Dataset for the Reporting of Carcinoma of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR) : International Journal of Gynecological Pathology

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Dataset for the Reporting of Carcinoma of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

Park, Kay J. M.D.; Selinger, Christina I. Ph.D.; Alvarado-Cabrero, Isabel M.D., Ph.D.; Duggan, Máire A. M.D.; Kiyokawa, Takako M.D., Ph.D.; Mills, Anne M. M.D.; Ordi, Jaume M.D.; Otis, Christopher N. M.D.; Plante, Marie M.D.; Stolnicu, Simona M.D., Ph.D.; Talia, Karen L. F.R.C.P.A.; Wiredu, Edwin K. M.D., F.W.A.C.P., F.R.C.Path.; Lax, Sigurd F. M.D.; McCluggage, W. Glenn F.R.C.Path.

Author Information
International Journal of Gynecological Pathology 41():p S64-S89, November 2022. | DOI: 10.1097/PGP.0000000000000909
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Abstract

Cervical cancer is the fourth most common malignancy in women worldwide, accounting for >500,000 new cases annually 1. The standardization of pathologic reporting of cervical cancer is crucial for relaying the necessary information for tumor classification, staging, treatment, and prognostication. Many countries expend a great deal of time, effort, and resources to produce their own standardized cancer-reporting datasets. Other countries lack sufficient pathologist workforce and resources to develop or implement standardized cancer-reporting protocols and benefit from the availability of internationally accredited datasets. To that end, the International Collaboration on Cancer Reporting (ICCR) was formed in 2011 by the Royal Colleges of Australasian and United Kingdom Pathologists, the College of American Pathologists and the Canadian Partnership Against Cancer with the aim of reducing the global burden of cancer dataset development and reduplication of effort by different international institutions that commission, publish, and maintain standardized cancer reporting datasets. Since then, the ICCR has formed alliances with an international network of pathology societies from 5 continents.

Improved patient outcomes have been linked to the standardization of data elements, terminology, dataset structure, and recommended methodology 2. The development of internationally standardized datasets encourages uniform best practice pathology reporting and is essential for research and benchmarking in cancer management. The ICCR has committed to synchronize the development of harmonized international datasets with each new World Health Organization (WHO) tumor classification (WHO Blue books) via a strategic partnership with the International Agency for Research on Cancer (IARC) (the organization that is responsible for producing the WHO monographs). In addition, partnerships with organizations responsible for tumor staging [the Union for International Cancer Control (UICC), American Joint Committee on Cancer (AJCC), and the International Federation of Gynecology and Obstetrics (FIGO)], the International Society of Gynecological Pathologists (ISGyP) and other bodies underpin the cancer dataset development process and facilitate the coordination of dataset development with new tumor classifications and updated cancer staging systems.

The ICCR has developed over 50 cancer datasets since its formation a decade ago, including datasets for gynecological neoplasms. A panel of internationally recognized expert pathologists and at least one clinician in each specific field are tasked to develop each evidenced-based dataset. An 8-wk period of international open consultation subjects the datasets to peer review. All ICCR datasets are freely available for global non-commercial use at the following website: http://www.iccr-cancer.org/datasets.

METHODS

The goal of this dataset revision was to review and update the essential pathologic data that are required for cervical cancer diagnosis, staging, prognostication and patient management in accordance with the updated WHO tumor classification and to align with the most recent FIGO staging manual. The update of the standardized dataset ensures that histopathology reports include all current and relevant information presented in a consistent, concise format that complies with the latest international standards. Standardized nomenclature and consistency of content allows cancer data to be aggregated across and between large populations. If datasets implemented in different countries include uniform information, defined in the same way and described using the same terms, meaningful international comparison, benchmarking, and epidemiological analysis are achievable.

The ICCR process of dataset development was produced and ratified in a suite of standard operating procedures (summarized in earlier publications 3–6. The selection process, roles and responsibilities of the chair, expert panel members, the ICCR Dataset Steering Committee (DSC) representative/s on the panel, and the project managers are outlined in guidelines agreed by the DSC. The DSC appointed a chair to develop the 4th edition dataset for reporting of carcinoma of the cervix and identified 9 other expert gynecological pathologists who together with the chair, a gynecological oncologist, the ICCR Series Champion for gynecologic datasets, the DSC representative and the project manager, formed the Carcinoma of the Cervix Dataset Authoring Committee. The Series Champion provided guidance and support to the chair regarding ICCR standards and ensured harmonization across datasets, while the project manager coordinated the development process.

Following the publication of the WHO Classification of Tumors, Female Genital Tumors, 5th edition, 2020, the ICCR identified seven gynecological cancer datasets that needed to be updated or produced. The gynecological dataset suite was developed through a collaboration between the ICCR and the ISGyP. Four new datasets and 3 updated datasets were developed and subjected to an 8-wk period of international open consultation. This consultation involved sending the draft datasets to international stakeholders for comment; the stakeholders predominantly comprise pathology societies and cancer organizations. The expert panel was convened to review and discuss each of the elements in the 4th edition dataset in a series of online meetings and email discussions. The elements under discussion by the expert panel included core and noncore elements. Elements which are unanimously agreed by the panel to be essential for the histologic diagnosis, clinical management, staging or prognosis of cervical cancer were categorized as core. Noncore elements are those which are clinically important, recommended as good practice and should ideally be included in the dataset but are not yet validated or regularly used in patient management. Core elements require evidentiary support at Level III-2 or above [based on prognostic factors in the National Health and Medical Research Council (NHMRC) levels of evidence document and defined as “Analysis of prognostic factors amongst persons in a single arm of a randomized controlled trial”] 7. An element can also be categorized as core with unanimous consensus of the expert panel in the rare occasion where Level III-2 evidence is not available. The collection of all core elements represents the minimum information which should be included in the pathology report. It is not uncommon in many countries to also include most of the noncore elements in the pathology report.

The accompanying commentary comprises explanatory text, diagrams or tables to: (i) clarify core and noncore elements, (ii) provide relevant evidence, and explain why each element is necessary (eg, how does it assist with diagnosis, clinical management or prognosis of the specific cancer); (iii) define the way each element should be reported. The core elements and associated commentaries are presented below, followed by the noncore elements and commentaries. Some dataset items which include an admixture of core and noncore elements are listed in the core data elements section.

RESULTS

Scope of the Dataset

The dataset has been developed for the pathology reporting of primary cervical carcinomas. Specimens reported using this dataset include loop/cone excisions, trachelectomies, simple and radical hysterectomies, and exenterations. The dataset applies to epithelial neoplasms only. Small biopsy specimens are excluded from the dataset.

The 4th edition of this dataset incorporates the 2018 FIGO staging for cancer of the cervix 8,9, with amendments as per the 2019 Corrigendum “Revised FIGO staging for carcinoma of the cervix uteri” 10. This dataset also includes changes to align the dataset with the WHO Classification of Tumors, Female Genital Tumors, 5th edition, 2020 11, and includes 5th edition Corrigenda, June 2021 12.

Core Data Elements

A list of the core elements for the reporting of cervical carcinomas is presented in Table 1 and described below.

TABLE 1 - Core data elements for pathologic reporting of carcinoma of the cervix.
Macroscopic Microscopic
Specimen(s) submitted Tumor site
Specimen dimensions Tumor dimensions
Histologic tumor type
Lymphovascular invasion
Extent of invasion
 Margin status*
 Margin status for invasive tumors
 Margin status for precursor lesions
Lymph node status
Laterality
Number of nodes examined
Number of positive nodes
Coexistent pathology/precursor lesions
Pathologically confirmed distant metastasis
 Provisional pathologic staging
 FIGO or TNM staging (UICC/AJCC 8th edition)
*Involvement by invasive tumor in hysterectomy/trachelectomy or loop/cone specimens, and involvement by precursor lesions high-grade squamous intraepithelial lesion, adenocarcinoma in situ, stratified mucin-producing intraepithelial lesion are core; the distance of tumor from the margin is considered noncore (Table 2).
Squamous intraepithelial lesion/cervical intraepithelial neoplasia, human papillomavirus–associated adenocarcinoma in situ/high-grade cervical glandular intraepithelial neoplasia and stratified mucin-producing intraepithelial lesion are core; the presence of other possible precursor lesions is considered noncore (Table 2).
The number of lymph nodes examined and number of positive nodes are core; the size of maximum tumor deposit is considered noncore (Table 2).
AJCC indicates American Joint Committee on Cancer; FIGO, International Federation of Obstetricians and Gynecologists; UICC, Union for International Cancer Control.

Specimen(s) Submitted

The type of operative procedure undertaken, such as a simple or radical hysterectomy, is defined by the surgeon. A radical trachelectomy or hysterectomy includes resection of the parametrium with parauterine node-bearing tissue. While the nature of the specimen(s) submitted for pathologic assessment can usually be deduced from the procedure, in some cases the tissue submitted may be incomplete or include more components than expected and therefore specifying the anatomic structures included in the specimen(s) provides complementary information and confirmation that entire organ(s) have been resected and submitted 13.

Gynecological oncologists typically divide lymph nodes into anatomic subgroups, and this should be documented in the report.

Specimen Dimension

Cervical specimens include loop/cone excisions, simple and radical hysterectomies, simple and radical trachelectomies, and pelvic exenterations. The cervix is a cylindrical structure and taking into account the various surgical procedures that are carried out to remove it, a conventional approach to measuring the size of the cervix in 3 dimensions is difficult to apply. Measurement is further complicated by differences between laboratories in how they fix and grossly examine the specimens. In loop/cone excisions and trachelectomies, the diameter of the ectocervix (2 dimensions) and the length (corresponding to the length of the endocervical canal) of the specimen should be recorded in millimeters. The metric should be accurate and reproducible since it may be important for documentation, diagnostic and prognostic purposes and therapeutic decision-making 13.

The minimum and maximum cranio-caudal lengths of the vaginal cuff, when present, should be measured in millimeters. If a parametrectomy has been performed, a measurement from the side of the uterus to the lateral edge of each unstretched parametrium (lateral extent) should be recorded in millimeters and it may be useful to specify whether the measurement was taken prefixation or postfixation. Surgically dissected parametrium (formal parametrectomy) is not part of a simple hysterectomy specimen. A small amount of paracervical/parametrial soft tissue may be included in the sections of cervix from a simple hysterectomy. Some pathologists submit this tissue as a paracervical/parametrial shave. Although paracervical/parametrial tissue is present, this does not represent a formal parametrial resection.

