7. Pathology – Cervical Carcinoma

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

Major changes in the chapter on pathology

Major changes in the chapter on pathology due to the guideline update:

Pathological diagnosis and prognostic factors: the section on pathological diagnosis and prognostic factors has been extensively revised.

Current studies have shown that a histopathologically based definition of growth patterns, mainly based on tissue architecture criteria (known as Silva patterns), in adenocarcinoma of the uterine cervix has prognostic relevance. These patterns have so far been best studied in high-risk HPV-associated adenocarcinoma of the endocervical subtype (not otherwise specified, NOS). Whether the Silva pattern is also prognostically relevant in other histological subtypes of cervical adenocarcinoma cannot be conclusively assessed at present.

The International Endocervical Adenocarcinoma Classification (IECC) was developed in 2019. It classifies cervical adenocarcinoma in principle into HPV-associated and non–HPV-associated carcinomas and their respective subtypes. This classification also has prognostic significance.

Although the usefulness of these two new classifications (Silva pattern and IECC) still needs to be confirmed by prospective clinical studies and they do not have any therapeutic implications results at present, they are presented in the guideline.

The redefinition of the stages of cervical carcinoma proposed by FIGO in 2018 is presented and discussed in the guideline. However, it is not applied.

The definition of multifocality in microinvasive cervical carcinoma is new — see Recommendation 7.9 on multifocal microinvasive carcinoma.

Taking intratumoral heterogeneity into account, which can occur particularly in adenocarcinomas, there are now specific procedural instructions for the extent of work-up relative to tumor size — see Recommendation 7.13 on intratumoral heterogeneity.

A recommendation on the documentation of isolated tumor cells (ITCs) and micrometastases (pN1mic) in lymph nodes in accordance with the TNM system requirements has been newly included — see Recommendation 7.19 on isolated tumor cells and micrometastases.

The sentinel lymph-node approach is also becoming increasingly important in cervical carcinoma. For this purpose, a separate section on work-up and reporting, including any intraoperative quick-section examinations that may be needed, has been newly created — see Recommendations 7.21, 7.22, and 7.23.

The section on morphological prognostic factors has been completely revised.

See the section on pathological diagnosis and prognostic factors, including:

Modified Recommendation 7.15, on reporting findings after radical hysterectomy
New Recommendation 7.9, on multifocal microinvasive carcinoma
New Recommendation 7.13, on intratumoral heterogeneity
New Recommendation 7.19, on isolated tumor cells and micrometastases
New recommendations 7.21, 7.22, and 7.23, on sentinel lymph nodes

L.-C. Horn, B. Pöschel, D. Schmidt

7.1 Classification of invasive cervical carcinomas

7.1.1 Classifying tumor types

Cervical carcinomas are classified typologically in accordance with the WHO classification of tumors of the female genitalia [142].

7.1 · Consensus-based Recommendation · checked 2021

Tumor classification shall be carried out on the basis of the currently valid edition of the WHO classification.

Consensus: Strong consensus

7.2 · Consensus-based Recommendation · checked 2021

In cervical carcinomas with neuroendocrine components, the latter shall be reported along with the percentage of the total tumor that they represent.

Consensus: Strong consensus

The majority of invasive cervical carcinomas are squamous cell carcinomas (≈ 80%) and adenocarcinomas (≈ 5–20%) [143]. Other tumor entities are rare.

Prognostically unfavorable tumor types include in particular neuroendocrine carcinomas (large-cell or small-cell) and non–HPV-associated adenocarcinomas, with the exception of clear cell adenocarcinomas. Serous carcinoma has been deleted from the current WHO classification. The WHO classification distinguishes between neuroendocrine tumors (low grade) and neuroendocrine carcinomas (high grade) [144]. One-quarter to one-third of all neuroendocrine carcinomas (high grade) have a non-neuroendocrine component [145] [146]. Due to the extremely poor prognosis [146] [147] [148] [149] [150] and possible modifications of treatment resulting when there is evidence of neuroendocrine differentiation, the latter should be explicitly stated in the pathology report, with details of the percentage of the neuroendocrine component as part of the overall tumor [145] [151] [152].

7.1.2 Staging of cervical carcinoma

7.3 · Consensus-based Recommendation · modified 2021

Staging shall be carried out in accordance with the current edition of the TNM classification.

Consensus: Strong consensus

Change note

The staging should follow the latest edition of the TNM classification.

Postoperative staging is carried out optionally in accordance with the TNM classification [87] (see also Table 19). In principle, a distinction is made between microinvasive and macroinvasive carcinomas.

7.4 · Consensus-based Recommendation · checked 2021

A diagnosis of microinvasive cervical carcinoma shall be based on the definitions given in the current editions of both the WHO and TNM classifications.

Consensus: Strong consensus

Microinvasive cervical carcinoma is an exclusively histological diagnosis (see Table 9). Stage pT1a1 is defined as a tumor with stromal invasion ≤ 3 mm and a horizontal extension of ≤ 7 mm [86][87]. Stage pT1a2 consists of tumors with stromal invasion > 3 mm to ≤ 5 mm and a horizontal extension of ≤ 7 mm.

In 2018/2019, FIGO made the suggestion that microinvasive cervical carcinoma should be defined only by depth of invasion with the above thresholds, omitting horizontal tumor extension — but without citing studies to support this approach [153] [154]. However, this change would have had a fundamental impact on staging classifications and also on staging-based therapy [95]. In addition, a revision of the TNM classification by the American Joint Committee on Cancer (AJCC) and UICC is not expected until 2025, so that it is recommended that the current TNM classification should be retained (see Table 19). The guideline committee has therefore decided not to implement the new FIGO classification at present. For supplementary information, the classification proposed by FIGO can be included in a commentary on the histopathological findings report [95].

The new 2018 FIGO classification has been evaluated below and confirms the improved prognostic discrimination of stage IB/T1b and the less favorable prognosis for patients with para-aortic lymph-node metastases [155], [156]. These studies do not address the new definition of stage IA/T1a.

In microinvasive squamous cell carcinoma, stromal invasion is measured from the base of the underlying CIN 3 lesion — located either superficially or growing into endocervical glands [157]. In microinvasive adenocarcinoma, stromal invasion is measured from the base of the underlying gland of the adenocarcinoma in situ (ACIS).

7.1.3 Definition of TNM-relevant parameters

Perineural sheath infiltration (Pn) is defined as evidence of tumor cells in the perineural spaces, independently of the extent of the tumor cells within the spaces and independently of whether or not the nerve itself is infiltrated [158] [159].

