Data Set for the Reporting of Carcinomas of the Vagina: Recommendations From the International Collaboration on Cancer Reporting (ICCR) : International Journal of Gynecological Pathology

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Data Set for the Reporting of Carcinomas of the Vagina: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

Wong, Richard Wing-Cheuk F.R.C.P.A.; Webster, Fleur M.Sc.; Bosse, Tjalling M.D., Ph.D.; Focchi, Gustavo M.D., Ph.D.; Gilks, C. Blake M.D.; Hoang, Lynn M.D.; Howitt, Brooke E. M.D.; McAlpine, Jessica M.D.; Ordi, Jaume M.D.; Singh, Naveena F.R.C.Path.; Lax, Sigurd F. M.D., Ph.D.; McCluggage, W. Glenn F.R.C.Path.

Author Information
International Journal of Gynecological Pathology 41():p S23-S33, November 2022. | DOI: 10.1097/PGP.0000000000000883
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Abstract

Primary carcinomas of the vagina are uncommon tumors, accounting for <1% of female cancers worldwide 1. There is a paucity of published evidence and recommendations that addresses the reporting of resection specimens of these neoplasms. As far as we are aware, apart from the cancer protocol published by the College of American Pathologists (CAP) 2, there is no other existing pathology reporting data set available for vaginal carcinomas. This is in contrast to the wide accessibility of resources for other gynecological cancers. There is a practical need to develop evidence-based recommendations for vaginal carcinomas in order to ensure high data quality and uniform reporting for these neoplasms.

The International Collaboration on Cancer Reporting (ICCR) has previously developed several gynecological cancer data sets including those for endometrial, ovarian/fallopian tube/primary peritoneal and cervical carcinomas, the most common gynecological malignancies 3–5. All of the data sets are evidence-based and have been produced by a panel of internationally recognized expert gynecological pathologists and a single clinician in each specific field. The gynecological data sets have been subject to international open consultation, and are freely available online from the ICCR website for worldwide use (http://www.iccr-cancer.org/datasets/published-datasets/female-reproductive). The process of production of each of these data sets and the reporting elements have been published in peer-reviewed journals 3–5. This ICCR data set on vaginal carcinomas is one of the 4 newly produced data sets, the others covering vulval carcinomas, gestational trophoblastic neoplasia, and uterine malignant and potentially malignant mesenchymal tumors. It is anticipated that these new data sets will provide evidence-based recommendations for pathologists worldwide when handling resection specimens of these less common gynecological malignancies.

METHODS

The ICCR has developed a set of standard operating procedures for the process of data set development [described in previous publications 3–5], and also defined the selection process, roles and responsibilities of the chair, expert panel members, the ICCR Dataset Steering Committee representative(s) on the panel, ICCR Series Champion, and the project manager. The ICCR Series Champion provided guidance and support to the Chair of the Dataset Authoring Committee (DAC) regarding ICCR standards and ensured harmonization across gynecological data sets. After the expert panel was established, the project manager collated existing international data sets for vaginal carcinomas (as discussed, only the CAP protocol was available) and scheduled a series of teleconferences to review and discuss each of the elements proposed to be included in the data set.

The cancer data set comprises a scope (see below) and series of elements which are considered important for clinical management, staging or prognosis of the cancer. Elements are included by consensus agreement of the DAC (the expert panel members). An element may be designated as core (required) or noncore (recommended) by the DAC as described below.

Core elements are those which are agreed by the DAC to be essential for the clinical management, staging or prognosis of the cancer. These elements will either have 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 6]. When level III-2 evidence is not available, an element may be designated as core where there is unanimous agreement by the DAC. The list of all core elements is considered to be the minimum reporting standard for the specific type of cancer.

Noncore elements are those which the DAC unanimously agree should be included in the data set but are not supported by level III-2 evidence. These elements may be clinically important and recommended as good practice but are not yet validated or regularly used in patient management.

Once the elements were agreed by the panel, the members then discussed and agreed on the value list of responses to each element. The Chair of the DAC then assigned the writing of a commentary for each element to members of the panel, based on a review of the current literature. The commentary comprises explanatory text, diagrams or tables to clarify core and noncore elements, presents the relevant evidence for each element, and defines the way each element should be reported. The lists of core and noncore elements and the associated commentaries are presented below. For those data set items which include both core and noncore elements, they are included in the core elements section in this paper.

The draft data set was subject to an international public consultation which involved sending the document to multiple stakeholders, mainly but not exclusively pathology societies, throughout the world and inviting them to comment. All feedback received was reviewed by the DAC. The finalized data set was subsequently submitted to the ICCR Dataset Steering Committee for ratification and publication. All of the ICCR data sets, including this one on vaginal carcinomas, are freely available worldwide at the ICCR website at https://www.iccr-cancer.org/datasets.

SCOPE OF THE DATA SET

The data set has been developed for the pathologic reporting of resection specimens of primary carcinomas of the vagina (including carcinosarcomas).