Tumor Site

The gross location of cervical tumors in all resection specimens, including hysterectomy specimens and trachelectomies, must be documented. In addition to providing the tumor dimensions (see the Tumor dimensions section) and the proximity of the tumor to surgical resection margins, the relationship to local anatomic structures such as the vaginal cuff, the resected parametrial tissue (if present) as well as involvement of the lower uterine segment and uterine corpus should be documented. Because there may be an increased risk of para-aortic lymph node spread 14 and a higher rate of ovarian metastases 15 in cases with invasion of the uterine corpus, the presence of macroscopic involvement of the uterine corpus should be recorded.

Tumor Dimensions

Reasons for Accurate Tumor Measurement. Measurement of tumor dimensions in cervical carcinomas is important for accurate FIGO staging of early cervical cancers, patient management and prognostication 16,17. The largest measure of horizontal extent and the depth of invasion should be measured in millimeters for all tumors. Although the 2018 FIGO revision removed horizontal extent as a parameter for early stage cervical cancer, it should still be reported as this gives a more complete picture of the extent of tumor and also allows for data collection for future studies to assess the importance of horizontal extent (see the Provisional pathologic staging section) 8,10. Furthermore, the horizontal extent is also important to appreciate the tumor volume. There are multiple problems with regard to measuring cervical tumors and these are discussed in detail in this section. In addition, it may not be possible to provide accurate tumor dimensions in fragmented or thermally damaged specimens. In situations where the tumor extends to resection margins, the tumor dimensions should be qualified by use of the term “at least” to indicate that the measurements may not indicate the true/final tumor size 13.

In most datasets, separate gross and microscopic measurements are mandated but this may result in confusion if different measurements are given. Some tumors (especially larger ones) are more accurately measured grossly while others (especially smaller tumors and some larger tumors with a diffusely infiltrative pattern or with marked tumor associated fibrosis) are best measured (or can only be measured) microscopically. In this dataset, separate gross and microscopic measurements are not included but rather one set of measurements is required which is based on a correlation of the gross and microscopic features with gross examination being more important in some cases and microscopic examination in others. A few other points are emphasized:

  • In providing the final tumor dimensions, the measurements in any prior specimens, for example loop/cone excisions, will need to be taken into account. Although it may overestimate the maximum horizontal extent, it is recommended to add together the maximum horizontal measurement in different specimens when calculating the final horizontal extent. However, adding the measurements of multiple specimens is sometimes challenging and may not always be possible. The depth of invasion can be taken as the maximum depth of invasion in any 1 specimen. Similar comments pertain if loop/cone excisions are received in more than 1 piece and where multifocal tumor can be excluded.
  • Many cervical carcinomas of large size or advanced stage are treated by chemoradiation, without surgical resection, once the diagnosis has been confirmed on a small biopsy specimen. In such cases, the tumor dimensions will be derived from clinical examination and the radiologic appearances. As indicated previously, this dataset applies only to excision/resection specimens and not to small biopsy specimens.
  • Occasionally resections are undertaken following chemoradiation for cervical carcinoma. In such cases, there may be no residual tumor or only small, microscopic foci making it impossible to assess the tumor dimensions. In such cases, the pretreatment clinical or radiologic tumor dimensions should be used for staging and the dimensions of the tumor in the resection should not be used for staging purposes. The exception is for those jurisdictions that use the TNM Staging System which includes the “y” prefix for staging cancers posttreatment.

Specific situations where tumor measurements are important include:

  • Small carcinomas where accurate depth of invasion measurement is paramount in distinguishing between FIGO Stage IA1, IA2, and small IB1 neoplasms 8–10. As well as providing an accurate stage, this may also be critical in dictating patient management. For example, FIGO IA1 neoplasms are often treated by local excision ensuring that the margins are clear of preinvasive and invasive disease while IA2 and IB1 neoplasms are usually treated by radical surgery (radical hysterectomy or trachelectomy).
  • In patients with FIGO Stage IB tumors treated by radical hysterectomy, the tumor size is often one of the parameters used, in conjunction with depth of invasion of the cervical wall in thirds, presence or absence of lymphovascular invasion (LVI) (Sedlis criteria) and distance to margins in assessing the need for adjuvant therapy 18.
  • The tumor measurements may be important in helping to determine whether radical hysterectomy or trachelectomy is performed; sometimes a cut-off size of 20 mm is used for performing a radical trachelectomy, although some surgeons would still perform this procedure for larger size lesions. Following radical trachelectomy, the recurrence rate is statistically higher with tumor size >20 mm and rates of adjuvant treatment are higher 19,20. There is also a trend toward more conservative surgery (simple as opposed to radical hysterectomy) in patients with tumors <20 mm as the probability of parametrial infiltration is very low.
  • Several studies have shown that in FIGO Stage IB1 cervical carcinomas, a cut-off size of 20 mm may be of prognostic value 21,22. In the 2018 FIGO Staging System, a cut-off of 20 mm distinguishes between Stage IB1 and IB2 carcinomas 8–10. A cut-off of 40 mm is also of prognostic significance and is used in FIGO 2018 to distinguish between FIGO Stage IB2 and IB3 neoplasms and between Stage IIA1 and IIA2 neoplasms 8–10,23.

Measurement of Horizontal Extent of Tumor. Although the 2018 FIGO Staging System no longer utilizes horizontal extent of tumor to stage microscopic cervical carcinomas, it is still recommended to provide the information in pathology reports for a more complete assessment of tumor characteristics, that is, tumor length or width 8–10. Stage IB in the 2018 FIGO Staging System uses tumor size cut-off values of 20 and 40 mm to distinguish IB1 (≤20 mm), IB2 (>20 and ≤40 mm) and IB3 (>40 mm) 8–10. Therefore, as discussed earlier for large tumors, this may best be done grossly if large block processing is not available, because in many cases these neoplasms will need to be submitted in multiple cassettes and the maximum tumor dimension may not be represented on a single slide. If a gross measurement is not performed in large circumferential tumors, there is a risk of overestimating the maximum horizontal extent of the tumor. This can occur when a circumferential tumor is “opened-up” and submitted in several sequential cassettes. When the other horizontal dimension (the third dimension) is calculated by adding up sequential slices in this situation (see below), this may result in an artificially greater measurement than is accurate. In the cases where no grossly visible tumor is present, yet there is extensive stromal invasion (eg, so called “barrel cervix”), and if tumor is present in multiple sections, the pathologist should attempt to give the most representative measurement based on the size of the cervix, the number of sections involved and possibly the quadrants that are involved. If a circumferential tumor without a grossly visible and measurable mass has full thickness stromal invasion of the cervical wall involving all quadrants, the diameter of the cervix can be used as a reasonable approximation of tumor size. If the circumferential tumor does not invade the full thickness of the cervical wall, then the deepest invasion and largest horizontal extent as measured on any single slide should be reported, along with the number of blocks involved by invasive carcinoma.

In smaller neoplasms, the horizontal extent is best determined histologically. One horizontal dimension is the measurement in a single slide in which the extent of invasion is the greatest. If the invasive focus is only represented in 1 block, then the other horizontal dimension is taken to be the thickness of the block (usually 2.5–3 mm or estimated as indicated below). In some cases, the maximum horizontal extent may need to be calculated in the manner below if this is not represented in one section but is spread over several adjacent sections. If invasive carcinoma is present in several adjacent sections of tissue and the invasive foci colocalize in the sections, the horizontal extent of the carcinoma should be calculated by an estimate of the thickness of the blocks, which is determined from the macroscopic dimensions of the specimen and the number of blocks taken. However, pathologists should be mindful that thickness of large or outsize blocks can vary from block to block, as compared with standard-sized blocks. While it is acknowledged that measurements from calculating block thickness may be somewhat inaccurate, it will in some cases be the only way to determine the maximum horizontal extent and this may affect staging, especially in small tumors. Some key points regarding measurement of the horizontal extent of tumors are outlined below:

  • In a case where a single tongue of stromal invasion is seen in continuity with the epithelium of origin (surface or glandular), the width of the single focus of invasion is measured across the invasive tongue.
  • Where clustered foci of stromal invasion arise close together from a single crypt or from dysplastic surface epithelium as detached cell groups, the maximum horizontal extent must encompass all the foci of invasion in the immediate area and the horizontal extent should be measured from the edge at which invasion is first seen to the most distant edge at which invasion is detected.
  • Where several foci of invasion arise in one single piece of cervical tissue as separate foci of invasion, but in close proximity (see section below on measurement of multifocal carcinomas), either as contiguous tongues of invasion or detached epithelial groups, the maximum horizontal extent is taken from the edge at which invasion is first seen to the most distant edge at which invasion is detected. The small amount of intervening tissue with no invasion (usually with in situ neoplasia) is included in the measurement.

Measurement of Depth of Invasion. The maximum depth of invasion must be measured in all cases. This measurement is taken from the base of the epithelium (surface or crypt) from which the carcinoma arises to the deepest point of invasion, as specified in the FIGO Staging System 8–10. If the deepest point of invasion involves the deep margin of the specimen, comment should be made regarding the possibility of underestimation of the depth of invasion; this is particularly applicable to loop/cone specimens. When the invasive focus is in continuity with the dysplastic epithelium from which it originates, this measurement is straightforward. If the invasive focus or foci are not in continuity with the dysplastic epithelium, the depth of invasion should be measured from the tumor base (deepest focus of tumor invasion) to the base of the nearest dysplastic crypt or surface epithelium. If there is no obvious epithelial origin despite multiple levels of the tissue block, the depth is measured from the tumor base (deepest focus of tumor invasion) to the base of the nearest surface epithelium, regardless of whether it is dysplastic or not.

There are some situations where it is impossible to measure the depth of invasion. In such cases, the tumor thickness may be measured, and this should be clearly stated on the pathology report along with the reasons for providing the thickness rather than the depth of invasion. In such cases, the pathologist and clinician should equate the tumor thickness with depth of invasion for staging and management purposes.