Lymphatic vessel infiltration (L category) consists of evidence of individual tumor cells or groups of tumor cells located inside spaces that are clearly lined with (lymph) endothelia (L1) [160]. The TNM committee has stated that when there is evidence of tumor cells within spaces without a clear endothelial lining, the findings are to be classified as L0 (no lymphatic infiltration) [160], as this usually represents contraction-related fixation artifacts. However, routine use of immunohistochemistry to identify lymphatic endothelia (e.g., D2-40) is not indicated outside of research studies. Quantification of lymphatic infiltration, as described for example in endometrial carcinoma [161] [162] is not recommended in cervical carcinoma due to the lack of a generally accepted definition as well as relevant studies.

With Invasion in veins (V category), a distinction is made between macroscopically visible (V2) and histologically confirmed venous infiltration (V1) [87]. Macroscopic venous infiltration is not relevant in cervical carcinoma. The microscopic V1 category is defined in the TNM system as evidence of tumor cells inside the lumen of the vein and/or evidence of tumor cells infiltrating the venous wall [160].

Grading is not relevant in the staging of cervical carcinoma, but should form an integral part of the documentation of findings (see below) and is also required, among other things, for tumor documentation in the setting of gynecological cancer centers. There is no grading system recommended by the WHO for squamous cell carcinoma or for the majority of adenocarcinomas of the cervix [91]. Despite recent studies on squamous cell carcinoma [163] [164] [165], there is also no accepted and standard grading system for squamous cell carcinoma as yet [166] [167]

For primary endometrioid adenocarcinoma of the cervix, grading analogous to the FIGO grading of endometrioid adenocarcinoma of the endometrium is recommended [91] [166]. However, findings in recent years suggest that the majority of endometrioid cervical carcinomas are a variant of the endocervical subtype adenocarcinoma (not otherwise specified, NOS) and that primary endometrioid adenocarcinoma of the cervix usually arising from endocervical endometriosis is extremely rare [168] [169] [170] [171]

The most frequent subtype, at 75%, is adenocarcinoma of the endocervical type (also known as “not otherwise specified,” NOS). A grading system based on the growth pattern has been developed in recent years for these lesions [172] [173] [174]. The pattern is also referred to as the Silva pattern, and the criteria for it are summarized in Table 10 [175] , [176].

The rarest type with pattern A has the fewest lymphatic vessel intrusions and the lowest number of pelvic lymph-node metastases, whereas pattern C has the most lymphatic vessel intrusions and consequently the highest number of lymph-node metastases and is prognostically the most unfavorable [173] [174]. It therefore seems useful to mention the growth pattern, mainly based on architectural tumor criteria, in the report on findings. In this context, it is important to note that this pattern-based system has mostly been studied in the endocervical subtype [173] [174], but may also be applicable to other HPV-associated subtypes of cervical adenocarcinoma [177].

The revised version of the NCCN guidelines recommends the use of the Silva pattern for the endocervical subtype [178].

Table 5: Histological criteria for the different invasion patterns in endocervical adenocarcinoma (the Silva system [158–160])

Pattern classification according to the Silva system (new 2021)
Pattern A	Sharply defined glandular proliferations with round outer contour Often group-shaped storage of the glands No single cell-growth No destructive stromal invasion (no peritumoral desmoplasia) No solid tumor parts Complex intraglandular morphology possible (e.g., cribriform, papillary growth, etc.) No lymphatic vessel invasion
Pattern B	Focal (initial) destructive tumor growth, originating from glands with pattern A morphology Infiltration of small tumor cell groups or single cells adjacent to pattern A proliferates (often associated with peritumoral desmoplasia and/or peritumoral inflammation) Lymphatic infiltration possible No solid tumor components
Pattern C	Diffuse and destructive tumor growth (often in association with high-grade peritumoral desmoplasia) Glandular proliferation with unclear borders and sometimes fragmentation of the glands Confluent glands occupying a low-power field (approx. fourfold magnification; 5 mm²) with evidence of solid tumor components and/or papillary growth and/or mucinous deposits in the stroma Polymorphic tumor cells With or without lymphatic invasion

([176], [177], [178])

7.2 Tissue processing

7.2.1 Diagnostic biopsies

7.5 · Consensus-based Recommendation · checked 2021

The biopsy sample that has been taken shall be processed in step sections.

Consensus: Strong consensus

7.6 · Consensus-based Recommendation · modified 2021

The report on the findings should mention the evidence and the grade of CIN, ACIS (and its variants in the form of stratified mucin-producing intraepithelial lesions [SMILE]), virus-associated changes, and possible invasion.

Consensus: Strong consensus

Change note

The report of findings should comment on the detection and grade of CIN, an ACIS, as well as virus-associated changes and any invasion.

Tissue that is biopsied for histological confirmation of a precancerous lesions or invasive carcinoma must be processed in step sections [179] [180]. This applies in particular to biopsies that have no correlation with the cytological and/or colposcopic findings in the initial sections [179] [181]. Preparing step sections increases the diagnostic certainty in relation to the extent of CIN or ACIS, or of a stratified mucin-producing intraepithelial lesion (SMILE), which is a special variant of ACIS, as well as providing evidence of microinvasion. In addition, step sections allow better correlation between the cytological/colposcopic findings and the histological findings (for purposes of quality assurance). At least three step sections at intervals of approximately 200 µm are usually sufficient. The report on the findings should mention the evidence and grade of CIN or ACIS, as well as virus-associated changes that are found on the hematoxylin–eosin (HE) sections, and should note any possible invasion. Routine use of molecular-pathological and/or immunohistochemical methods for identifying HPV is not indicated outside of research studies. In addition, a distinction is made between low-grade squamous intraepithelial lesions (LSIL; = CIN 1) and high-grade squamous intraepithelial lesions (HSIL; = CIN 2 and CIN 3/CIS) [86].

When there is evidence of invasion, information about lymphatic, vascular, and perineural sheath invasion must also be given [182] [183] [184] [185].

7.2.2 Conizations

7.7 · Consensus-based Recommendation · checked 2021

The pathology report shall state the size and characteristics of the excised (conization) specimen. The conization specimen shall be completely processed and step sections must be prepared from each paraffin block.

Consensus: Strong consensus

7.8 · Consensus-based Recommendation · modified 2021

The histological report shall note the type of lesion (CIN, ACIS and its variants in the form of stratified mucin-producing intraepithelial lesions [SMILE]), its location (endocervical, ectocervical), and its extent, as well as the presence of invasive tumor. When there is evidence of invasion, details shall also be given of its extent and of lymphatic, vascular and perineural sheath invasion, as well as grading. The status of the resection margins shall also be noted.