Hematopoietic neoplasms, mesenchymal neoplasms, mixed epithelial and mesenchymal neoplasms, malignant melanomas, other nonepithelial malignancies and metastatic tumors are excluded from this data set. Due to the rarity of primary vaginal carcinomas, there is little published research regarding some of the elements included in this data set and some of the parameters included are “extrapolated” from primary cervical and vulval carcinomas and/or represent the opinions and experience of the members of the DAC.

CORE DATA ELEMENTS

A list of the core elements for the reporting of vaginal carcinomas is presented in Table 1.

TABLE 1 - Core data elements for pathologic reporting of resection specimens of primary carcinomas of the vagina
Clinical Macroscopic Microscopic Other
Clinical information Specimen dimensions Histologic tumor type Ancillary studies
 History of previous cancer Prior neoadjuvant therapy In-utero exposure to DES History of vaginal adenosis Operative procedure Tumor dimensions  Maximum horizontal  tumor dimension  Depth of invasion Lymphovascular invasion Margin status  Margin status for invasive  tumor  Distance of invasive tumor from  closest peripheral margin  Distance of invasive tumor from  deep margin  Margin status for high-grade  precursor lesions Lymph node status  Number of nodes examined  Number of positive nodes  Size of maximum tumor deposit  Extracapsular spread Coexistent pathology/precursor lesions  Low-grade squamous  intraepithelial lesion  High-grade squamous  intraepithelial lesion  Adenosis  Other precursor lesions Pathologically confirmed distant metastasis Provisional pathologic staging  FIGO or TNM staging (UICC/AJCC 8th edition)  p16 immunohistochemistry and/or HPV testing for squamous cell carcinoma
AJCC indicates American Joint Committee on Cancer; DES, diethylstilbestrol; FIGO, International Federation of Obstetricians and Gynaecologists; HPV, human papillomavirus; UICC, Union for International Cancer Control.

Clinical Information

In most ICCR data sets, clinical information is a noncore element but the DAC felt that clinical information is vital in reporting vaginal carcinomas and thus this is included as a core element. In reporting a vaginal carcinoma, knowledge of a history of any prior tumor, precursor lesion or treatment is important. While in many cases, this information can be identified from the laboratory information system/electronic care record, this is not always the case and this information should be provided by the clinician on the specimen request form. This is especially so with vaginal squamous cell carcinoma (SCC) since tumor recurrence is common. Knowledge of a history of a prior cervical carcinoma is important since before diagnosing a primary vaginal SCC, exclusion of a cervical primary is mandated; although there are no “hard and fast” rules, a diagnosis of a cervical SCC concomitantly or in the past 5 yr is usually taken as evidence for exclusion of a primary vaginal SCC 7. Knowledge of a history of a prior malignancy is also important in reporting the very rare primary vaginal adenocarcinomas since a metastasis, from elsewhere in the female genital tract or outside this (especially the colorectum), should always be excluded before rendering such a diagnosis. A history of vaginal adenosis is also important since some primary vaginal adenocarcinomas of clear cell, gastric or human papillomavirus (HPV)-associated types arise in adenosis, which may be sporadic or secondary to in utero exposure to diethylstilbestrol (DES) 8–11. Some primary vaginal endometrioid adenocarcinomas arise in endometriosis and this may be stimulated by hormones, including unopposed estrogens. Knowledge of a history of any prior neoadjuvant therapy (chemotherapy, radiotherapy, chemoradiation) is also important since this can have a marked effect on the pathological appearances of the neoplasm (gross and morphologic).

Operative Procedure

Vaginectomy describes removal of the vaginal mucosa by either a vaginal or abdominal approach and may be partial or total 12,13. The extent of vaginectomy depends on various parameters such as the location of the lesion, patient preference/expectations, prior hysterectomy, prior radiation, hormonal status, and proximity to other vital structures.

Vaginectomy specimens may also be part of a pelvic exenteration specimen.

The “other” category may be used to cover other organs, which have been removed as part of the operative procedure.

Specimen Dimensions

Although not necessary for staging, clinical management or prognosis, it is recommended that the specimen dimensions be recorded on the pathology report 2,14. This gives clinicians dealing with the patient an indication as to how radical a resection has been undertaken.

Tumor Dimensions

Measurement of tumor dimensions in vaginal carcinomas is important for accurate staging, patient management and prognostication. Tumors should be measured in millimetres. The maximum horizontal dimension is the greatest tumor dimension measured parallel to the mucosal surface. This measurement is typically made based on macroscopic assessment for larger tumors but for very small tumors this may be best measured or can only be measured on the histologic section. A second horizontal dimension taken perpendicular to the first and also parallel to the mucosal surface is often included in the pathology report but this is not necessary for staging, management, or prognostication. The depth of invasion should also be reported. While there are no widely used recommendations for measuring depth of invasion, it is recommended that this is taken from the base of the epithelium from which the tumor arises to the deepest point of invasion.