Situations where it may be necessary to measure the tumor thickness rather than the depth of invasion include:

  • In some glandular lesions, it may be impossible to accurately assess where adenocarcinoma in situ (AIS) ends and where invasive adenocarcinoma (ACA) begins. This is because, in general, identification of invasion in a glandular lesion is more difficult than in a squamous lesion and this is an area where a specialist opinion may be of value. In some cases where the thickness is measured (from the epithelial surface to the deepest point of the tumor) because the point of origin is impossible to establish, this may result in overestimation of the depth of invasion.
  • In ulcerated tumors with no obvious origin from overlying epithelium, the thickness may need to be measured. In this situation, measurement of tumor thickness may result in an underestimate of the depth of invasion.
  • Uncommonly, squamous cell carcinomas (SCCs), ACAs and other morphologic subtypes are polypoid with an exclusive or predominant exophytic growth pattern. In such cases, the carcinoma may be grossly visible and project above the surface with little or even no invasion of the underlying stroma. These should not be regarded as in situ lesions and the tumor thickness may need to be measured in such cases (from the surface of the tumor to the deepest point of invasion). Depth of invasion, that is, the extent of infiltration below the level of the epithelial origin, should also be provided in these cases with a clear description of how each measurement was derived (see examples below). Exophytic tumors should be staged based on largest dimension, even if superficially invasive (≤5 mm). If the depth of invasion is >5 mm, it is staged as IB. The FIGO Staging System explicitly states that the depth of invasion measurements for staging in IA1 and IA2 apply to tumors that can be diagnosed only on microscopy, that is, does not apply to grossly visible tumors 8–10. It remains to be seen, however, whether staging in this manner truly reflects tumor behaviour and future studies may help to elucidate this controversial issue.

Some examples include:

Polypoid/exophytic tumor, ≤20 mm in largest dimension:

  • With a total thickness of 15 mm (top of tumor to deepest invasion). The portion of the tumor with true destructive stromal invasion into the cervical wall (nonexophytic component) measures 4 mm in depth—Stage IB1.
  • With total thickness of 15 mm (top of tumor to deepest invasion). The portion of the tumor with true destructive stromal invasion into cervical wall (nonexophytic component) measures 8 mm in depth—Stage IB1.
  • With total thickness of 4 mm (top of tumor to deepest invasion) (shallow wide tumor). The portion of the tumor with true destructive stromal invasion into cervical wall (nonexophytic component) measures 1 mm in depth—Stage IA2.
  • With total thickness of 2.5 mm (top of tumor to deepest invasion) (shallow wide tumor). The portion of the tumor with true destructive stromal invasion into cervical wall (nonexophytic component) measures 1 mm in depth—Stage IA1.

Polypoid/exophytic tumor, >20 mm, ≤40 mm in largest dimension—Stage IB2 regardless of thickness or depth of invasion.

Polypoid/exophytic tumor >40 mm in largest dimension—Stage IB3 regardless of thickness or depth of invasion.

Avoid the Term “Microinvasive Carcinoma.” The term “microinvasive carcinoma” appears in the 2018 FIGO Staging System for cervical cancer where it is equated with Stage IA disease 8–10. However, use of the term “microinvasive carcinoma” has different connotations in different geographical areas. For example, in the United Kingdom and in several other European countries, “microinvasive carcinoma” was considered to be synonymous with FIGO Stage IA1 and IA2 disease in most, but not all, institutions (some used the term “microinvasive carcinoma” to denote only FIGO Stage IA1 tumors) 8–10. In the United States and Canada where the Lower Anogenital Squamous Terminology (LAST) 24 recommendations have been adopted, the term superficially invasive squamous cell carcinoma (SISCCA) is used to describe FIGO Stage 1A1 tumors with negative margins, and the term “microinvasive squamous cell carcinoma” is no longer in routine use. Thus, to avoid confusion, it is recommended to avoid using the term “microinvasive carcinoma” for all morphologic subtypes and to use the specific FIGO stage.

Measurement of Multifocal Carcinomas. Early invasive carcinomas of the cervix, especially squamous, are sometimes multifocal comprising tumors that show multiple foci of invasion arising from separate sites in the cervix and separated by uninvolved cervical tissue. In those rare cases where more than one primary tumor is present, separate datasets should be completed for each neoplasm. These should include all the elements in this dataset, except for lymph node status which does not need to be documented separately for each tumor.

Specifically, multifocal tumors should be diagnosed if foci of invasion are:

  • separated by blocks of uninvolved cervical tissue (levels must be cut to confirm this);
  • located on separate cervical lips with discontinuous tumor, not involving the curvature of the canal; and
  • situated far apart from each other in the same section (see below).

Again, because FIGO 2018 no longer requires horizontal extent to be measured for staging of early carcinoma, the measuring of multifocal tumors is less of an issue in determining stage, especially since most multifocal tumors tend to be superficially invasive 8–10. The individual foci of stromal invasion may be attached to, or discontinuous from, the epithelium from which they arise. Multifocal carcinomas should not be confused with the scenario in which tongues or buds of invasion originate from more than one place in a single zone of transformed epithelium and will, over time, coalesce to form a single invasive tumor which represents unifocal disease (and should be measured, as indicated above, in 3 dimensions).

The frequency of multifocality in FIGO Stage IA1 cervical squamous carcinomas has been reported to be between 12% and 25% 25–27 although multifocality in larger, advanced tumors is uncommon. There are few (and some rather dated) guidelines regarding measurement of multifocal carcinomas 25,27,28. Although preinvasive disease may be present, when foci of stromal invasion arise from separate sites or are separated by cervical tissue without invasion (after levels/deeper sections have been cut to confirm this), the foci of invasion should be measured separately, in 3 dimensions, as described above, and staged according to the dimensions of the larger/largest tumor with a clear statement that the tumor is multifocal. However, in the last of the scenarios mentioned above (foci of stromal invasion situated far apart from each other in the same section) measurement of the multifocal disease is problematical. Options include measuring from the edge of one invasive focus to the edge of the furthest invasive focus according to 2018 FIGO guidelines (irrespective of the distance between foci of invasion), adding the maximum horizontal extent of each invasive focus together (which clearly does not reflect the biological potential of the individual invasive foci) or regarding widely separated foci as representing small independent areas of invasion 8–10,25–29. Two studies have regarded such lesions as representing multiple foci of invasion (multifocal FIGO IA1 carcinomas) if the foci of invasion are clearly separated 25,26. An arbitrary minimum distance of 2 mm between each separate focus of invasion was applied in these studies 25,26. Follow-up of patients in these studies, which include a combined total of 46 cases of “multifocal IA1 cervical squamous carcinomas” treated by local excisional methods (loop/cone excision) with margins clear of premalignant and malignant disease, showed no evidence of recurrent premalignant or malignant disease with median follow-up periods of 45 mo and 7 yr, respectively 25,26. Moreover, one of the studies showed that the prevalence of residual preinvasive (20%) and invasive disease (5%) on repeat excision were comparable to data available for unifocal FIGO Stage IA1 cases 26. These studies included cases which would have been regarded as FIGO Stage IB1 in the 2009 Staging System (but IA in the 2018 Staging System) had the horizontal extent been measured from the edge of one invasive focus to the edge of the furthest invasive focus, as per FIGO guidelines 8–10,30. Although limited by a relatively small number of cases and the selection of an arbitrary distance of separation of 2 mm, the findings support the hypothesis that with regard to tumor staging and management, it may be appropriate to consider superficial, widely separated foci of invasion as representing multifocal lesions. In addition, it may be appropriate to measure each focus separately, and to determine the FIGO stage on the basis of the invasive focus with the higher/highest FIGO stage. Although the Carcinoma of the Cervix Dataset Authoring Committee cannot justify implementation of an approach based only on 2 studies involving 46 patients in total, the Carcinoma of the Cervix Dataset Authoring Committee recommends that this approach be considered and discussed at multidisciplinary tumor board meetings to avoid unnecessary surgery in young patients who wish to preserve their fertility in this specific clinical situation. This approach needs to be verified by additional larger collaborative studies and trials. It is also stressed that in such cases, the tissue blocks containing the invasive foci and those in between should be levelled to confirm that the invasive foci are truly separate and ensure that there is no occult stromal invasion in the intervening areas. If this approach is adopted, the pathology report should clearly indicate how the measurements have been obtained to arrive at a diagnosis of multifocal invasion, provide the dimensions of the separate foci of invasion and indicate how the FIGO stage has been ascertained. Such cases may need to be referred to cancer centers for review and, as indicated above, should be discussed individually at the multidisciplinary tumor board meeting. There have been no similar studies for multifocal ACAs but anecdotally these are less common than multifocal squamous carcinomas and until further evidence becomes available, a similar approach is recommended.

Measurement of Tumor Volume. In most studies, tumor size is based on measurement of 2 dimensions but in a few studies, tumor volume (based on the 3 measured tumor dimensions) has been shown to predict prognosis more reliably than measurements in only 1 or 2 dimensions 31–33. Some older studies have suggested tumor volume as a reliable prognostic factor for early stage tumors: a volume of <420 mm3 has been suggested to be associated with no lymph node metastasis 31–33. This is one of the main reasons for recommending that 3 tumor dimensions (2 of horizontal extent and 1 of depth of invasion or tumor thickness) are provided. However, only a few centers continue to routinely factor tumor volume into patient management.

Histologic Tumor Type

The major subtypes of cervical carcinoma are SCC, ACA (with various subtypes), adenosquamous carcinoma and neuroendocrine tumors (NETs). In the era of molecular characterization and targeted therapy, correct identification of the tumor subtypes will be even more crucial for understanding tumor biology and discovery of potential therapeutic targets. While it is beyond the remit of this document to detail the morphologic appearances of the different tumor types in detail, a few points should be noted. All cervical carcinomas should be typed according to the 2020 WHO Classification 11. The ICCR dataset includes 5th edition Corrigenda, June 2021 12. This 2020 edition of the WHO Classification divides epithelial tumors of the cervix on the basis of their association (or lack thereof) with human papillomavirus (HPV) infection, which results in a classification that allows more accurate assessment of the success of HPV testing in cervical screening programs, as well as the role of HPV vaccination. In addition, as in other anatomic areas, HPV-independent cervical carcinomas have been shown to have worse prognosis compared with HPV-associated neoplasms 34,35.

To harmonize the classification across lower genital tract sites and other anatomic sites such as the head and neck region, SCCs are subdivided in the 2020 WHO Classification into HPV-associated and HPV-independent categories. Histologic growth patterns, the presence of keratinization and other morphologic variations (eg, papillary, basaloid, warty, verrucous, etc.) are no longer the basis for subclassification, as they have no bearing on clinical behavior. However, it may be useful to record unusual subtypes, for example, lymphoepithelioma-like carcinoma, since the behavior is not well established. Unfortunately, the 2 categories of cervical SCC, HPV-associated and HPV-independent, cannot be reliably distinguished on the basis of morphologic criteria. Thus, p16 immunostaining and/or HPV testing are considered essential criteria, required to classify SCC of the cervix into the 2 categories. It is recognized that routinely performing these ancillary techniques on all cervical carcinomas is not feasible in many pathology laboratories. Thus, a diagnosis of SCC not otherwise specified, without differentiating the 2 categories, is an acceptable alternative where the facilities necessary to make this distinction are not available. However, the presence of concomitant high grade squamous intraepithelial lesion (HSIL) and/or a recent history of HSIL or high-risk HPV positivity is considered sufficient to classify a tumor as HPV-associated. There is no evidence, as yet, that an HPV-independent precursor lesion exists, and squamous intraepithelial lesions (SILs) are therefore grouped into a single, HPV-associated, category. However, it should be emphasized that although HPV-independent SCCs have been described 36, the vast majority of cervical SCC are HPV-associated. HPV-independent tumors represent a small percentage of all SCC, even in countries with active cervical cancer screening programs, where HPV-independent tumors are probably over-represented.