Consensus: Strong consensus

Change note

The type of lesion (CIN, ACIS), its location (endocervical, ectocervical) and its extent as well as the presence of an invasive tumour should be noted in the histological report. If invasion is detected, the size extension should also be indicated and a statement made on lymphatic, blood vessel and perineural sheath invasion as well as grading. The status of the resection margins should be commented on.

Diagnostic or therapeutic resection of the transformation zone can be carried out using various techniques — e.g., laser conization, large loop excision of the transformation zone (LLETZ), loop excision, or scalpel conization. In accordance with the Rio nomenclature for colposcopy, the corresponding resection specimens are no longer described as conizations, but as excision types 1–3.

The classification of the excision specimen and the size of the specimen is given in accordance with the 2011 Rio classification (http://www.ifcpc.org/images/docs/nomenclature711.pdf) [186] (see Table 11) and should be carried out by clinicians. Details of the three-dimensional size of the resection specimen are given by the pathologist.

The prerequisite for standardized morphological processing of these excision specimens is the sending of a specimen that is intact and marked (usually with a thread marking at the 12-o’clock position [182] [187] [188] [189]. The report on the pathological findings must provide information about the quality of the excision specimen [182] [183] [185] [188][189]. The size of the specimen should be stated with three-dimensional measurements [190]. The entire excision specimen must be completely processed [182] [183] [185], and the segmental processing technique is preferred [182]. Step sections of each paraffin block must be made [182]. At least three step sections, at intervals of approximately 200 µm, are usually sufficient. Precancerous lesions of the cervix usually arise in the area of the transition from the endocervix to the ectocervix, known as the transformation zone. The report on the findings should therefore mention whether that zone is contained in the excision specimen, or whether and where it is missing [182] [187]. The same applies to evidence of iatrogenic changes (such as thermal damage, for example) of the type that occur during conizations obtained with laser or diathermy techniques [191] [192]. Thermal damage can impair the diagnostic certainty of the histological examination.

The report on the histological findings should note the type of lesion (CIN, ACIS, SMILE), its location (endocervical, ectocervical), and its extent (with details given clockwise — e.g., from the 2-o’clock to 6-o’clock positions). For practical purposes, details of the extent of a precancerous lesion can be given in millimeters [190]. When there is evidence of invasion, details of its size must be given along with information about lymphatic, vascular, and perineural sheath invasion [182] [183] [184] [185].

Microinvasive carcinomas may be multifocal [193] [194] [195]. On the basis of previous studies, albeit with limited case numbers [194] [195], multifocal growth is defined by the International Collaboration on Cancer Reporting (ICCR) as evidence of invasive foci that are histologically clearly separate from each other at a minimum distance of 0.2 cm [167]. The ESGO guideline on cervical carcinoma states that the size of each invasive tumor should be reported separately, with the largest single lesion being relevant for staging [188] [189]. To exclude a confluence of various separate invasive foci, it is useful to make (additional) step sections.

7.9 · Consensus-based Recommendation · new 2021

A multifocal microinvasive carcinoma is defined as evidence of invasive foci that are histologically clearly separate from each other at a minimum distance of 0.2 cm.

The size of each invasive tumor focus shall be reported separately, with the largest single lesion being relevant for staging.

Consensus: Strong consensus

Precise details on the status of the resection margins (free, involved [196], [197], [198], [199], [200], [188], [189], are obligatory, and firm details should be given on the vaginal (ectocervical), endocervical, and lateral margins (soft-tissue resection margin of the cervical stroma), preferably with information about the measured distance from the resection margin.

When each resection margin is being checked and HPV-induced, non-precancerous changes are being distinguished, p16 immunohistochemistry can be recommended in cases of doubt, and with glandular lesions Ki-67 immunohistochemistry as well [196], [201], [202].

Table 6: Rio classification (2011), addendum 1

Addendum (checked 2021)

Excision types

Type 1 – flat; type 2 – medium; type 3 – steep

[Editors’ note: by analogy with the nomenclature for the transformation zone]

Dimensions of conization specimens

Height (length): distance from the cervical to the vaginal resection border

Width (thickness): distance from the stromal resection border to the epithelial surface

Circumference (optional): perimeter of the opened cone specimen

7.2.3 Cervicectomy

7.10 · Consensus-based Recommendation · checked 2021

Morphological processing shall take place in such a way that all therapeutically and prognostically relevant parameters can be assessed. The report shall be produced on the basis of the currently valid WHO classification for tumor type and the current TNM classification for staging, as well as the R classification (UICC).

Consensus: Consent

7.11 · Consensus-based Recommendation · modified 2021

The tracheclectomy report shall include the following details:

Histological type (WHO)
Grading
Presence/absence of lymphatic or venous invasion (L and V status)
Presence/absence of perineural sheath infiltration (Pn status)
Staging (TNM),
Depth of invasion and extent in millimeters in pT1a1 and pT1a2
Three-dimensional tumor size in centimeters (from pT1b1)
Minimum distance from the resection margins (endocervical stroma in pT1b tumors)
R classification (UICC).

Consensus: Consent

Change note

The report of findings for trachelectomy should include the following information: - histological type according to WHO, - grading, - evidence/absence of lymphatic or venous infiltrates (L- and V- status), - evidence/absence of perineural sheath infiltrates (Pn-status), - staging (TNM), - depth of invasion and extension in mm for pT1a1 and pT1a2, - three-dimensional tumor size in cm (from pT1b1), - minimal distance to resection margins, - R-classification (UICC).

The prerequisite for standardized morphological processing is the sending of a specimen that is intact and marked (usually with a thread marking at the 12-o’clock position [197], [203]). The report on the pathological findings must provide information about the size and quality of the excision specimen (cervix component, parametria, vaginal cuff if appropriate) [198], [200], [188], [189]. The ESGO guideline recommends that changes following a previous conization should be described (e.g., erosions, ulcerations) [188], [189]. The specimen should be completely processed [198], [200], this applies in particular to the proximal and vaginal resection margins [188], [189]. The processing should be carried out in such a way that all the details required as listed in the section on radical hysterectomy can be collected [198], [199], [200], [204]. The ESGO guideline recommends complete embedding/processing of the resected parametrial tissue [188], [189]. The ICCR does not comment on this [167].

The report on the findings must be based on the WHO classification of tumor types [91] and the current pTNM classification for staging [87] and the R classification must be based on the current UICC classification for (see also Table 20), which is an obligatory component of the pTNM classification. For the definition and staging of multifocal (microinvasive) carcinomas, see section 7.2.2.