Note that the final pathology report should only contain one set of measurements; in other words, there should not be separate gross and microscopic measurements in the report. The single set of measurements provided should be based on a correlation of the gross and microscopic features, with gross examination being more important for some tumor measurements and microscopic examination for others.

In providing the final tumor dimensions, the measurements in a prior specimen, for example an excisional biopsy, may 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. The depth of invasion can be taken as the maximum depth of invasion in the 2 different specimens.

If the tumor involves a margin, a comment should be made regarding the possibility of underestimation of the horizontal dimension or depth of invasion.

Histologic Tumor Type

All vaginal carcinomas should be typed according to the most recent edition of the World Health Organization (WHO) Classification of Female Genital Tumours, 5th edition, 2020 (Table 2) 15. The ICCR data set includes 5th edition Corrigenda, June 2021 17. While SCC is by far the most common carcinoma to arise in the vagina, these neoplasms are uncommon and thus care should be taken to rule out secondary involvement from adjacent sites, especially the cervix and vulva. Although there are no “hard and fast” rules, a diagnosis of a cervical SCC in the past 5 yr is usually taken as evidence for exclusion of a primary vaginal SCC. Aligning with SCC of the vulva and cervix, SCC of the vagina is divided in the 2020 WHO Classification 15 into HPV-associated and HPV-independent types. HPV-associated SCC are secondary to persistent infection by oncogenic high-risk HPV (most commonly type 16) and are associated with smoking, immunosuppression, and often multifocal disease including HPV-associated lesions in other areas of the lower female genital tract (vulva, cervix) and anal/perianal regions 18,19. Similar to the vulva, primary vaginal HPV-associated SCC are more likely to be nonkeratinizing, basaloid and warty, while HPV-independent SCC are more likely to be keratinizing. The presence of an adjacent high-grade squamous intraepithelial lesion (HSIL) may be useful in suggesting an HPV-associated lesion. However, as in the vulva, in practice, ancillary testing is necessary to determine the HPV status given the overlap in morphology in some cases (see the Ancillary studies section) 19,20. When HPV status cannot be confidently determined or resources are not available to undertake ancillary testing, a morphologic diagnosis of SCC, not otherwise specified is acceptable, although this is not recommended. Although because of the rarity of these neoplasms within the vagina, evidence is much more limited compared with the vulva, HPV-independent SCC have worse disease-free and overall survival compared with HPV-associated SCC, independent of age and stage 21.

TABLE 2 - World Health Organization classification of malignant epithelial tumors of the vagina 15
Descriptor ICD-O codes*
Squamous cell carcinoma, HPV-associated 8085/3
Squamous cell carcinoma, HPV-independent 8086/3
Squamous cell carcinoma NOS 8070/3
Adenocarcinoma NOS 8140/3
Adenocarcinoma, HPV-associated 8483/3
Endometrioid adenocarcinoma NOS 8380/3
Clear cell adenocarcinoma NOS 8310/3
Mucinous carcinoma, gastric type 8482/3
Mucinous adenocarcinoma 8480/3
Mesonephric adenocarcinoma 9110/3
Carcinosarcoma NOS 8980/3
Carcinoma of Skene, Cowper, and Littré glands 8140/3
Adenosquamous carcinoma 8560/3
Adenoid basal carcinoma 8098/3
*These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2). 16 Behavior is coded /0 for benign tumors; /1 for unspecified, borderline, or uncertain behavior; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumors, primary site; and /6 for malignant tumors, metastatic site. Incorporates all relevant changes from the 5th Edition Corrigenda June 2021 17.
HPV indicates human papillomavirus; NOS, not otherwise specified.
Reproduced with permission. Copyright World Health Organization/International Agency for Research on Cancer, Lyon, France. All permission requests for this image should be made to the copyright holder.

Grading of vaginal SCC is not recommended and is not included as a core or noncore item in this data set. Grading has not been shown to correlate with clinical outcome. In fact, as with vulval SCC, there is a paradox in that HPV-independent SCC, which tend to be keratinizing and often well-differentiated have a worse prognosis than HPV-associated SCC, which are typically nonkeratinizing, basaloid and poorly differentiated. In addition, no validated grading system exists for primary vaginal SCC.

Primary adenocarcinomas of the vagina are extremely rare and of various morphologic types, including HPV-associated, endometrioid, clear cell, mucinous (gastric-type or intestinal-type) and mesonephric; adenocarcinoma of periurethral Skene gland origin may also occur and present as a primary vaginal neoplasm 8,9,22–24. The specific histologic type should be specified in the report. These categories of adenocarcinoma are broadly similar to those described in the cervix and before diagnosing a primary vaginal adenocarcinoma, a metastasis from elsewhere should always be excluded. The most likely alternative site of primary depends on the morphological type. For example, before diagnosing an HPV-associated adenocarcinoma or a gastric-type adenocarcinoma, a primary in the cervix should be excluded and before diagnosing an intestinal-type adenocarcinoma, a large intestinal primary should be ruled out. Some primary vaginal adenocarcinomas, for example, those of gastric, HPV-associated and clear cell type may be associated with and arise from vaginal adenosis via “atypical adenosis” which is usually sporadic but which may be secondary to in utero exposure to DES.