Recent comprehensive studies have shown that although the majority (85%) of endocervical ACAs are associated with HPV infection, about 15% are not and there are clinically significant outcomes based on association with HPV infection 37,38. The 2020 WHO Classification recognizes this by separating HPV-associated and HPV-independent ACAs 11. Contrary to SCC, HPV-associated and HPV-independent ACAs of the cervix can be distinguished based on morphology alone with easily identifiable luminal mitoses and apoptotic bodies typically being identified at scanning magnification in HPV-associated ACAs. The HPV-independent ACAs can be further subcategorized by traditional nuclear, cytoplasmic and architectural features, and comprise gastric, clear cell, mesonephric, and endometrioid types. It should be emphasized that most ACAs with an “endometrioid” appearance represent HPV-associated ACAs with mucin depletion and should be classified as usual type, HPV-associated. In addition, most true endometrioid neoplasms involving the cervix are likely due to direct extension from an endometrioid carcinoma in the corpus or, rarely, arises from cervical endometriosis. Thus, true endometrioid carcinoma should be diagnosed only when HPV-associated ACA and other mimics (eg, extension from an endometrial carcinoma) have been rigorously excluded. Of note, mismatch repair deficiency is not thought to be a feature of endocervical carcinoma and the loss of mismatch repair protein expression should raise considerable suspicion for an endometrial primary, particularly given the predilection of MLH1/PMS2-deficient, MLH1 hypermethylated tumors to involve the lower uterine segment 39. p16 and/or HPV testing are considered desirable (not essential) criteria, as the morphologic features usually allow accurate differentiation. The ubiquitous use of and reliance on p16 immunohistochemistry to diagnose cervical ACA may cause diagnostic problems for HPV-independent tumors, since these typically do not exhibit the diffuse strong immunoreactivity characteristic of HPV-associated tumors (see the Ancillary studies section) 40,41. Invasive stratified mucin-producing carcinoma is the invasive counterpart of stratified mucin-producing intraepithelial lesion (SMILE) and a variant of HPV-associated ACA characterized by solid nests of tumor cells with mucin vacuoles scattered throughout the entire thickness of the nests; the term invasive SMILE can also be used. These can mimic squamous carcinomas when mucin-poor and have likely been categorized as adenosquamous carcinomas in the past. This ACA subtype appears to have more aggressive behavior than usual type ACA or adenosquamous carcinoma and should be mentioned in the diagnostic report 42–44.

Primary serous carcinoma of the cervix is likely nonexistent and is no longer included in the 2020 WHO Classification 11. Most cases reported as primary cervical serous carcinoma are likely to represent a metastasis from the corpus or extrauterine sites or a usual HPV-related ACA with marked nuclear atypia, including the micropapillary variant. Metastasis should be excluded in cases that are morphologically consistent with serous carcinoma in the cervix. Both HPV-associated usual type cervical ACAs, adenosquamous carcinomas and HPV-independent gastric type ACAs can have a papillary and micropapillary growth pattern with high grade nuclear atypia, mimicking serous carcinoma 45.

Adenosquamous carcinomas (defined in the WHO 2020 Classification 11 as a malignant epithelial tumor exhibiting both squamous and glandular differentiation) are usually related to high-risk HPV. To make a diagnosis of adenosquamous carcinoma, unequivocal malignant squamous and glandular components should be identifiable on routine haematoxylin and eosin–stained sections. The demonstration of foci of intracytoplasmic mucin by mucin stains in an otherwise typical SSC should not result in diagnosis of an adenosquamous carcinoma. Carcinomas which lack evidence of squamous differentiation (intercellular bridges, keratinization) but have abundant mucin-producing cells should be diagnosed as poorly differentiated ACAs. Adenosquamous carcinoma should also be distinguished from a spatially separate squamous carcinoma and ACA, which occasionally occurs. While some studies have indicated a worse outcome than pure squamous or ACAs, there is not robust evidence to confirm these findings and recent studies suggest similar outcomes to ACA 42,44,46,47.

Carcinosarcoma is also included in the WHO 2020 Classification in the category of epithelial neoplasms of the cervix since it is considered a carcinoma which has undergone sarcomatous differentiation 11.

Neuroendocrine carcinomas (NECs) (small cell and large cell NEC) are uncommon but well described in the cervix and can occur in pure form or associated with another tumor type, ACA (most common), SCC or adenosquamous carcinoma. The vast majority of cervical NECs are associated with high-risk HPV, typically HPV 18, with only rare exceptions. The WHO 2020 Classification has separated neuroendocrine neoplasia of the gynecologic tract as a stand-alone section 11. A unified terminology across all organs has been incorporated into the 2020 WHO Classification, following the agreement reached at a consensus conference held at the IARC in November 2017, and subsequently published 11,48. Neuroendocrine neoplasia is categorized into NET and NEC, the former defined as low or intermediate grade epithelial neoplasms with morphologic and immunohistochemical features of neuroendocrine differentiation (formerly carcinoid and atypical carcinoid tumor), the latter as either small cell or large cell NEC. When mixed with another tumor type, the percentage of the neuroendocrine component should be given. Regardless of the percentage of NEC, it is recommended that the tumor be reported as mixed since all tumors containing a component of NEC have a very poor prognosis and the NEC component may be underestimated in a limited sample 49. Several studies of small cell NECs of the cervix have shown that adjuvant chemotherapy after surgery for early stage disease provides significant clinical benefit compared with surgery alone and therefore, it is extremely important to correctly diagnose any component of NEC. In addition, in many institutions surgical resection is not undertaken for a NEC even if early stage but instead chemotherapy treatment is given. Diagnosing NEC or a component of NEC can be difficult, especially in small samples, but a combination of synaptophysin, chromogranin A, CD56, TTF1, INSM-1, p40, p63, and somatostatin analogues (SST2 and SST5) has been shown to be helpful in making the distinction between NEC and poorly differentiated non-NEC (see the Ancillary studies section) 50–52.

LVI

LVI does not affect FIGO or TNM staging (eg, if there is LVI in tissues outside the cervix but the tumor itself is confined to the cervix, this is still FIGO Stage I) but should be clearly documented in the pathology report 8–10,53,54. The significance of LVI in cervical carcinoma has been debated for predicting overall survival, disease-free interval, recurrence-free survival and regional lymph node metastasis for decades. Although studies conflict, there is general agreement that LVI is an independent predictor of adverse outcome 55–65. Early studies indicated that LVI was an independent predictor of disease-free interval, with 1 study reporting a 1.7 times higher rate of recurrence in patients with LVI compared with those without LVI in low-stage cervical carcinoma 57. This has been confirmed in later studies, particularly in low-stage (FIGO Stage IB) cervical carcinoma 59. The significance of LVI in SISCCA is unclear, likely due to the rarity of adverse outcomes including lymph node metastasis in SISCCA. Studies have shown that LVI does not predict lymph node metastasis in cases of SISCCA with a depth of invasion of ≤3 mm 66–69.

Lack of standardized criteria and marked variability in recognition of LVI have undoubtedly led to conflicting outcomes in previous studies. Fixation retraction around tumor cell groups is a well recognized artefact which mimics LVI. Features that may help in the recognition of LVI include a tumor nest within a space associated with other vascular structures, the presence of an endothelial lining, adherence of the tumor cell group to the side of the space, the contour of the intravascular component matching the contour of the vessel and the presence of adherent fibrin. Immunohistochemical demonstration of an endothelial cell lining may assist but is not performed routinely. D2-40 (recognising lymphatic endothelium) and CD31 and CD34 (recognizing both lymphatic and blood vascular endothelium) may be useful in confirming the presence of LVI 70–73.

In rare situations when specimens are severely traumatized or cauterized, LVI may be suspected but it may not be possible to reliably determine whether or not LVI is present. In these circumstances “indeterminate” should be recorded in the reporting guide, although it is expected this will be a rare response and should be used sparingly.

Most studies which have examined the significance of LVI in cervical carcinoma have not distinguished between lymphatic and blood vessel invasion and there is little evidence to support separating out the type of invasion, especially since this is not reliable in haematoxylin and eosin–stained sections. Occasional studies have found blood vessel invasion to have a worse prognosis than lymphatic invasion and to be a predictor of ovarian involvement 74. However, there is insufficient evidence to warrant inclusion of blood vessel and lymphatic invasion as separate data items. Likewise, there is currently limited evidence to support counting the number of blood vessels containing tumor. A comment may be made if there is obvious extensive LVI, and there are no standard cut off values that can be applied currently.

Extent of Invasion

The involvement of any extracervical structures by invasive tumor should be documented. Documentation of the involvement of various extracervical tissues is prognostically significant and is important for tumor staging. Involvement of the pelvic sidewall, vagina, parametria, rectum and bladder upstage the tumor. Involvement of the uterine body, whilst not formally part of FIGO or 8th edition TNM Staging 8–10,53,54, has also been shown to be of prognostic significance 75. Adnexal involvement also does not upstage cervical cancer though the presence of tubo-ovarian tumor generally results in some form of adjuvant therapy. Documentation of the extent of invasion is also important for correlation with clinical and radiologic findings.

The parametria are composed of fibrous tissue, which surrounds the supravaginal part of the cervix and separates this part of the cervix anteriorly from the bladder and posteriorly from the rectum. The fibrous parametrial tissue extends onto the sides of the supravaginal cervix and between the layers of the broad ligaments. The fibrous connective tissue around the isthmus at the cervix/lower uterine segment junction should be regarded as part of the parametria and included in the sampling of parametrial tissue. Lymph nodes and the uterine blood vessels and lymphatics that supply and drain the cervix are contained within the fibrous parametrial tissue.

The uterine body includes both endometrial (glandular/stromal) and myometrial structures.

If the bladder or rectum is involved, the pathologist should state which compartments are infiltrated; in particular, if the bladder or rectal mucosa is involved, this implies that the tumor is Stage IVA at least.

