentgenol, 2018. 211(5): p. 1112-1121., https://www.ncbi.nlm.nih.gov/pubmed/30207790

[126] Liu, F. Y., Lai, C. H., Yang, L. Y., Wang, C. C., Lin, G., Chang, C. J., et.al. Utility of (18)F-FDG PET/CT in patients with advanced squamous cell carcinoma of the uterine cervix receiving concurrent chemoradiotherapy: a parallel study of a prospective randomized trial, Eur J Nucl Med Mol Imaging, 2016. 43(10): p. 1812-23., https://www.ncbi.nlm.nih.gov/pubmed/27160224

[127] Ding, X. P., Feng, L., Ma, L., Diagnosis of recurrent uterine cervical cancer: PET versus PET/CT: a systematic review and meta-analysis, Arch Gynecol Obstet, 2014. 290(4): p. 741-7., https://www.ncbi.nlm.nih.gov/pubmed/24798933

[128] Xiao, Y., Wei, J., Zhang, Y., Xiong, W., Positron emission tomography alone, positron emission tomography-computed tomography and computed tomography in diagnosing recurrent cervical carcinoma: a systematic review and meta-analysis, Arch Med Sci, 2014. 10(2): p. 222-31., https://www.ncbi.nlm.nih.gov/pubmed/24904653

[129] Meads, C., Auguste, P., Davenport, C., Malysiak, S., Sundar, S., Kowalska, M., et.al. Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling, Health Technol Assess, 2013. 17(12): p. 1-323., http://www.ncbi.nlm.nih.gov/pubmed/23537558

[130] Meads, C., Davenport, C., Malysiak, S., Kowalska, M., Zapalska, A., Guest, P., et.al. Evaluating PET-CT in the detection and management of recurrent cervical cancer: systematic reviews of diagnostic accuracy and subjective elicitation, BJOG, 2014. 121(4): p. 398-407., https://www.ncbi.nlm.nih.gov/pubmed/24299154

[131] Brooks, R. A., Rader, J. S., Dehdashti, F., Mutch, D. G., Powell, M. A., Thaker, P. H., et.al. Surveillance FDG-PET detection of asymptomatic recurrences in patients with cervical cancer, Gynecol Oncol, 2009. 112(1): p. 104-9.

[132] Schwarz, J. K., Siegel, B. A., Dehdashti, F., Grigsby, P. W., Association of posttherapy positron emission tomography with tumor response and survival in cervical carcinoma, Jama, 2007. 298(19): p. 2289-95.

[133] Arbyn, M., Anttila, A., Jordan, J., Ronco, G., Schenck, U., Segnan, N., et.al. European Guidelines for Quality Assurance in Cervical Cancer Screening. Second edition-summary document, Ann Oncol, 2010. 21: p. 448-58., https://www.ncbi.nlm.nih.gov/pubmed/20176693

[134] Testa, A. C., Di Legge, A., De Blasis, I., Moruzzi, M. C., Bonatti, M., Collarino, A., et.al. Imaging techniques for the evaluation of cervical cancer, Best Pract Res Clin Obstet Gynaecol, 2014. 28(5): p. 741-68., https://www.ncbi.nlm.nih.gov/pubmed/24861248

[135] Pinkavova, I., Fischerova, D., Zikan, M., Burgetova, A., Slama, J., Svarovsky, J., et.al. Transrectal ultrasound and magnetic resonance imaging in the evaluation of tumor size following neoadjuvant chemotherapy for locally advanced cervical cancer, Ultrasound Obstet Gynecol, 2013. 42(6): p. 705-12., https://www.ncbi.nlm.nih.gov/pubmed/23495185

[136] Alcazar, J. L., Arribas, S., Minguez, J. A., Jurado, M., The role of ultrasound in the assessment of uterine cervical cancer, J Obstet Gynaecol India, 2014. 64(5): p. 311-6., https://www.ncbi.nlm.nih.gov/pubmed/25368452

[137] Palsdottir, K., Fischerova, D., Franchi, D., Testa, A., Di Legge, A., Epstein, E., Preoperative prediction of lymph node metastasis and deep stromal invasion in women with invasive cervical cancer: prospective multicenter study using 2D and 3D ultrasound, Ultrasound Obstet Gynecol, 2015. 45(4): p. 470-5., https://www.ncbi.nlm.nih.gov/pubmed/25092154

[138] Huang, Y. F., Cheng, Y. M., Wu, Y. P., Chen, H. H., Hsu, K. F., Wu, Y. H., et.al. Three-dimensional power Doppler ultrasound in cervical carcinoma: monitoring treatment response to radiotherapy, Ultrasound Obstet Gynecol, 2013. 42(1): p. 84-92., https://www.ncbi.nlm.nih.gov/pubmed/22744872

[139] Testa, A. C., Ferrandina, G., Moro, F., Pasciuto, T., Moruzzi, M. C., De Blasis, I., et.al. PRospective Imaging of CErvical cancer and neoadjuvant treatment (PRICE) study: role of ultrasound to predict partial response in locally advanced cervical cancer patients undergoing chemoradiation and radical surgery, Ultrasound Obstet Gynecol, 2018. 51(5): p. 684-695., https://www.ncbi.nlm.nih.gov/pubmed/28620930

[140] Byun, J. M., Kim, Y. N., Jeong, D. H., Kim, K. T., Sung, M. S., Lee, K. B., Three-dimensional transvaginal ultrasonography for locally advanced cervical cancer, Int J Gynecol Cancer, 2013. 23(8): p. 1459-64., https://www.ncbi.nlm.nih.gov/pubmed/24257560

[141] Bakay, O. A., Golovko, T. S., Use of elastography for cervical cancer diagnostics, Exp Oncol, 2015. 37(2): p. 139-45., https://www.ncbi.nlm.nih.gov/pubmed/26112943