Carcinosarcomas, adenosquamous carcinomas, and adenoid basal carcinomas are extremely rare as primary neoplasms in the vagina and before diagnosing a primary vaginal carcinosarcoma or adenosquamous carcinoma, a metastasis from another site in the female genital tract should be excluded. Neuroendocrine neoplasia is classified according to the 2020 WHO Classification 15 (neuroendocrine tumor, small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, mixed neuroendocrine non-neuroendocrine carcinoma); again, these are extremely rare primary vaginal neoplasms.

Lymphovascular Invasion

There is a lack of published evidence regarding the prognostic significance of lymphovascular invasion in primary vaginal carcinomas probably due to the rarity of these neoplasms. Two studies evaluated lymphovascular invasion as a prognostic factor for primary vaginal carcinoma 25,26; this was not statistically significant in one study 25 and no conclusion was documented in the other 26. The consensus of the DAC supports including lymphovascular invasion as a core item, based on its possible role in altering clinical management in some cases, and also by extrapolating from cervical and vulval carcinomas, many of which are biologically analogous to vaginal carcinomas.

While usually straightforward, the assessment of lymphovascular invasion may be difficult in a minority of cases, for which the reasons may include (but are not limited to) suboptimal fixation, “carry-over” or cauterization artifacts. In such cases, examination of multiple levels and/or immunostaining for endothelial or lymphatic markers (such as CD31, CD34, D2-40) may be employed to assist with the decision-making. Cases that are still equivocal after taking additional steps may be reported as “indeterminate” for lymphovascular invasion, but this designation should only be sparingly used and it is useful to provide the reason in a comment in the report.

Margin Status

Due to the rarity of primary vaginal carcinomas, there is little published research regarding the value of positive tumor margins or distance from tumor to the various margins in predicting tumor recurrence and prognosis. However, by extrapolation from primary cervical and vulval carcinomas and the opinions and experience of the members of the DAC, tumor involvement of or distance from the margins are considered to represent a core element. Appropriate sections need to be taken to include the nearest peripheral mucosal margin and the deep margin and assessment of the margins may be facilitated by the placing of sutures or provision of a diagram or photograph by the clinician. Separate gross and microscopic distances to margins should not be provided on the pathology report but rather a single set of measurements. To ensure a standardized approach regarding margin measurements for vaginal carcinomas, it is recommended that surgical margins should be inked and the following recommendations adhered to:

  • Involvement of a peripheral mucosal surgical margin by tumor should be recorded and the margin specified if possible.
  • The minimum distance from invasive carcinoma to the peripheral margin should be reported and the margin specified if possible.
  • Involvement of a peripheral margin by a high-grade precursor lesion (HPV-associated HSIL) should be recorded and the margin specified if possible. Margin involvement by a low-grade precursor lesion (low-grade squamous intraepithelial lesion) does not need to be recorded.
  • The distance of a high-grade precursor lesion from the nearest peripheral margin is regarded as a noncore element but it is recommended that this measurement be included in the report and collection of this data prospectively may facilitate future studies which will determine the importance of this.
  • The minimum distance of invasive tumor to the deep soft tissue margin should also be recorded. This should be measured from the deepest infiltrating tumor nest to the deep soft tissue margin.

Lymph Node Status

The vagina has complex lymphatic drainage. The upper two-thirds of the vagina, the location of the majority of carcinomas, drains like the uterine cervix into pelvic lymph nodes (obturator, internal iliac/hypogastric, and external iliac), and rarely to the para-aortic lymph nodes. The lower one-third drains like the vulva into the inguinofemoral lymph nodes. Tumors arising in the middle third of the vagina may spread to both pelvic and inguinofemoral nodes and defining “regional” nodes may not be possible in each case, especially as the pathologist may not be aware of the location of the tumor. This is reflected in the International Federation of Gynecology and Obstetrics (FIGO) Staging System 27,28, where only involvement of “nearby lymph nodes,” that is, pelvic or groin, is taken into account.

When lymphadenectomy is performed, one or more sections of all identified nodes should be submitted for histologic examination, including sections containing perinodal fat to confirm the presence or absence of extracapsular extension, especially if grossly suspected. For nodes which are grossly involved by tumor, representative sampling is acceptable, whereas nodes which are not suspicious should be submitted in their entirety after sectioning at 2 mm intervals perpendicular to the long axis of the node.