LVI should be documented wherever it is identified, but anatomic structures where there is only LVI and no direct stromal infiltration, should not be recorded as being involved by tumor and the presence of LVI should not alter the FIGO stage.

Margin Status

The status of all surgical resection margins should be recorded (ectocervical, endocervical, radial/deep stromal, and vaginal cuff). At the time of specimen grossing, it may be useful to ink the various resection margins with different colours to assist precise margin recognition.

The recording of margin involvement by tumor is a core data element. When invasive carcinoma is close to a surgical margin, documentation of the distance to the margin is noncore. No data are available to indicate the optimal margin of clearance of carcinoma in simple hysterectomy, trachelectomy, cone or loop biopsy specimens. Consistent recording of the distance to the margins will enable data to be collected prospectively and provide evidence for future practice. A small number of retrospective studies has assessed the impact of close margins on local and overall recurrence in patients undergoing radical hysterectomy for cervical cancer 76. The crude local recurrence rate was 20% in 284 patients with FIGO Stage IB carcinomas with “close” margins (close was defined as <10 mm) in 1 study 77. In the same study, patients with negative margins, defined as a clearance of ≥10 mm, had a crude recurrence rate of 11% 77. Another study of close surgical margins after radical hysterectomy in early-stage cervical cancer found that close surgical margins, defined as ≤5 mm, were associated with recurrence rates of 24% as compared with recurrence rates of only 9% in patients with negative margins 78. In the same study, close surgical margins were significantly associated with positive lymph nodes, parametrial involvement, larger tumor size, deeper stromal invasion, and LVI 78.

In occasional cases where tumor involvement of the margin cannot be determined for various reasons (processing artefact, multiple pieces or poor tissue orientation), the margin status should be specified as “cannot be assessed” and the reason explained. In hysterectomy or trachelectomy specimens, the lateral radial margin may consist of parametrial soft tissue, which should be measured (see the Specimen dimensions section), based on gross examination, and calculated into the margin evaluation. In contrast, anterior and posterior radial/deep stromal margins in a hysterectomy specimen will consist of cervical stromal tissue.

The presence of margin involvement by HSIL, AIS, or SMILE should be documented (core element). If not involved, the distance to the resection margin is a noncore element, although, as with invasive tumor, there are no data available to indicate the optimal margin of clearance. In hysterectomy specimens with Stage IA or small IB carcinomas, the entire cervix should be assessed histologically to ensure an accurate measurement of the extent of the disease and surgical margins 79–82.

Lymph Node Status

Lymph node status is one of the most important prognostic factors for survival in patients with cervical cancer 83. The 5-yr survival rate decreases from 85% to 50% when lymph node metastases are identified 84.

Radical hysterectomy or trachelectomy and pelvic lymphadenectomy are the standard of treatment in most canters for FIGO Stage IB1, IB2 and IIA1 cervical carcinomas and, in some centers, for Stage IA2 carcinomas. There is an increasing trend for a more conservative approach, such as loop/cone excision, in the treatment of FIGO Stage IA2 and small Stage IB1 carcinomas, particularly if additional risk factors such as LVI are absent 85. In such cases, lymphadenectomy is often performed. Lymphadenectomy may also occasionally be performed for bulky nodal metastases (>20 mm) which are resistant to radiotherapy and/or chemotherapy; debulking of enlarged pelvic nodes has been shown to reduce the risk of pelvic recurrence but does not benefit survival 86,87.

Core data items regarding lymph node status are restricted to the number of lymph nodes identified from the various sites and the number involved by tumor. The size of the tumor deposit is included as a noncore item. Some of the other parameters discussed below (extracapsular spread and lymph node ratio) may be recorded if locally agreed. Recording these parameters may be useful for future research.

Resected lymph nodes are categorized as regional (paracervical, parametrial, various pelvic lymph node groups, including obturator, internal, common or external iliac, presacral and lateral sacral, and para-aortic) or nonregional nodes (inguinal and other nodes) 53. The FIGO 2018 Staging System 8–10, unlike previous systems, includes lymph node status and is thus now closely aligned with the structure of the UICC and AJCC 8th edition TNM Classifications (see the Provisional pathologic staging section) 53,54. In the FIGO 2018 Staging System, pelvic lymph node involvement is Stage IIIC1 and para-aortic nodal involvement Stage IIIC2 8–10. In applying a TNM stage, regional lymph node metastases contribute to the N category, but nonregional node involvement is regarded as distant metastasis. One point to emphasize is that the TNM8 Classification takes into account the size of the nodal metastasis in assigning the N category 53,54. According to TNM8 53, macrometastases are >2 mm, micrometastases are >0.2 to 2 mm and isolated tumor cells (ITCs) are up to 0.2 mm. Macrometastases are regarded as pN1, micrometastases as pN1 (mi) and ITCs are pN0 (i+); ITCs do not upstage a carcinoma. The 2018 FIGO Staging System originally stated that micrometastases and ITCs can be recorded but this does not alter the tumor stage 8–10. However, a corrigendum was later issued stating that micrometastases should be counted as nodal involvement and FIGO Stage IIIC 88.

According to the UICC, a pelvic lymphadenectomy specimen should normally include 6 or more lymph nodes, but if this node count is not met and the resected lymph nodes are negative, the carcinoma should still be classified as pN0 53. The mean or median number of lymph nodes removed during pelvic lymphadenectomy varies widely in different studies and ranges from 13 to 56 nodes. Apart from the arbitrary minimum number of nodes proposed by the UICC, there is no internationally accepted minimum for the number of resected lymph nodes required as part of a lymphadenectomy for cervical cancer. A study by Inoue and Morita 89 reported that the number of positive nodes was of greater prognostic significance than the presence of nodal metastasis per se. A more recent study by Park and Bae 90, showed that the number of lymph nodes with metastases is an independent risk factor for reduced survival in patients with cervical cancer.

In many centers, sentinel lymph node (SLN) biopsy is now being undertaken in patients with presumed low-stage cervical carcinoma 80,91,92. Overall, in FIGO Stage I cervical cancer the incidence of pelvic lymph node metastasis is ~10% 93. If the SLN is negative, this avoids the morbidity associated with full pelvic lymphadenectomy in the remaining 90% of patients, that is, SLN biopsy is of value in reducing the requirement for a complete lymphadenectomy with its attendant morbidity in a patient population at low risk for lymph node metastases. With regard to the issue of micrometastases [which, as discussed, should be staged as pN1 (mi)] and the use of immunohistochemistry (usually cytokeratin AE1/AE3), a study by Juretzka et al. 94 found immunohistochemically-detected micrometastases in 8.1% of patients with initially reported “negative” nodes (comprising 4 of 976 or 0.41% of pelvic lymph nodes examined). The immunohistochemically-detected micrometastases were more frequent in tumors with LVI; another study showed that immunohistochemically detected micrometastases were a risk factor for tumor recurrence 95. Other studies have shown higher rates of lymph node micrometastases in early stage cervical carcinomas for example, 10.1% of cases in a study by Cibula et al. 96 and 15% in a study by Lentz et al. 97. The latter study also showed that micrometastases were more likely in patients in whom larger numbers of lymph nodes were removed. A study by Horn et al. 98 revealed that lymph node micrometastases were prognostically significant; patients with micrometastases had a reduced 5 yr survival rate compared with node-negative patients, but fared better than those patients with macrometastases. In the study by Cibula et al. 96 ITCs were detected in 4.5% of cases and were found to be of no prognostic significance. If SLN biopsy is carried out, the number of nodes examined, the number of positive nodes and the size of the tumor deposit should be recorded. It is acknowledged that there are few published data regarding micrometastases and ITCs in cervical cancer and until further data emerge it is recommended that these should be reported in the same way as ITCs at other sites.

Frozen section of SLNs is also performed routinely in some institutions, while others may take a more selective approach in choosing SLNs to send for frozen. If positive lymph nodes are detected at the time of surgery, the procedure is abandoned, and the patient receives adjuvant chemoradiation therapy and is spared also undergoing a radical surgical procedure. The sensitivity for detecting metastases at frozen section varies depending on the method of sectioning the lymph nodes and appears to be better in high volume centres. In general, frozen section has low sensitivity (47%–56%) 99,100 for detecting clinically relevant metastases 99–101. In addition, performing frozen section on all SLNs is resource heavy and may not be feasible in under resourced areas. It may be more efficient to only send clinically or radiologically suspicious lymph nodes for frozen section evaluation.

The size of lymph nodes with metastatic carcinoma has been reported to be a prognostic factor in 1 study; patients with lymph nodes >15 mm in short-axis diameter had significantly lower survival rates than nodes of smaller size 102.

Lymph node ratio, the ratio of positive to negative lymph nodes, has been assessed in a wide range of different cancers. The significance of lymph node ratio in cervical carcinoma has only recently been evaluated and there is insufficient evidence to include this as a data item in the current dataset. However, in early stage cervical cancer, the lymph node ratio identifies node-positive patients with a worse prognosis 103 and has been found to be an independent prognostic indicator of overall survival and disease-free survival in patients with SCC 104.

There are very few studies that assess the significance of extracapsular/extranodal spread of metastatic cervical carcinoma, and the item has not been included in this dataset. One study showed extracapsular spread to correlate with advanced stage disease, the number of involved nodes and the size of metastatic deposits 105. In another study, patients with extracapsular lymph node spread had a significantly lower 5-yr recurrence-free survival rate compared with patients whose nodes showed no extracapsular spread 106.

The lymph node parameters, lymph node ratio and extracapsular spread have not been included as specific data items due to a lack of supporting evidence. However, as indicated above, individual pathologists or institutions may choose to include some or all these items in their own protocols. This may be useful for prospective data collection.

Coexistent Pathology/Precursor Lesions

Carcinomas of the cervix are often associated with premalignant precursor lesions, which are mostly squamous or glandular in type. Their pathology is well described and illustrated in the WHO 2020 Classification and a number of reviews 11,107,108. There are also numerous benign squamous or glandular lesions which can be broadly classified as inflammatory, metaplastic, and neoplastic. Their importance is in recognising the lesions as benign as they can morphologically mimic premalignant or malignant glandular or squamous lesions and result in a false positive diagnosis.

It is important to report coexisting premalignant lesions and document whether they involve resection margins since this may influence patient management and follow up. Most clearly defined premalignant lesions are caused by HPV. The terminology of HPV-associated premalignant squamous lesions was revised in the 2014 WHO Classification to SIL 24. The change also harmonizes with The Bethesda System 109 for the reporting of cytologic abnormalities in cervical smears. SILs are divided into low grade SIL which is a viral infection with a high spontaneous resolution rate, and HSIL which is a true premalignant lesion that can progress to SCC. The corresponding cervical intraepithelial neoplasia terms can be included in parentheses.