If the transformation zone has previously been excised (known as conization) and in the presence of findings, the tumor size from the conization specimen and from the cervicectomy specimen should be combined to calculate the final tumor size. It is useful to note here that the additively measured tumor size is a calculated tumor size, which may also combine findings from different pathologies [167], [188], [189]. If conization and cervicectomy have been assessed in different pathologies, the measurement of the calculated tumor size is the responsibility of the gynecologists who last handled the case.

If there is evidence of adenocarcinoma, then it is currently recommended as an option that details on the growth pattern (known as the Silva pattern [172], [174], [178]; (see Table 10 and section 7.1.3) and the IECC classification [177]; see section 7.3 and Table 12) should be given [167].

7.2.4 Specimen after radical hysterectomy

7.12 · Consensus-based Recommendation · checked 2021

Consensus: Strong consensus

If a conization was performed prior to (radical) hysterectomy, it is useful to include the relevant macroscopically visible changes in the macroscopic description (e.g., erosions, ulcerations) [188], [189].

Morphological processing should be carried out in such a way that all of the details given in the following list can be obtained [167], [197], [198], [199], [200], [188], [189], [204], [205]. The report on the findings must be based on the WHO classification for tumor type [78] and on the current TNM classification for staging [206], as well as the current UICC classification for the R classification, which is an obligatory component of the pTNM classification.

The ESGO guideline here recommends, among other things, complete embedding/processing of the resected parametrial tissue, as well as of the distal vaginal resection margin [188], [189], [205].

In order to record the intratumoral heterogeneity that has been reported in particular with adenocarcinomas [207], [208], [209] and also neuroendocrine carcinomas [145], [146], the ESGO recommends complete processing of macroscopically visible tumors < 2 cm and embedding of at least one block per centimeter at the greatest tumor extension in tumors larger than 2 cm [188], [189]. Adequate embedding of tumor tissue also appears to be important in relation to the precise assignment of the invasion pattern in the endocervical subtype of adenocarcinoma [174].

7.13 · Consensus-based Recommendation · new 2021

To document intratumoral heterogeneity, macroscopically visible tumors ≤ 2 cm in size should be completely processed and at least one block per centimeter at the greatest tumor extension should be embedded from tumors larger than 2 cm.

Consensus: Strong consensus

The report on findings is to be based on the WHO classification for tumor typing [88] and the current pTNM classification for staging [89], as well as the current UICC classification for R classification (see Table 20), which is an obligatory component of the pTNM classification. For the definition and staging of multifocal (microinvasive) carcinomas, see section 7.2.2 on conizations.

After previous excision of the transformation zone (known as conization) and presentation of the findings, the tumor sizes from the previous conization specimen and/or from the previous cervicectomy specimen should be combined in order to calculate the final tumor size. It is useful to note here that the additively measured tumor size is a calculated tumor size that may combine findings from different pathologies [167], [188], [189]. If conization and trachelectomy have been assessed in different pathologies, the assessment of the calculated tumor size is the responsibility of the gynecologists who last handled the case.

Standard factors required for the report on histological findings in hysterectomy specimens are [167], [178], [198], [210], [188], [189], [205], [211]:

WHO histological type
Grading
Presence/absence of lymphatic or venous invasion (L and V status)
Presence/absence of perineural sheath infiltration (Pn status)
Staging (TNM and FIGO)
Depth of invasion and extent in millimeters in pT1a1 and pT1a2
Three-dimensional tumor size in centimeters (from pT1b1)
Minimum distance from the nearest resection margin of the endocervical stroma in pT1b tumors
Minimum distance from the vaginal margin in pT2a tumors
Distance from the lateral (parametrial) margin in pT2b
R classification (UICC)

Measurement of the distance from each resection margin is carried out at the point of deepest tumor infiltration to the surgical resection margin, either after marking with a ruler on the microscopic slide or using an ocular micrometer for small distances.

Studies in recent years have shown in adenocarcinoma that the growth pattern (known as the Silva pattern; see Table 10 and section 7.1.3) correlates with tumor stage, evidence of lymphatic invasion, and lymph-node metastases, and that it is relevant for the prognosis [172], [173], [174], [175]. In accordance with the ICCR recommendation [167] and the 2020 revised version of the NCNN guidelines [178], it is recommended that the growth pattern should be mentioned in the histological findings.

Mention of the IECC classification of an adenocarcinoma [170]; (see section 7.3 and Table 12) is optional, but recommended.

7.14 · Consensus-based Statement · checked 2021

Deep stromal infiltration is defined as invasion by the cervical carcinoma into the outer third of the cervical stroma (> 66%).

Consensus: Strong consensus

In the majority of studies, deep stromal infiltration is defined — due to its prognostic importance — as invasion of the cervical carcinoma into the outer third of the cervical stroma (> 66% [107], [212]). The ICCR classifies depth of infiltration as a “required data item” [167], and it should therefore be reported in the findings. Measurement of the depth of infiltration is carried out, by analogy with measurement of endometrial carcinoma, from the level of the cervical mucosa to the deepest point of tumor infiltration. This value is expressed as a proportion of the total thickness of the cervix, obtained from a measurement from the level of the cervical mucosa to the transition between the cervical stroma and the parametrium.

The relative stromal infiltration is the ratio of the measured deepest point of tumor infiltration relative to the total thickness of the cervical wall [213] [205].

7.15 · Consensus-based Recommendation · modified 2021

The radical hysterectomy report shall include the following details:

WHO histological type
Grading
Presence/absence of lymphatic or venous invasion (L and V status)
Presence/absence of perineural sheath infiltration (Pn status)
Staging (TNM), taking the conization findings into account in patients who have undergone conization
Depth of invasion and extension in millimeters in pT1a1 and pT1a2
Depth of invasion relative to the cervical wall thickness (measurement or percentage figure)
Three-dimensional tumor size in centimeters (from pT1b1)
Minimum distance from the resection margins (endocervical stroma in pT1b tumors, vagina in pT2a tumors, and parametrium in pT2b tumors)
R classification (UICC)

Consensus: Strong consensus

Change note

The findings report for radical hysterectomy should include the following information: - histological type according to WHO, - grading, - evidence/absence of lymphatic or venous invasion (L- and V- status), - evidence/absence of perineural sheath infiltrates (Pn-status), - staging (TNM), depth of invasion and extension in mm for pT1a1 and pT1a2, - three-dimensional tumour size in cm (from pT1b1), - minimum distance to the resection margins, - R-classification (UICC).