The anatomic location and number of lymph nodes dissected, the number containing tumor, the size of the largest tumor deposit and the presence or absence of extracapsular spread should be accurately documented in the pathology report. According to TNM8 29, nodal involvement should be recorded as the presence of isolated tumor cells (<0.2 mm), micrometastases (0.2–2 mm) or macrometastases (>2 mm). Macrometastases are regarded as pN1, micrometastases as pN1 (mi) and isolated tumor cells are pN0 (i+); isolated tumor cells do not upstage a carcinoma.

Coexistent Pathology/Precursor Lesions

Recording the presence of precursor lesions and coexistent pathology is important for vaginal SCC since this gives insight into the pathogenesis of the tumor, specifically whether it is HPV-associated or HPV-independent. Margin involvement by a high-grade precursor lesion is also important (see the Margin status section). The presence of HPV-associated squamous intraepithelial lesion (low-grade squamous intraepithelial lesion or HSIL) should be recorded. HSIL (vaginal intraepithelial neoplasia grades 2/3) is the precursor of HPV-associated vaginal SCC and, as discussed earlier (see the Histologic tumor type section), is associated with smoking, immunosuppression and often multifocal disease including HPV-associated lesions in other areas of the lower female genital tract (vulva, cervix) and anal/perianal regions 18,19. Unlike in the vulva, there is currently no recognized precursor lesion of HPV-independent vaginal SCC. p16 may be useful in diagnosing HSIL and in distinguishing this from morphologic mimics (see the Ancillary studies section).

There are also recognized precursor lesions of some primary vaginal adenocarcinomas and these should be recorded on the pathology report; the presence of these lesions may be useful in helping to confirm a vaginal primary and in excluding a metastasis from elsewhere. Some of these adenocarcinomas, for example, those of gastric, HPV-associated and clear cell type may be associated with and arise from vaginal adenosis via “atypical adenosis” which is usually sporadic but which may be secondary to in utero exposure to DES 8. Primary vaginal endometrioid adenocarcinomas may arise in endometriosis 23, and intestinal-type adenocarcinomas may arise in tubular and tubulovillous adenomas 22. Mesonephric adenocarcinomas may arise from benign mesonephric remnants.

Ancillary Studies

As discussed (see the Histologic tumor type section), the 2020 WHO Classification categorizes vaginal SCC into 2 main types, HPV-associated and HPV-independent 6, with prognostic implications which have already been discussed 18,20,21,30,31. This new diagnostic approach has consequences since, as discussed, morphology is not always reliable in distinguishing between the 2 types. It implies that the use of ancillary techniques, namely p16 immunohistochemistry and/or HPV molecular testing, are considered as essential to correctly classify vaginal SCC 7. p16 immunohistochemistry and/or HPV testing is considered a core element in cases of vaginal SCC. In practice, almost all laboratories will perform p16 immunohistochemistry rather than HPV testing. As discussed earlier, when HPV status cannot be confidently determined or resources are not available to undertake ancillary testing, a morphological diagnosis of SCC, NOS is acceptable, although this is not recommended. This is especially likely in laboratories in low- and middle-income settings and including these ancillary techniques as a core element may enable laboratories to introduce these tests. If p16 immunohistochemistry and/or HPV testing has been performed on a diagnostic biopsy, it does not need to be repeated on the resection specimen, although it is useful to record the results on the report of the resection specimen. Similarly, these tests do not need to be repeated on a tumor recurrence.

The 2 accepted tools for confirming an HPV-association are the direct identification of HPV products (DNA or mRNA) and the presence of immunohistochemical overexpression of p16, a cell protein typically overexpressed in transforming HPV infections. Although the results of both methods are usually in agreement and it has been proposed that a positive result with both techniques is the gold standard for classifying a tumor as HPV-associated, a small number of discrepancies are observed when the 2 techniques are applied. Moreover, many laboratories may not have access to HPV testing and, as discussed, p16 immunohistochemistry is likely to be the method of choice in most laboratories.

One of the main challenges of HPV molecular testing methods in tissue samples is that HPV identification is usually performed on formalin-fixed, paraffin-embedded tissues, which may result in limitations due to fragmentation of DNA and RNA associated with the tissue processing. Thus, highly sensitive methods, such as SPF10 PCR testing are the most used tests, but large series have reported both false positive and false negative results with this test 32–34. In situ hybridization for HPV E7 mRNA, one of the oncogenic HPV genes, has shown good results in tumors of the uterine cervix 35 but the experience in vaginal lesions is limited.