AIS HPV-associated is the precursor lesion of usual HPV-related cervical ACA. High grade cervical glandular intraepithelial neoplasia is an alternative terminology used in some jurisdictions 110. SMILE is a variant of AIS (and should be coded as such) according to the WHO 2020 Classification 11 but others consider it a form of high grade reserve cell dysplasia and report it separately 111,112.

In the WHO 2020 Classification, the precursor lesions of HPV-independent gastric-type cervical ACA is listed as AIS, HPV-independent 11. Atypical lobular endocervical glandular hyperplasia and gastric-type AIS comprise these precursor lesions 113,114.

Pathologically Confirmed Distant Metastases

Documentation of known metastatic disease is an important part of the pathology report. Such information, if available, should be recorded with as much detail as is available including the site, whether the specimen is a histopathology or cytopathology specimen and with reference to any relevant prior surgical pathology or cytopathology specimens.

Provisional Pathologic Staging

The pathologic staging must be provided on the pathology report and is therefore a core element. The term “provisional pathologic staging” is used in this dataset to indicate that the stage that is provided may not represent the final tumor stage which should be determined at the multidisciplinary tumor board meeting where all the pathologic, clinical and radiologic features are available 8–10,53,54.

The latest version of either FIGO or TNM staging, or both, can be used depending on local preferences 8–10,53,54. The FIGO Staging System is in widespread use internationally and is the system used in most clinical trials and research studies. However, UICC or AJCC versions of TNM are used or mandated in many parts of the world 53,54. With regards to updating of staging systems, there is collaboration between FIGO and those agencies responsible for TNM with an agreement to adopt changes to FIGO Staging. Following the introduction of a new FIGO Staging System, this is usually incorporated into TNM (both UICC and AJCC) versions) at a later date. Apart from minor discrepancies in terminology, the UICC and AJCC 8th edition systems are broadly concurrent.

A new FIGO Staging System for cervical cancer was introduced in 2018 8–10. The main changes from the prior 2009 FIGO Staging System are outlined below:

  • The horizontal dimension of 7 mm is no longer considered in defining the upper boundary of a Stage IA carcinoma.
  • Stage IB has been subdivided into IB1, IB2, and IB3 based on maximum tumor size.
  • Nodal status is included; the presence of nodal involvement upstages a tumor to Stage IIIC, with IIIC1 indicating pelvic and IIIC2 indicating para-aortic nodal involvement. As discussed, the revised FIGO Staging System is now more closely aligned with the TNM Classification.
  • Prior FIGO Staging Systems were based mainly on clinical examination, while the 2018 Staging System allows imaging and pathology findings to be taken into account to supplement clinical staging with respect to tumor size and extent in all stages. The notation of r (imaging) or p (pathology) should indicate the parameters that are used to allocate the case to Stage IIIC; for example, if imaging indicates pelvic lymph node metastasis, the stage would be Stage IIIC1r, and if confirmed by pathologic findings, it would be Stage IIIC1p.

There are several difficulties inherent in the staging of carcinoma of the uterine cervix as follows 8–10:

  • There are difficulties in obtaining precise tumor measurements in low-stage disease (FIGO Stage IA and IB); this has been discussed in the Tumor dimensions section.
  • Clinical staging, as previously recommended by FIGO, may underestimate or overestimate true anatomic extent of disease as it does not include information obtained from postsurgical pathology specimens or radiologic/surgical techniques which may not be universally available. Reliance on clinical staging tends to occur in underdeveloped or under-resourced countries where surgical facilities and ancillary investigations (such as radiology and pathology) may be limited 8–10. A provisional FIGO stage should be provided on the pathology report but the definitive stage is assigned at the multidisciplinary tumor board meeting.

A tumor should be staged following diagnosis using various appropriate modalities (clinical, radiologic, pathologic). While the original tumor stage should not be altered following treatment, TNM systems allow staging to be performed on a resection specimen following nonsurgical treatment (eg, chemotherapy, radiotherapy); in such cases, if a stage is being provided on the pathology report (this is optional), it should be prefixed by “y” to indicate that this is a posttherapy stage.

The reference document TNM Supplement: A commentary on uniform use, 5th edition (Wittekind et al. 115 editors) may be of assistance when staging.

Noncore Data Elements

A list of the noncore elements for the reporting of cervical carcinomas is presented in Table 2 and described below.

TABLE 2 - Noncore data elements for pathologic reporting of carcinoma of the cervix.
Clinical Macroscopic Microscopic Other
Clinical information Macroscopic appearance of tumor(s) Histologic tumor grade Ancillary studies
Block identification key Pattern classification for HPV-associated adenocarcinomas
Margin status*
 Distance of tumor from margin
Lymph node status†
 Size of maximum tumor deposit
Coexistent pathology/precursor lesions‡
 Other possible precursor lesions
*Distance of tumor from the margin is noncore; involvement by invasive tumor in hysterectomy/trachelectomy or loop/cone specimens, and involvement by precursor lesions (high grade squamous intraepithelial lesion, adenocarcinoma in situ, stratified mucin-producing intraepithelial lesion) are considered core (Table 1).
Size of maximum tumor deposit is noncore; the number of lymph nodes examined, and number of positive nodes are considered core (Table 1).
The presence of other possible precursor lesions is noncore; squamous intraepithelial lesion/cervical intraepithelial neoplasia, HPV-associated adenocarcinoma in situ/high grade cervical glandular intraepithelial neoplasia and stratified mucin-producing intraepithelial lesion are considered core (Table 1).
HPV indicates human papillomavirus.

Clinical Information

Prior chemotherapy, chemoradiation and radiation therapy may significantly alter the original tumor size. Patients with FIGO 2018 8 clinical Stage IB3 and greater cervical cancer (with the exception of IIA1) usually receive chemotherapy, radiation or chemoradiation as definitive therapy. Although controversial, some institutions treat such patients with neoadjuvant chemoradiation followed by hysterectomy 85,116–121. Studies have shown that the cervical tumor totally disappears in the majority of cases with only a third of hysterectomy specimens containing residual tumor after neoadjuvant chemoradiation. Chemotherapy, chemoradiation or radiation may also introduce histologic changes that were not present in the untreated tumor, such as multinucleate tumor giant cells and degenerate nuclei. Metastatic carcinomas may mimic primary cervical malignancies and knowledge of the patient’s cancer history is important for the diagnostic workup (immunohistochemistry or molecular studies) of a newly discovered cervical malignancy. Finally, histologic findings (tumor size, histologic type, grade, and sometimes other parameters) in a prior cervical loop or cone excision may be important for the ultimate tumor staging and grading in a hysterectomy specimen. In patients with a prior loop excision, the size of the tumor in the original loop has to be taken into consideration in determining the overall tumor size (see the Tumor dimensions section) 116–121.

Macroscopic Appearance of Tumour(s)

Documentation of the macroscopic appearance of cervical tumors allows correlation with the clinical and radiologic assessment of the tumor. According to FIGO 2018, clinically visible cervical cancers are Stage IB 8–10. However, it now allows for pathologic or radiologic measurements to assign final stage if available. Therefore, even if a tumor is clinically visible, if on histologic examination the lesion has the dimensions of a Stage IA neoplasm, it is recommended that it should be categorized as Stage IA (eg, associated erosion with minimal tumor present) 8–10. This should also be discussed at the gynecological oncology multidisciplinary tumor board.

Exophytic/polypoid carcinomas may have a growth pattern that results in very little or even no invasion of the underlying stroma and ulcerated tumors may entirely or predominantly supplant the surface epithelium. In both these circumstances, it may be necessary to measure tumor “Thickness” rather than “Depth of invasion’ and it is helpful to document the macroscopic appearance to provide context and explanation for the use of the alternative measurements. In large circumferential tumors, there is a risk of overestimating the maximum horizontal extent of the tumor (see the Tumor dimensions section). The type of growth pattern in bulky (>40 mm) tumors may be prognostic. In one study, barrel-shaped cervical tumors >40 mm had a significantly worse overall and disease-free survival compared with exophytic tumors >40 mm 122.

The macroscopic appearance of the tumor influences tumor sampling. For cases where there is no macroscopically visible tumor either because there has been a prior surgical procedure or prior therapy the entire cervix should be blocked. For cases with a large visible tumor, it is not necessary to block the whole tumor, but instead careful block selection ensuring representative sampling of the tumor, accurate assessment of margins and tumor extent is required. The blocks should be taken to include the nearest margin(s) and show the maximum depth of stromal invasion. In departments where the facility for processing oversize blocks is available, a good overview of the tumor and resection margins can be obtained. In departments where this facility is not available, large blocks may need to be subdivided; in such cases, the relationship of the blocks to one another should be clearly documented.

Block Identification Key

The origin/designation of all tissue blocks should be recorded. This information should ideally be documented in the final pathology report and is particularly important should the need for internal or external review arise. The reviewer needs to be clear about the origin of each block in order to provide an informed specialist opinion. If this information is not included in the final pathology report, it should be available on the laboratory computer system and relayed to the reviewing pathologist. It may be useful to have a digital image of the specimen and record of the origin of the tumor blocks in some cases.

Recording the origin/designation of tissue blocks also facilitates retrieval of blocks for further immunohistochemical or molecular analysis, research studies or clinical trials.

Histologic Tumor Grade

Grading of Cervical Carcinoma. Tumor grade is regularly included in histopathology reports of cervical SCC and ACA. However, at present no particular grading system has achieved universal acceptance and grading of these tumors remains of uncertain clinical value 59,123,124. For example, grade is not among the factors considered in determining the Gynecology Oncology Group (GOG) score which is used to assess the need for adjuvant therapy following surgery for low-stage cervical carcinomas 125. Not uncommonly, studies that assess grade as a potential prognostic variable provide no details of the grading system employed, and this is also true of large multicentre investigations utilizing data from the Surveillance Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) 126,127. For these and other reasons (discussed below), tumor grading is not listed as core but rather a non-core element. While no particular grading system for squamous carcinoma is recommended, ISGyP has recently published a consensus statement on grading cervical ACA 128.

General Considerations. As with tumors arising in other anatomic sites, grading of cervical carcinomas has a considerable subjective component and this probably explains, at least in part, the variable proportion of well, moderately, and poorly differentiated tumors reported in different studies. However, some investigators have demonstrated reasonable intraobserver and interobserver agreement using more complex multifactor grading schemes in SCC (discussed below).