If the transformation zone has previously been excised (known as conization) and in the presence of findings, the tumor size from the conization specimen and from the hysterectomy specimen should be combined to calculate the final tumor size.

7.2.5 Lymphadenectomy specimens

7.16 · Consensus-based Recommendation · checked 2021

Micrometastases are defined as histological evidence of tumor cells in lymph nodes measuring ≥ 0.2 mm, but no larger than 0.2 cm.

Consensus: Strong consensus

7.17 · Consensus-based Recommendation · checked 2021

In lymphadenectomy specimens obtained during surgical treatment for cervical carcinoma, all removed lymph nodes shall be histologically examined.

Consensus: Strong consensus

7.18 · Consensus-based Recommendation · checked 2021

Lymph nodes up to approx. 0.3 cm in size should be completely paraffin-embedded, and larger lymph nodes should be halved along the long axis and also completely paraffin-embedded.

Consensus: Strong consensus

With lymphadenectomy specimens obtained during surgery for cervical carcinoma, all removed lymph nodes must be histologically examined. Lymph nodes up to approximately 0.3 cm in size should be completely paraffin-embedded, and larger lymph nodes should be halved along their long axis and also completely paraffin-embedded [183] [184] [185] [213]. Preparing step sections increases the chances of detecting small metastases or micrometastases [214].

In accordance with the UICC and TNM classifications, micrometastases are defined as histological evidence of tumor cells in lymph nodes ≥ 0.2 mm, but no larger than 0.2 cm [215] [160]. Tumor cells with an overall size of < 0.2 mm are defined as isolated tumor cells in the lymph node [215] [160].

The prognostic and therapeutic significance of isolated tumor cells is as yet unclear, as is molecular-biological evidence of HPV DNA in pelvic or para-aortic lymph nodes. The same also applies to isolated evidence of lymphatic invasion in perinodal adipose tissue or in the lymph-node capsule without the simultaneous presence of lymph-node metastases. Isolated evidence of lymphatic invasion in perinodal adipose tissue or in the lymph-node capsule without the simultaneous presence of lymph-node metastases should be mentioned in the findings report and should classified as L1 [205].

In a revision of the FIGO classification of cervical carcinoma, FIGO has proposed that evidence of isolated tumor cells should not be mentioned in the report [153]. This suggestion by FIGO contradicts the general TNM staging recommendations [160]. As there are insufficient data, the prognostic significance of isolated tumor cells in cervical carcinoma is unclear [216], [217]. However, evidence of isolated tumor cells should still be stated in the findings report [95], [188], [189], [205].

7.19 · Consensus-based Recommendation · new 2021

Evidence of isolated tumor cells or micrometastases should be mentioned in the histological report and included in the TNM classification.

Consensus: Strong consensus

7.20 · Consensus-based Recommendation · checked 2021

The report on lymph nodes shall include the following details: number of affected lymph nodes relative to the number of lymph nodes removed, correlated with the location of removal (pelvic/para-aortic).

Consensus: Consent

Standard factors required for the report on histological findings in lymphadenectomy specimens are [183] [184] [185] [213]:

Details of the number of removed/examined lymph nodes, correlated with the removal site
Details of the number of affected lymph nodes relative to the number of lymph nodes removed/examined, correlated with the removal site (e.g., 4/12 left communicating lymph nodes)
Details of largest extension of the largest lymph-node metastasis, in mm/cm
Details of the presence/absence of capsule penetration by the lymph-node metastasis

7.2.6 Sentinel lymph nodes

7.21 · Consensus-based Recommendation · checked 2021

Sentinel lymph nodes in cervical carcinoma shall be completely paraffin-embedded and examined in step sections.

Consensus: Strong consensus

A standardized protocol for the histopathological examination of sentinel lymph nodes in cervical carcinoma is not currently available [167], [189], [217], [218], [219]. On the basis of the results of larger studies [218], [220], [221], [222], [223] and the ESGO guideline, the following procedure is recommended for the processing of sentinel lymph nodes [188], [189], [219]:

Lamellation of the adipose tissue that has been received, with identification of all sentinel lymph nodes
Complete embedding of all lymph nodes,
Halving of all lymph nodes ≤ 0,3 cm in size
Lamellation of all lymph nodes > 0, 3 cm into 0,2 cm thick lamellae
Preparation of step sections (see below),
Immunohistochemical ultrastaging (see below).
With sentinel lymph nodes that cannot be identified macroscopically, complete embedding of the adipose tissue

7.22 · Consensus-based Recommendation · new 2021

Sentinel lymph nodes in cervical carcinoma should be processed as follows:

Lamellation of the adipose tissue that has been received, with identification of all sentinel lymph nodes
Complete removal of all lymph nodes
Halving of all lymph nodes ≤ 0.3 cm in size,
Lamellation of all lymph nodes > 0.3 cm into 0.2 cm thick lamellae
Preparation of step sections
Immunohistochemical ultrastaging
With sentinel lymph nodes that cannot be identified macroscopically, complete embedding of the adipose tissue

Consensus: Strong consensus

There are no generally valid recommendations for the preparation of step sections [167], [189], [204], [219]. In analogy with other AWMF guidelines and previous recommendations [204], [205], at least three step sections should be made from the paraffin blocks, each at a maximum distance of 200 µm, and HE-stained.

If no tumor cells can be detected in the HE-stained section specimens, immunohistochemical examination with one (or more) pancytokeratin antibodies (known as “ultrastaging”) is useful [217], [218], [219], [220], [221]. In addition, an antibody against p16 can be used. It should be noted that not all histological tumor types are p16-positive, particularly in adenocarcinoma [170], [224], [225].

There are no generally valid guidelines for intraoperative quick-section examination of sentinel lymph nodes in cervical carcinoma [167], [217], [226] The ESGO guideline on cervical carcinoma recommends [188]:

Macroscopic work-up, as described above
Examination of ALL sentinel lymph nodes in quick section
If there is a macroscopically visible tumor, intraoperative examination of a sample of the involved lymph node is sufficient
Macroscopically unremarkable lymph nodes must be examined completely intraoperatively
Step sections (three) should be made from the frozen blocks (see below)
The histological frozen-section examination can be supplemented with intraoperative imprint cytology

7.23 · Consensus-based Recommendation · new 2021

Intraoperative rapid frozen-section examination (when clinically indicated) of sentinel lymph nodes in cervical carcinoma should be performed as follows:

Standard work-up of the sentinel lymph nodes
Examination of ALL sentinel lymph nodes in quick section
If there is a macroscopically visible tumor, intraoperative examination of a sample of the involved lymph node is sufficient
Macroscopically unremarkable lymph nodes must be examined completely intraoperatively
Step sections (three) should be made from the frozen blocks
The histological frozen-section examination can be supplemented with intraoperative imprint cytology

Consensus: Strong consensus

The ESGO guideline does not comment on the number of step sections in the context of quick-section examinations [189]. In analogy with the recommendations in other AWMF guidelines (e.g., vulvar and vaginal carcinoma, endometrial carcinoma) and with the above-mentioned recommendations on the work-up of sentinel lymph nodes in the paraffin block, preparation of three step sections from the frozen block appears useful.