p16 immunohistochemical staining generally shows a good correlation with HPV testing, although there are few studies specifically focusing on vaginal lesions. Although isolated cases of HPV-associated tumors with “negative” p16 staining have been reported in the cervix and vulva 36, there is evidence indicating that the accuracy to classify a tumor as HPV-associated or HPV-independent is probably higher for p16 than for most of the available HPV tests 32. In addition to its high accuracy, p16 immunohistochemistry is available in most pathology laboratories. It is important to stress that only so-called “block-type” p16 staining in a squamous lesion (in situ or malignant) is supportive of an association with oncogenic high-risk HPV. Block-type staining in an in situ lesion is defined as strong and continuous nuclear or more typically nuclear and cytoplasmic expression in all epithelial cells in the basal and parabasal layers with upward extension. Upward extension must involve at least the lower one-third of the epithelial thickness and expression must extend for at least 6 cells across 37. It is acknowledged that the criteria defining the horizontal and upward extent are arbitrary but these serve to improve specificity. In HPV-associated SCC, there is typically diffuse positive staining involving almost every tumor cell but keratinous areas may be negative. It is also stressed that p16 staining should not be reported simply as positive since HPV-independent premalignant and malignant lesions and non-neoplastic tissues may exhibit focal (so-called mosaic) staining. Instead terms such as “block-type,” “abnormal,” or “aberrant” should be used in the pathology report or alternatively when the term positive is used this should be qualified as diffuse or “block-type.”

Other ancillary studies are regarded as noncore and when undertaken the results should be documented on the pathology report. One of the most useful markers is p53 and many HPV-independent vaginal SCC contain TP53 mutations. Almost all HPV-associated SCC and high-grade precursor lesions exhibit a “wild-type” pattern of p53 immunoreactivity while many HPV-independent SCC exhibit “mutation-type” immunoreactivity.

Other immunohistochemical markers and ancillary studies may be of value in helping to classify primary vaginal adenocarcinomas. For example, HPV-associated adenocarcinomas exhibit diffuse block-type p16 immunoreactivity and are HPV positive. Intestinal-type adenocarcinomas may be positive with intestinal markers such as CK20 and CDX2, mesonephric carcinomas with GATA3, CD10, and TTF1 and clear cell carcinomas are typically positive with napsin A. Skene gland adenocarcinomas are usually positive with prostatic markers such as prostate-specific antigen, prostatic acid phosphatase, and NKX3.1.

Pathologically Confirmed Distant Metastasis

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 should be provided on the pathology report and is therefore a core element. The term “provisional pathologic staging” is used in this data set to indicate that the stage that is provided may not represent the final tumor stage which should be determined at the multidisciplinary board meeting where all the pathologic, clinical, and radiologic features are available 27–29,38.

The latest version of either FIGO or TNM staging or both, can be used depending on local preferences 27–29,38. The FIGO Staging System is in widespread use internationally and is the system used in most clinical trials and research studies. However, Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) versions of TNM are used or mandated in many parts of the world 29,38. 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 systems are broadly concurrent.

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 post-therapy stage.

The reference document TNM Supplement: A commentary on uniform use, 5th Edition, may be of assistance when staging 39.

NONCORE DATA ELEMENTS

A list of noncore elements for the reporting of vaginal carcinomas is presented in Table 3.

TABLE 3 - Noncore data elements for pathologic reporting of resection specimens of primary carcinomas of the vagina
Macroscopic Microscopic Other
Tumor site Margin status Ancillary studies
Block identification key  Distance from high-grade precursor lesions to closest peripheral margin  Ancillary studies other than p16 immunohistochemistry and HPV testing (such as p53 immunohistochemistry) for squamous cell carcinoma p16 immunohistochemistry, HPV testing, and/or other ancillary studies for nonsquamous histologic types
HPV indicates human papillomavirus.

Tumor Site

Most primary carcinomas arise in the upper two-thirds of the vagina. Recording the location within the vagina of a primary carcinoma may be important for several reasons and is facilitated by the specimen being orientated by the surgeon in the absence of attached anatomical structures. Exclusion of secondary involvement by a cervical (or upper genital tract) neoplasm is more important in tumors located in the upper two-thirds of the vagina 7. HPV-associated SCC tend to arise in the upper two-thirds of the vagina, while HPV-independent SCC tend to involve the lower-third 7,21. HPV-independent clear cell carcinomas related to in utero exposure to DES show a predilection for the upper two-thirds 7, mesonephric adenocarcinomas are usually located in the lateral walls 7 and mucinous carcinomas of intestinal type in the lower posterior third 22. In addition, there are different, albeit not always predictable, lymphatic drainage patterns of the upper, middle and lower thirds of the vagina 40,41.

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.

DISCUSSION

Publicly available resources and data sets regarding reporting of resection specimens of primary vaginal carcinomas are scarce, probably in large part due to the rarity of these neoplasms. As such, the reporting practice of individual pathologists is likely to significantly vary across different centers, which is an obstacle to collecting consistent information to help benchmarking and to facilitate research studies on vaginal carcinomas.