  • Almost all cervical SCCs are HPV-associated and given that HPV-associated SCCs very commonly have a “basaloid” morphology with minimal keratinization, they are very commonly poorly differentiated.
  • Most clinically advanced cervical carcinomas are treated with primary chemoradiation rather than surgery and histologic sampling may be limited to a small diagnostic biopsy. This may not be fully representative due to tumor heterogeneity and could be potentially misleading as regards tumor differentiation or grade 123. This may be particularly relevant since less differentiated appearing tumor elements may be located more deeply toward the invasive margin 59.
  • There is an implicit correlation between tumor type and grade in certain cervical carcinomas and therefore a separate grade may not be applicable. For example, pure villoglandular ACA of the cervix (considered a morphologic variant of usual-type HPV-associated ACA) is by definition a low grade neoplasm while clear cell carcinoma, as in the endometrium, is considered high grade by default 129. Similarly, “gastric-type” cervical ACAs and NECs are clinically aggressive regardless of their histologic pattern and therefore are best considered high grade automatically 130,131. There is no published grading system for cervical mesonephric ACAs. Several variants of cervical SCC are also recognized, although most do not differ from conventional SCC in terms of prognosis or therapy 132.
  • It is uncertain whether a truly “undifferentiated” cervical carcinoma should be regarded as a separate tumor subtype analogous, for example, to similar tumors arising in the endometrium.
  • Grading of very small superficially (early) invasive carcinomas of either squamous or glandular type is probably not possible or relevant.

Grading of Cervical SSC. Historically, cervical SCCs were graded using the Broder system or modifications thereof based upon the degree of keratinization, cytologic atypia and mitotic activity 133. In some schemes, the pattern of invasion (pushing vs. infiltrating) has also been taken into account 134. As noted above, this raises the issue whether such categorization represents a tumor subtype (arguably not further graded), or a grade within a spectrum of a single type of tumor. It should be noted that some studies have found that the keratinizing variant of large cell SCC actually has a poorer prognosis than the nonkeratinizing variant, an apparently paradoxical finding if keratinization is deemed to be evidence of better differentiation 135. This may be because unlike in skin, evidence of keratinization in the cervix is abnormal and therefore, should not be equated with being well-differentiated. It is also possible that some keratinizing SCCs of the cervix are not driven by HPV (HPV-independent SCCs), and these tumors, in the cervix and other organs, generally have a worse prognosis than HPV-associated tumors. It is also uncertain what proportion of small cell SCCs reported in the older literature would now be classified as high-grade NECs (small cell NECs), and this could potentially bias the supposedly poor outcome of this tumor category.

At present, no single grading system has been widely adopted in routine diagnostic practice and it is recommended at this time to not grade SCCs.

Grading of Cervical ACA. As with SCC, it is controversial whether grading has independent prognostic value in cervical ACA. While a correlation between higher grade and adverse outcomes has been reported 136–140, at least for poorly differentiated tumors, this has not been a universal finding 141,142. It should also be noted that some studies have included a variable proportion of less common histologic subtypes such as adenosquamous carcinoma, mesonephric, gastric-type and clear cell carcinoma 136,139,140, and often tumor details are not provided. Therefore, it is not clear whether the reported grading data are applicable to usual-type cervical ACA or have been biased by the inclusion of other more aggressive tumor subtypes (eg, gastric-type ACA).

There is a lack of consensus regarding the prognostic value of grading of endocervical ACAs and no universally adopted, validated system for grading exists. Despite this, clinicians expect tumor grade to be included in the pathology report, irrespective of whether it will influence treatment. Several grading schemes have been proposed, most combining an evaluation of the extent of solid tumor growth and nuclear grade, similar to the FIGO Staging System for grading endometrial endometrioid carcinoma 8–10, although some schemes modify the proportion of solid tumor required to separate grades 1 and 2 from 5% to 10%. Two sizeable studies using a 3-tier system with cut-off points for the proportion of solid architecture set at ≤10%, 11% to 50%, and >50%, with tumors upgraded for marked nuclear atypia, have demonstrated the independent prognostic value of tumor grade by multivariate analysis 140,143. Other studies have reached varied conclusions, although some, including large multicentre population analyses, have similarly found tumor grade to have independent prognostic value, although the grading systems used and histologic tumor types examined were not always reported 34,126,127,144–147.

Based on the available evidence, the ISGyP recommends that HPV-associated ACAs with ≤10% solid growth is designated grade 1, 11% to 50% solid growth is designated gGrade 2, and >50% solid growth is designated grade 3. Tumors should be upgraded in the presence of marked nuclear atypia involving the majority (>50%) of the tumor, and a confluent microacinar pattern is regarded as solid tumor growth. Tumors with a micropapillary, signet ring or invasive stratified mucinous carcinoma component should not be graded as these are automatically considered high grade. Grading is also not recommended for HPV-independent ACAs as most of these neoplasms exhibit intrinsically aggressive behavior regardless of their morphologic appearance. Importantly, grading should not be performed for gastric-type ACAs, particularly as these tumors may appear deceptively “low grade” yet still exhibit aggressive behavior. With the emergence of new aetiology and pattern-based classification systems for endocervical ACA, both of which offer effective risk stratification, traditional grading of these tumors may, in future, become redundant.

Grading of Cervical Adenosquamous Carcinoma. Although it has been suggested that adenosquamous carcinomas are graded on the basis of the degree of differentiation of both the glandular and squamous components, there is no well established grading system for these neoplasms which has been shown to be of prognostic significance.

Patterns of Invasion for HPV-associated ACAs

Recently, a system of assessing cervical ACAs based upon their invasive growth pattern has been developed, the Silva Pattern Classification, and this has been shown to be reproducible amongst pathologists and to correlate with the risk of lymph node metastasis and patient outcomes 148–152. If these findings are confirmed by additional studies, it may be argued whether this system could be considered a complement to, or even an alternative to, conventional grading. The latter has traditionally been based upon the cytoarchitectural pattern of the neoplasm itself but as noted above, tumor-stromal relationships including the pattern of stromal invasion have been included in earlier grading schemes of cervical SCC. It is important to highlight that the pattern classification is only applicable to HPV-associated cervical ACAs on complete resections (loop electrosurgical excision procedure or cone with negative margins, trachelectomies, hysterectomies). Studies have shown that the pattern classification is not clinically relevant in HPV independent cervical ACAs 153, and therefore, should not be applied in those scenarios. One study has also shown that the pattern classification is highly concordant between loop electrosurgical excision procedure and hysterectomy, but this was not shown for biopsies and hysterectomies 152.

The Silva Pattern Classification system for HPV-associated cervical ACAs was developed in 2013 in an attempt to correlate histologic invasion patterns to outcomes, regardless of tumor size or stage so that patients could potentially be spared unnecessary lymphadenectomies for cases with no risk of nodal involvement 149. Pattern A endocervical ACAs are characterized by well-formed glands frequently forming groups with relatively well preserved lobular architecture without destructive stromal invasion, single cells or detached clusters of tumor cells. There should be no solid growth or high grade cytology but complex intraglandular proliferations are acceptable (cribriforming or papillae). LVI should be absent in these lesions. Pattern B tumors show localized (limited/early) destructive invasion arising in a background of pattern A glands. Individual cells or clusters of tumor cells are seen in desmoplastic or inflamed stroma, and these foci can be single, multiple or linear at the base of the tumor, but should not exceed 5 mm contiguously. Pattern C tumors show diffuse destructive invasion that usually elicits a desmoplastic/inflammatory response. The glands can be angulated, or have a canalicular/labyrinthine appearance, and incomplete/fragmented (as seen in microcystic, elongated and fragmented pattern of endometrioid carcinomas) glands are frequent, sometimes associated with mucin lakes. Solid or confluent growth can also be seen. LVI can be present in either pattern B or C and should be documented separately. In the original study, the risk of lymph node metastases for the various patterns was 0%, 4.4%, 23.8% for patterns A, B and C, respectively. Subsequent studies have reproduced the original findings and also showed good reproducibility amongst pathologists 151,154–156. While more and larger prospective studies to evaluate and confirm these retrospective results are necessary, gynecologic surgeons are increasingly becoming aware of the classification system and this may in the future become an important part of surgical planning and prognostication. It should be emphasized that the classification can only be applied in HPV-associated ACAs which have been completely resected on loop/cone/trachelectomy/hysterectomy specimens.

Ancillary Studies. Ancillary testing is becoming increasingly important for diagnosis and treatment across all tumor types. In the cervix, immunohistochemistry for p16 and in-situ hybridization for HPV play vital roles in the diagnostic setting, and PD-L1 immunohistochemistry is necessary to determine eligibility for immunotherapy in treating recurrent/metastatic cervical cancer. In low resource countries, it may not be possible to perform immunohistochemical or molecular studies; however, histochemical stains can also be of value in certain situations.

Given the importance of the performance and accuracy of these markers, one should ensure proper, timely fixation of surgical specimens. It is also recommended that the best representative block(s) be designated in the pathology report block key to facilitate any future testing.

HPV Testing. HPV is universally accepted to play a key etiological role in cervical carcinogenesis. HPV is detectable in over 95% of preinvasive and invasive cervical carcinomas, with HPV 16 and 18 being the most frequent types 157. Molecular testing for HPV is useful for separating HPV-associated and HPV-independent cervical cancer. It may also be useful in confirming metastatic HPV-associated cervical neoplasms.

Immunohistochemistry. It is beyond the scope of this document to provide a detailed review of the immunophenotype of cervical neoplasms, but some relevant issues should be noted.

p16 Immunohistochemistry. Diffuse immunoreactivity (nuclear and cytoplasmic) for p16 is a surrogate marker of integrated high-risk HPV and is seen in malignant or high grade, premalignant epithelial lesions associated with high-risk HPV infections 158. In HSIL, the staining is typically contiguous involving two-thirds to full thickness of the epithelium, referred to as “block type” immunoreactivity. p16 is useful in the separation of HPV-associated and HPV-independent cervical cancers. AIS and high-risk HPV-associated cervical cancers also show strong diffuse p16 nuclear and cytoplasmic staining in nearly all tumor cells (close to 100%). However, it should be noted that other gynecological malignancies, for example uterine serous carcinoma and high-grade serous carcinoma of the ovary/fallopian tube typically exhibit strong diffuse immunoreactivity with p16. This should be distinguished from focal/patchy (so-called “mosaic-type”) staining, which is not in keeping with a high-risk HPV-associated neoplasm.