With lymph nodes that are free of tumor in the quick section, the work-up and ultrastaging should be carried out as described above.

7.3 Morphological prognostic factors

Established prognostic factors in cervical carcinoma include the tumor stage and evidence of pelvic or para-aortic lymph-node metastases [227], [228], [229], [230], [231], [232], [233].

The prognostic relevance of a positive resection margin after radical hysterectomy is a comparatively rarely studied parameter. The majority of studies have reported unfavorable recurrence-free and overall survival rates [227], [234] [148], [235], [236], [237]. However, this unfavorable prognostic significance can be positively influenced by adjuvant radiotherapy or radiochemotherapy [230].

Tumor size is an established prognostic factor, independently of the tumor type [232], [238], [239], [240], and it is relevant for staging in FIGO stage IB/T1b (FIGO IB1/T1b1 versus FIGO IB2/T1b2 [231] or, in accordance with a proposal made by FIGO: FIGO IB1/T1b1 versus FIGO IB2/T1b2 versus FIGO IB3/T1b3 [153], [154]. It has been shown in recent years that FIGO IB1/T1b1 tumors ≤ 2 cm are associated with a better prognosis than tumors 2–4 cm in size [240], [241] so that a more limited radical surgical approach may be possible [242]. FIGO has therefore proposed further subdividing IB/T1b tumors on the basis of the tumor size [153], [154]: FIGO IB1/T1b1 macroinvasive tumors ≤ 2 cm in size, FIGO IB2/T1b2 tumors 2–4 cm in size, and FIGO IB3/T1b3 tumors > 4 cm in size.

In FIGO stage II/T2, tumor size is prognostically relevant with surgical therapy (cut-off 4 cm [240], [241]), and also with primary radiotherapy (cut-off 6 cm [240]).

All other risk factors or prognostic factors have no predictive, prognostic, or therapeutic relevance as individual factors. It is only with a combination of at least two additional factors that they have any influence on treatment decision-making. pT1a1 tumors with lymphatic vessel invasion are an exception to this. In these cases, sentinel-node biopsy is recommended (see recommendation 8.11.).

With regard to the histological tumor type, it is important that neuroendocrine carcinomas are associated with a poor prognosis [146], [147], [148], [243] With regard to the prognostic distinction between squamous cell carcinoma and adenocarcinoma, there are contradictory findings [230], [244]. In relation to current therapeutic modalities, the distinction between adenocarcinoma and squamous cell carcinoma is apparently of only secondary prognostic relevance [166], [244], [245], [246], [247], [248], [249]. To what extent this will be confirmed when HPV status and specific histological subtypes are taken into account, as well as the IECC classification in adenocarcinoma (see below), is currently unclear. Independently of the HPV status, adenocarcinomas continue to show a less favorable response to radiotherapy alone [246].

The International Endocervical Adenocarcinoma Criteria and Classification (IECC) has been developed on the basis of the HPV status and thus the pathogenetic background [171], [250] (see Table 12). Non–HPV-associated adenocarcinomas here show a significant association with higher age at onset, larger tumors, a larger number of lymphatic vessel invasions or (pelvic) lymph-node metastases, a higher tumor stage, and Silva pattern C [175], [250] — and thus also a less favorable prognosis.

Table 7: International Endocervical Adenocarcinoma Criteria and Classification (IECC) for adenocarcinoma of the cervix uteri [153, 224]

IECC classification (new 2021)
1) HPV-associated adenocarcinomas	a. Endocervical subtype (synonym: usual type, not otherwise specified (NOS) i. Villo-glandular growth ii. Micropapillary growth iii. Endometrioid phenotype (corresponds to secretion-poor variant of endocervical subtype; see text) b. Mucinous subtype i. Intestinal ii. With signet-ring cells iii. Stratified mucin-producing intraepithelial lesions (SMILE) c. Unclassified
1) HPV-negative adenocarcinomas	a. Gastric subtype b. Clear cell subtype c. Mesonephric carcinoma d. Endometrioid subtype e. Unclassified f. (Serous)

IECC classification (new 2021)

1) HPV-associated adenocarcinomas

a. Endocervical subtype (synonym: usual type, not
otherwise specified (NOS)

            i.          Villo-glandular growth
            ii.         Micropapillary growth
            iii.        Endometrioid phenotype (corresponds to
                        secretion-poor variant of endocervical subtype; see text)

b. Mucinous subtype

            i.          Intestinal
            ii.         With signet-ring cells
            iii.        Stratified mucin-producing intraepithelial lesions (SMILE)

c. Unclassified

1) HPV-negative adenocarcinomas

a.         Gastric subtype
b.         Clear cell subtype
c.         Mesonephric carcinoma
d.         Endometrioid subtype
e.         Unclassified
f.          (Serous)

[250], [250]

Independently of HPV association and the IECC classification, studies in recent years have shown that adenocarcinoma with gastric [251] and micropapillary morphology [207], as well as invasive stratified mucin-producing carcinoma [171], [209] are associated with an unfavorable prognosis, with atypical (distant) metastases (particularly in the lung) [252].

Lymphatic infiltration in microinvasive cervical carcinoma was long under debate as having prognostic relevance [253], [254], [255], [256], but the available case numbers were considered too low. A recent study indicates that in both stage pT1a1 and pT1a2, when there is evidence of lymphatic invasion the number of pelvic lymph-node metastases is twice as high, leading to a less favorable prognosis [257]. In macroinvasive squamous cell carcinoma, there is a strong correlation between evidence of lymphatic infiltration and tumor stage, tumor size, depth of invasion into the cervical stroma, and lymph-node metastases [258]. There is a lack of multivariate analyses with Cox regression analysis and studies with larger case numbers of node-negative patients within a defined tumor stage [245], so that lymphatic status in macroinvasive squamous cell carcinoma cannot so far be regarded as a confirmed prognostic factor so far [259]. The evidence for the significance of quantifying lymphatic infiltration in squamous cell carcinoma is considered to be too slight [260]. Quantification of lymphatic infiltration — as described, for example, in endometrial carcinoma [161], [162] — is not recommended in cervical carcinoma, due to the lack of a generally accepted definition and of relevant studies.