In the process of the vaginal carcinoma data set development, it was acknowledged by the DAC that there is extremely limited published evidence specifically addressing many of the parameters. The inclusion and designation of certain data items thus represents an extrapolation from the data sets for cervical and vulval carcinomas. SCC of the vagina, which accounts for a large majority of vaginal carcinomas, shares similar pathways of pathogenesis to its cervical and vulval counterparts with HPV-associated and HPV-independent neoplasms and there is limited evidence that this is of prognostic significance with HPV-associated neoplasms having a better prognosis 21. Although the prognostic significance of distinguishing between HPV-associated and HPV-independent SCC is not as clearly demonstrated as in the vulva, routine reporting of this which requires p16 immunohistochemistry and/or HPV molecular testing is recommended and these ancillary studies are regarded as a core element. Regarding the nonsquamous histologic types of vaginal carcinoma, which chiefly comprise various pathogenetically distinct types of adenocarcinomas, all of these are rare tumors with only case reports or small series in the literature. While the relevance of certain data elements for these rare tumor types may not be supported by clear evidence, we hope that the routine application of this data set to these cases will facilitate the collection of consistent data for future studies. Given the rarity of primary vaginal carcinomas, future studies will be difficult unless they comprise multi-institutional collaborative efforts.

Several controversial issues were addressed during the development of the data set. One major issue was whether tumor grading, which is traditionally included as an element for most tumor types in various organs and which is often requested by clinicians, should be included as a data element. Apart from the lack of validation studies and proven prognostic value for any grading system in the vagina, the DAC believe that the conventional grading of SCC based on the extent of keratinization is misleading to clinicians. As discussed, well-differentiated and keratinizing vaginal SCC are often HPV-independent and thus tend to be aggressive, whereas poorly differentiated tumors with no or minimal keratinization are usually HPV-associated with a better prognosis 21. The DAC decided not to include tumor grading as a core or noncore element for vaginal SCC. It is of interest that a novel grading system based on tumor budding and cell nest size has been proposed for cervical SCC as well as SCC of several nongynecological organs 42–44; whether similar systems could be applied to vaginal SCC warrants further studies but these are likely to be difficult due to the rarity of this neoplasm and, as discussed, will likely require collaborative multi-institutional studies.

There are certain other aspects of reporting that are relatively unique to vaginal carcinomas and deserve special attention. Clinical information and precursor lesions play a significant role in defining the histologic tumor type and the distinction between a primary and metastatic tumor. Regarding the margin status for precursor lesions, while the involvement of a peripheral margin by a high-grade precursor lesion should be routinely reported (core element), the distance from a high-grade precursor lesion to the margin is designated as a noncore element, the significance of which may be clarified by routine collection of this information which will facilitate future studies. Regarding ancillary studies, p16 immunohistochemistry, and/or HPV testing is regarded as a core element in determining the HPV status of a vaginal SCC since this is more reliable than morphology alone.

CONCLUSIONS

This paper describes the development of the ICCR data set for the reporting of resection specimens of primary vaginal carcinomas. The data set was developed by the consensus of an international panel of expert gynecological pathologists and a clinician after reviewing the latest published evidence. A list of core and noncore data elements are provided, together with explanatory commentaries which incorporate the concepts and terminology in the 2020 WHO Classification 15. We hope that the implementation of this data set worldwide will facilitate the collection and comparison of data on a global scale, which can be used for research and benchmarking, thereby contributing to improved patient outcomes.

Acknowledgments

The authors acknowledge the support of the International Society of Gynecological Pathologists (ISGyP) toward the production of this data set.