Immunohistochemistry: Cervical Versus endometrial ACA. Immunohistochemistry can be helpful in the differential diagnosis between a cervical and an endometrial ACA 159. In the distinction between an endometrial and a cervical origin for an ACA, the panels of markers which are useful will depend on the morphologic type and not just the site of origin. In the distinction between a high-risk HPV-associated (usual type) cervical ACA and a low-grade endometrial endometrioid ACA, the most useful immunohistochemical markers are p16 and hormone receptors (estrogen receptor and progesterone receptor) with cervical ACAs exhibiting diffuse (near every cell) immunoreactivity with p16 and usually negative or only focally positive staining with hormone receptors (with occasional exceptions). In contrast, low-grade endometrial endometrioid ACAs are usually diffusely positive with hormone receptors and exhibit patchy “mosaic-type” staining with p16. Even when low-grade endometrial endometrioid ACAs exhibit diffuse positivity with p16, this is still usually patchy with alternating positive and negative areas. Vimentin (usually positive in low grade endometrial endometrioid ACA and negative in cervical ACAs) and carcinoembryonic antigen (usually positive in cervical ACAs and negative in low-grade endometrial endometrioid ACAs) may also be of value. However, it should be emphasized that there may be unexpected positive and negative staining reactions with any of the markers. HPV studies will be of value in such cases.

In the distinction between a high-risk HPV-associated (usual type) cervical ACA and a high-grade endometrial ACA, p16, and hormone receptors are often of limited value. p53 immunohistochemistry and HPV studies may be of value in this scenario. Most uterine serous carcinomas and many other high-grade endometrial carcinomas exhibit mutation-type p53 staining (“all or nothing” staining) and are HPV negative. High-risk HPV-related cervical ACAs rarely, if ever, exhibit “mutation-type” p53 expression.

Immunohistochemistry of HPV-independent cervical ACAs. HPV-independent cervical ACAs have a different immunophenotype than usual HPV-associated ACAs. They tend to be negative or only focally positive with p16 and some, such as gastric type ACAs, may exhibit mutation-type staining with p53 160. Gastric type ACAs are usually positive with gastric markers such as MUC6 and HIK1083 and are flat negative with hormone receptors 160. There is no specific immunohistochemical marker of mesonephric ACAs but they tend to be flat negative with hormone receptors and may stain with CD10, TTF1 and GATA3 161,162. Clear cell carcinomas are usually hormone receptor negative, exhibit wild-type staining with p53 and may be positive with napsin A and hepatocyte nuclear factor 1-beta.

Immunohistochemistry of cervical NECs. Cervical NECs are variably positive with the neuroendocrine markers chromogranin A, CD56, synaptophysin and INSM1. Of these, INSM1 163 and synaptophysin are highly sensitive and specific, while CD56 is sensitive but lacks specificity. Chromogranin A is the most specific neuroendocrine marker but lacks sensitivity with only about 50% of these neoplasms being positive 51. Chromogranin A positivity is often very focal in small cell NECs with punctate cytoplasmic immunoreactivity which is only visible on high-power magnification. A diagnosis of small cell NEC can be made in the absence of neuroendocrine marker positivity if the morphologic appearances are typical. Small cell NEC may be only focally positive (often punctate cytoplasmic staining) or even negative with broad-spectrum cytokeratins. A diagnosis of large cell NEC requires neuroendocrine marker positivity and most of these neoplasms are diffusely positive with broad-spectrum cytokeratins.

A high percentage of primary cervical NECs are TTF1 positive, including some with diffuse immunoreactivity, and this marker is of no value in the distinction from a pulmonary metastasis 51. Most cervical NECs are diffusely positive with p16 secondary to the presence of high-risk HPV 51. Diffuse p63 nuclear positivity is useful in confirming a small cell variant of squamous carcinoma rather than small cell NEC. However, occasional cervical NECs exhibit p63 nuclear immunoreactivity 51.

PD-L1. PD-L1 immunostaining is approved as a biomarker for anti-PD-1-based immunotherapy in some countries 164–169. The United States Food and Drug Administration has approved the use of immunotherapy based on the Combined Positive Score (CPS), which comprises membranous staining in tumor cells as well as membranous or cytoplasmic staining in tumor-associated (both immediately peritumoral and intratumoral) lymphocytes and macrophages 164–166. Importantly, PD-L1 expression in inflammatory cells associated with normal adjacent epithelium and dysplasia should not be included in this assessment, nor should inflammation in stroma distant from the tumor. The CPS is averaged across the entire tumor, rather than focused exclusively on hot spots. The CPS equation is as follows: ((PD-L1-positive tumor cells + lymphocytes + macrophages)/(total number of tumor cells)×100. The maximum CPS is 100.

Histochemical Stains for Mucin Detection. Mucicarmine, PAS or alcian blue can be used to detect intracytoplasmic mucin in tumors that are morphologically ambiguous (squamous vs. ACA). This may be particularly helpful in differentiating between HSIL and SMILE or between SSC and poorly differentiated ACA or between SSC and invasive stratified mucin-producing carcinoma. Gastric type ACA expresses neutral gastric mucin that stains bright pink/magenta with the combined PAS/alcian blue stain, while endocervical and intestinal type acidic mucin stains dark blue/navy. This can be a helpful tool in detecting gastric type mucin in glandular neoplasias and preneoplastic lesions.

DISCUSSION

The major changes in the revised 4th edition of the ICCR dataset for the reporting of cervical carcinomas are few but significant and reflect the most recent updates in international guidelines for tumor classification and staging. The most significant change in tumor classification is the explicit need to report HPV-association for both squamous and glandular tumors of the cervix. It is now well-recognized, and reflected in the 2020 WHO Classification, that HPV-associated and HPV-independent SCCs and ACAs have different clinical outcomes and molecular underpinnings. This is particularly applicable to ACAs which are now not only categorized into 2 broad categories based on HPV association, but in the HPV-independent group further classified based on histologic and immunohistochemical features. The HPV-independent cervical ACAs include gastric-type, clear cell, mesonephric and endometrioid carcinoma. Serous carcinoma is no longer recognized as a distinct entity in the cervix, but rather either a drop metastasis from the corpus or adnexa or a high-grade variant of HPV-associated ACA, for example the micropapillary variant of HPV-associated ACA.

The other major update in histologic reporting of cervical ACAs is the Silva Pattern Classification which categorizes HPV-associated ACAs based on the amount of destructive stromal invasion and this has been shown to consistently correlate with risk of nodal metastases. While considered a noncore element, routine reporting of the Silva pattern is recommended and collecting this information will be important in obtaining more prospective data for future studies.

One problematic area in the reporting of cervical carcinomas is determining tumor dimensions and guidance is provided in several contentious areas such as multifocal tumors. This subject has become even more confusing since the 2018 FIGO staging revision eliminated horizontal extent as a staging parameter, relying only on depth of invasion for staging microscopic tumors. A common question asked regarding this update is how to stage superficially invasive tumors that are large/exophytic/clinically visible. The answer to this is that FIGO explicitly states that the horizontal extent is no longer used to stage cervical carcinomas in microscopic only disease, effectively excluding those that are large and clinically visible. Although microscopic horizontal extent is no longer required for staging, it is the recommendation of the Carcinoma of the Cervix Dataset Authoring Committee that this parameter still be included in reports, as it allows for data collection for future studies and provides a more complete picture of tumor dimensions, which treating physicians often desire. This dataset now also includes scenarios where it may be necessary to use tumor thickness rather than depth of invasion, for example, to appropriately stage exophytic tumors.

Grading of cervical carcinomas is another problematic area since there are no well-established grading schemes that correlate with clinical outcomes. This is particularly true for SCCs since most cervical SCCs would be considered “poorly differentiated” based on their typically basaloid appearance with minimal keratinization, yet studies have shown that the amount of keratin formation does not predict tumor behavior 135. Therefore, grading of cervical SCCs is not recommended. In contrast, although grading of cervical ACAs also does not have robust data-driven correlation with outcomes, the ICCR dataset follows the recommendations of the ISGyP to use ≤10% solid growth for well differentiated, 11% to 50% solid growth for moderately differentiated, and >50% solid growth for poorly differentiated, with allowance to upgrade by one grade if >50% of the tumor shows severe nuclear atypia. Again, this approach facilitates data collection for future studies and appeases clinicians who often ask for cervical ACAs to be graded. It should be noted that grading only applies to HPV-associated ACAs and excludes micropapillary, signet ring and stratified mucinous variants of HPV-associated ACA which are regarded as high-grade. HPV-independent ACAs are regarded as inherently high-grade and provision of a grade is not necessary.

New commentary has been added in the section on ancillary studies to stress the importance of fixation for accurate interpretation of PD-L1 and p16 immunohistochemistry and HPV in situ hybridization. In addition, detailed commentary on PD-L1 testing and its interpretation have been added, as this has important implications for targeted therapy of cervical carcinoma in the recurrent or metastatic setting. Finally, a section on frozen section of SLNs has been added to state that SLNs need not be sent routinely for frozen section, but only in the context of clinically or radiologically suspicious findings, as the yield with SLN frozen sections is low.

The changes to core and non-core elements are listed below.

Core elements:

  • Specimen dimensions: lateral extent of left and right parametrium is upgraded to core (now all of specimen dimensions is core).
  • Histologic tumor type: now consistent with the 2020 WHO Classification.
  • Provisional pathologic staging: Includes 2021 edition of UICC TNM 8th edition and upgrades this to core (alongside FIGO Staging which was already core).

Noncore elements:

  • Pattern classification for HPV-associated ACAs: added as new noncore element.
  • Lymph node status: added a noncore item to specify the size of maximum tumor deposit.
  • Ancillary studies: added a noncore item to specify representative blocks for ancillary studies.
  • Coexistent pathology: value added in “other possible precursor lesions”—atypical lobular endocervical glandular hyperplasia.

CONCLUSION

This paper describes the revision of the ICCR dataset for the reporting of cervical carcinomas. The dataset has been developed by an international panel of expert gynecological pathologists and a clinician with expertise in gynecological oncology. Core elements which should be recorded in cervical carcinoma pathology reports, and noncore elements which may be included, are defined along with response values for each element and explanatory notes/commentaries. Internationally peer reviewed, standardized evidence-based, structured pathology datasets facilitate consistent and accurate reporting, data collection, and comparison of epidemiological and pathologic parameters for quality and research purposes.

Acknowledgments

The authors acknowledge the support of ISGyP toward the production of this dataset. The author would like to acknowledge Meagan Judge from the ICCR for providing expert editorial and dataset administration management.

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Keywords:

Cervix; Carcinoma; Pathology; Dataset; Protocol; Tumor classification; Structured report; Synoptic report; ICCR

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