In adenocarcinoma of the cervix uteri, lymphatic vessel infiltration correlates with tumor size and depth of invasion [238], as well as with the growth pattern (pattern C) [170], [173], [207]. Quantification of lymphatic infiltration appears to be prognostically relevant in the pattern C growth pattern [171], [207], [261] although there is as yet no generally accepted definition of quantification.

The WHO classification [91], does not have a standardized grading for all of the histological subtypes of cervical carcinoma. For squamous cell carcinoma, what is known as conventional grading, based on the extent of keratinization, is mentioned in the WHO classification [91]. Due to a lack of detailed stage-by-stage and multivariate analyses, very different results have been published for this [107], [262], [263]. A binary grading model based on conventional grading (low-grade versus high-grade cases) may possibly allow better prognostic discrimination [165], [264]. The same applies to a grading system based on the degree of tumor cell dissociation and adapted from colorectal adenocarcinoma, distinguishing between various so-called “budding” types [163]. In summary, however, none of the grading systems so far developed for squamous cell carcinoma currently has sufficient prognostic evidence [167], [245]. In adenocarcinoma, grading analogous to FIGO grading of endometrioid endometrial carcinoma is recommended for the endometrioid subtype [91], [166]. However, there are increasing doubts as to whether primary endometrioid cervical carcinoma is a distinct entity, or rather a variant of the endocervical subtype [170], [171]). The extent to which the growth pattern (known as the pattern system or Silva system [173], [174]; see 7.1.3 above) can be used as a surrogate for grading in the endocervical subtype (not otherwise specified, NOS) or in HPV-associated adenocarcinoma of the cervix uteri, independently of the histological subtype [177], is currently an open question. A grading system based on the degree of tumor cell dissociation and adapted from colorectal adenocarcinoma, distinguishing between different “budding” types with prognostic relevance, has also been reported in one study [265]. This budding-based system shows some overlapping with the above-mentioned Silva patterns. It is currently unclear whether or not certain histological subtypes of cervical adenocarcinoma, such as the HPV-negative gastric subtype [251] and HPV-positive micro-papillary subtype [207] as well as the mostly HPV 18-associated invasive SMILE [171], [209] in analogy with serous endometrial carcinoma, should be classified per se as “high-grade” (G3) due to their unfavorable prognosis.

Assessment of the prognostic relevance of venous infiltration is problematic, as it is too rare, at up to 11% of cases [266] and only few studies have analyzed this parameter [267]. Venous infiltration is not explicitly evaluated in many studies, or infiltration into small veins/venules is subsumed into “vascular invasion” or involvement of the lymphovascular space.

Perineural sheath infiltration is a parameter that has so far only been examined in a few studies in relation to cervical carcinoma [268]. However, a meta-analysis classed it as prognostically relevant [269] although with limited evidence due to the small numbers of cases so far investigated.

The depth of infiltration of cervical carcinoma into the cervical stroma is a parameter that has been investigated in numerous studies [107], [212], [238], [270], [271], [272] It usually has some prognostic significance, but it is often associated with the tumor size and pelvic lymph-node metastases. The definition of deep stromal infiltration is not standardized and varies between > 50% to > 75% in various studies [107], [212], [238], [270], [271], [272], [273]. On the basis of existing research results and to allow standardization of the procedure for future studies as well, infiltration by the carcinoma into the cervical stroma of up to or more than two-thirds (≥ 66%) is defined as deep stromal infiltration. In addition to the relative depth of infiltration, the absolute depth of infiltration is often also examined, but without any definition of standardized threshold values and without multivariate analyses of each cohort. Overall, there is insufficient evidence for deep stromal infiltration as an independent prognostic factor. The ICCR classifies depth of infiltration as a “required data item” [167].

The extent to which the distinction between micrometastases and macrometastases into the pelvic lymph nodes may be of prognostic significance cannot currently be assessed due to the small number of available studies [233], [274], [275], [276]. In addition, evidence of isolated tumor cells and of micrometastases is not infrequently combined into “minimal nodal disease” [153] , [154], [277]. Nevertheless, it appears that patients with conventional lymphadenectomy and evidence of micrometastases have a less favorable prognosis than those without lymph-node involvement [233], [274], [277]. The extent to which this is applicable to patients with sentinel lymph nodes remains to be seen [222]. In addition, evidence of micrometastases is usually an indication for adjuvant radiotherapy, which also applies to a limited extent to isolated tumor cells [216]. Even fewer data area available in relation to evidence of isolated tumor cells or the differentiation between micrometastases and macrometastases in para-aortic lymph nodes [278], [279], [280].

Immunohistochemical ultrastaging of pelvic and para-aortic lymph nodes (outside of the work-up for sentinel lymph nodes) may increase the detection rate for (micro)metastases [278], [279], [280]. Due to the small number of cases, the prognostic significance of this kind of ultrastaging is still insufficiently clear [278], [279], [280].

In recent years, HPV status in cervical carcinoma has been the subject of numerous studies. The rate of HPV-negative squamous cell carcinomas, at < 10 %, is in all probability not prognostically relevant [224], [281]. In contrast, HPV-negative adenocarcinomas represent a group with an unfavorable prognosis [171], [225], [281], [282] HPV-negative adenocarcinomas, in comparison with HPV-positive adenocarcinomas, are associated with significantly older age, greater horizontal tumor extension, greater depth of invasion, more lymphatic invasion, higher tumor stage, and increased destructive tumor growth (Silva pattern C [171], [250]). HPV-negative tumors are mostly gastric or clear cell or mesonephric, and more rarely genuine primary endometrioid adenocarcinomas [171], [250]. For the IECC classification of endocervical adenocarcinoma, which is based on HPV status in addition to morphological criteria [170], reference may be made to the section on histologic tumor types and Table 12. HE staining is usually sufficient to classify adenocarcinoma in the IECC classification, and it can be supplemented by p16 immunohistochemistry if appropriate. HPV assessment and typing are only necessary in individual cases.

The prognostic evidence is limited due to the association between HPV-negative adenocarcinomas and the above-mentioned unfavorable prognostic factors [171], as well as the above (rare) histologic subtypes, and, again, by the lack of stage-by-stage and multivariate analyses. However, histopathological evidence of gastric clear cell or mesonephric adenocarcinoma should be taken into account in decision-making on adjuvant therapy and in the prognostic assessment at the multidisciplinary tumor conference.

Only limited data are currently available on the relevance of molecular marker and of the TCGA classification (based on molecular investigations in the Cancer Genome Atlas project (low-keratin versus high-keratin squamous cell carcinomas) [231], [283], [284]. Probably the most common mutation in cervical cancer is the PIK3CA mutation, accounting for about 33%. There are no differences between squamous cell carcinomas and adenocarcinomas in terms of mutation frequency, but mutant tumors are associated with a significantly shorter survival [285]. KRAS mutation appears to be exclusive to adenocarcinomas [285], although it may be characteristic of mesonephric carcinomas [286]. TCGA analysis has also revealed amplification of immunomodulatory genes [284]. In this context, it is worth mentioning that assessment of intratumoral microsatellite instability [287], as well as the tumor mutational burden (TMB), as well as pathological-anatomical evaluation of PD-L1 expression [288], [289] is also possible a posteriori using archived tumor tissue (FFPE material). Testing PD-L1 expression as a prerequisite for immunomodulatory therapy in locally advanced or recurrent cervical carcinoma has been reported [289], [290], [291]. Pembrolizimab has been approved by the FDA in the United States (FDA 2018), but not currently by the European Medicines Agency (EMA). In the FDA approval, the combined positive score (CPS) with the antibody PD-L1 IHC 22C3 pharmDx kit is on file [178]. In the revised version of the NCCN guidelines, the use of pembrolizumab in second-line therapy is classified as category 2A in terms of its evidence [160], but this requires testing of the tumor tissue with a PD-L1 antibody or an assessment of microsatellite status. In the same setting, the use of neurotrophic tyrosine receptor kinase (NTRK) inhibitors is classified with an evidence level of category 2B after prior testing.

Due to the currently limited state of the data, molecular markers and the TCGA classification do not yet play any role in the prognostic assessment of cervical carcinoma, or as possible therapeutic targets [231], [249], [292], [293], [294], [295], [296], [297].

Table 8: Summary of standard factors, risk factors, and prognostic factors and their therapeutic relevance in microinvasive carcinoma (stage T1a in the TNM classification) (modified 2021)

Name	Standard factor¹	Risk/Prognostic factor	Treatment relevance²
Tumor stage	Yes	Yes	Yes
Tumor type	Yes	Yes (only neuroendocrine)	Unclear
Perineural sheath infiltration (Pn status)	Yes	Unclear	no
Lymphatic vessel infiltration (L-status)	Yes	Unclear (possibly sentinel in pT1a1)	Yes³
Venous invasion (V status)	Yes	Unclear	Yes³
Location (endocervical/ectocervical)	Yes	No	No
Resection margins (R classification)	Yes	Yes	Yes
Grading	Yes	Unclear⁴	No
p16	No (only CIN)	No (only CIN)	No
Ki-67	No (only CIN)	No (only CIN)	No
Depth of invasion and extent in mm	Yes	Yes	Yes⁵
Pelvic lymph node metastases	Yes	Yes	Yes⁶
Micro/macrometastases	Yes	Unclear	Yes (pN0 vs. pN1)
Immunohistochemical ultrastaging of lymph nodes (apart from sentinel nodes)	No	Unclear	No
¹ Standard factors are regarded as factors for tumor classification that are regularly recorded in routine practice and are described in the corresponding sections on specimen processing. ² Treatment relevance refers to the guideline statements. In unclear factors, decisions were taken at expert level. ³ Only in combination with other risk factors, not as an individual factor. ⁴ In addition, G3 is hardly seen in microinvasive carcinoma. ⁵ Depending on the tumor stage. ⁶ Para-aortic lymph nodes are almost excluded in microinvasive carcinoma.

Table 9: Summary of standard factors, risk factors, and prognostic factors and their therapeutic relevance in macroinvasive carcinoma (stage > T1a in the TNM classification) (modified 2021)

Name	Standard- factor¹	Risk/Prognostic Factor	Therapy relevance²
Tumor stage	Yes	Yes	Yes
Tumor type	Yes	Yes (only neuroendocrine)	Yes (only neuroendocrine)
Growth pattern in adenocarcinoma	Yes/no³	Yes (probably only endocervical subtype)	Unclear
Perineural sheath infiltration (Pn status)	Yes	Unclear	No
Lymphatic infiltration (L status)	Yes	Unclear	Unclear
Venous invasion (V status)	Yes	Unclear	Unclear
Location (endocervical/ectocervical)	No	Unclear	No
Resection margins (R classification)	Yes	Yes	Yes
Deep stromal invasion	Yes	Unclear⁴	Yes⁴
Grading	Yes	Yes	Yes⁵
p16	No (only CIN)	No (only CIN)	No
Ki-67	No (only CIN)	No (only CIN)	No
Depth of invasion and extent in mm	Yes	Unclear	No
Three-dimensional tumor size in cm	Yes	Yes⁶	Yes
Pelvic lymph node metastases (N-status)	Yes	Yes	Yes
Para-aortic lymph node metastases (M-status)	Yes	Yes	Yes
Micro-/macrometastases	Yes	Unclear	Yes (pN0 versus pN1)
Isolated tumor cells in lymph nodes	Yes	Unclear	Unclear
Immunohistochemical ultrastaging of lymph nodes (apart from sentiel lymph nodes)	No	Unclear	No
HPV status in adenocarcinoma	No	Unclear⁷	No
PD1/PDL1 testing	No	Unclear	Unclear (poss. in advanced carcinoma)
¹ Standard factors are regarded as factors for tumor classification that are regularly recorded in routine practice and are described in the corresponding sections on specimen processing. ² Treatment relevance refers to the guideline statements. In unclear factors, decisions were taken at expert level. ³ Giving details of what is known as the growth pattern (or Silva pattern) is recommended in particular in the endocervical subtype of cervical adenocarcinoma, where it is evidently of prognostic relevance. Insufficient data are currently available regarding its prognostic relevance in other histological subtypes. ⁴ Various studies, with different definitions. ⁵ Only in combination with two other risk factors, not as an individual factor. ⁶ In FIGO IB/T1b tumors, the cut-off point for maximum tumor extent 2 cm or 4 cm (see text); in FIGO IIA/T2a tumors, the cut-off point is 4 cm. ⁷ HPV-negative adenocarcinomas probably have a more unfavorable prognosis; on this point, see also the IECC classification and WHO 2020.

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