REFERENCES

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424.
2. College of American Pathologists. Protocol for the examination of resection specimens from patients with primary carcinoma of the vagina. 2021. Available at: https://documents.cap.org/protocols/Vagina_4.3.0.0.REL_CAPCP.pdf. Accessed July 1, 2021.
3. McCluggage WG, Colgan T, Duggan M, et al. Data set for reporting of endometrial carcinomas: recommendations from the International Collaboration on Cancer Reporting (ICCR) between United Kingdom, United States, Canada, and Australasia. Int J Gynecol Pathol 2013;32:45–65.
4. McCluggage WG, Judge MJ, Clarke BA, et al. Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR). Mod Pathol 2015;28:1101–22.
5. McCluggage WG, Judge MJ, Alvarado-Cabrero I, et al. Data set for the reporting of carcinomas of the cervix: recommendations from the International Collaboration on Cancer Reporting (ICCR). Int J Gynecol Pathol 2018;37:205–28.
6. Merlin T, Weston A, Tooher R. Extending an evidence hierarchy to include topics other than treatment: revising the Australian “levels of evidence”. BMC Med Res Methodol 2009;9:34.
7. Herrington CS, Kim K-R, Kong CS, et al. WHO Classification of Tumours Editorial Board. Tumours of the vagina. Female Genital Tumours, WHO Classification of Tumours (Vol 4), 5th ed. Lyon: IARC Press; 2020:391–418.
8. Wong RW, Moore M, Talia KL, et al. Primary vaginal gastric-type adenocarcinoma and vaginal adenosis exhibiting gastric differentiation: report of a series with detailed immunohistochemical analysis. Am J Surg Pathol 2018;42:958–70.
9. Voltaggio L, McCluggage WG, Iding JS, et al. A novel group of HPV-related adenocarcinomas of the lower anogenital tract (vagina, vulva, and anorectum) in women and men resembling HPV-related endocervical adenocarcinomas. Mod Pathol 2020;33:944–52.
10. Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer 1970;25:745–57.
11. Robboy SJ, Young RH, Welch WR, et al. Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring. Cancer 1984;54:869–75.
12. Karam A, Berek JS, Kidd EA. Vaginal cancer. 2021. Available at: https://www.uptodate.com/contents/vaginal-cancer. Accessed February 14, 2021.
13. Chi DS, Berchuck A, Dizon DS, et al. Principles and Practice of Gynecologic Oncology. Philadelphia: Lippincott Williams & Wilkins; 2017.
14. Heatley MK. Dissection and reporting of the organs of the female genital tract. J Clin Pathol 2008;61:241–57.
15. WHO Classification of Tumours Editorial Board. Female Genital Tumours, WHO Classification of Tumours (Vol 4), 5th ed. Lyon: IARC Press; 2020.
16. Fritz A, Percy C, Jack A, et al. International Classification of Diseases for Oncology, 3rd ed, Second revision ICD-O-32. Geneva: World Health Organization; 2020 . Available at: http://www.iacr.com.fr/index.php?option=com_content&view=category&layout=blog&id=100&Itemid=577. Accessed June 16, 2021.
    17. WHO Classification of Tumours Editorial Board. Female Genital Tumours, WHO Classification of Tumours, 5th ed, Volume 4—Corrigenda June 2021. 2021. Available at: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Female-Genital-Tumours-2020. Accessed June 16, 2021.
    18. Ferreira M, Crespo M, Martins L, et al. HPV DNA detection and genotyping in 21 cases of primary invasive squamous cell carcinoma of the vagina. Mod Pathol 2008;21:968–72.
    19. Bertoli HK, Rasmussen CL, Sand FL, et al. Human papillomavirus and p16 in squamous cell carcinoma and intraepithelial neoplasia of the vagina. Int J Cancer 2019;145:78–86.
    20. Fuste V, del Pino M, Perez A, et al. Primary squamous cell carcinoma of the vagina: human papillomavirus detection, p16(INK4A) overexpression and clinicopathological correlations. Histopathology 2010;57:907–16.
    21. Alonso I, Felix A, Torné A, et al. Human papillomavirus as a favorable prognostic biomarker in squamous cell carcinomas of the vagina. Gynecol Oncol 2012;125:194–9.
    22. Staats PN, McCluggage WG, Clement PB, et al. Primary intestinal-type glandular lesions of the vagina: clinical, pathologic, and immunohistochemical features of 14 cases ranging from benign polyp to adenoma to adenocarcinoma. Am J Surg Pathol 2014;38:593–603.
    23. Staats PN, Clement PB, Young RH. Primary endometrioid adenocarcinoma of the vagina: a clinicopathologic study of 18 cases. Am J Surg Pathol 2007;31:1490–501.
    24. Tregnago AC, Epstein JI. Skene’s glands adenocarcinoma: a series of 4 cases. Am J Surg Pathol 2018;42:1513–21.
    25. Blecharz P, Reinfuss M, Ryś J, et al. Radiotherapy for carcinoma of the vagina. Immunocytochemical and cytofluorometric analysis of prognostic factors. Strahlenther Onkol 2013;189:394–400.
    26. Yang J, Delara R, Magrina J, et al. Management and outcomes of primary vaginal cancer. Gynecol Oncol 2020;159:456–63.
    27. Adams TS, Cuello MA. Cancer of the vagina. Int J Gynaecol Obstet 2018;143(suppl 2):14–21.
    28. FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 2009;105:3–4.
    29. Brierley JD, Gospodarowicz MK, Wittekind C. Union for International Cancer Control TNM Classification of Malignant Tumours, 8th ed. USA: Wiley; 2016.
    30. Missaoui N, Abdelkarim SB, Mokni M, et al. p16INK4A expression in squamous cell carcinomas of the vagina and the vulva in Tunisian women. Asian Pac J Cancer Prev 2014;15:10803–8.
    31. Hellman K, Lindquist D, Ranhem C, et al. Human papillomavirus, p16(INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina. Br J Cancer 2014;110:1561–70.
    32. Rakislova N, Clavero O, Alemany L, et al. Histological characteristics of HPV-associated and -independent squamous cell carcinomas of the vulva: a study of 1,594 cases. Int J Cancer 2017;141:2517–27.
    33. Santos M, Landolfi S, Olivella A, et al. p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol 2006;30:1347–56.
    34. de Sanjosé S, Alemany L, Ordi J, et al. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer 2013;49:3450–61.
    35. Hodgson A, Park KJ, Djordjevic B, et al. International endocervical adenocarcinoma criteria and classification: validation and interobserver reproducibility. Am J Surg Pathol 2019;43:75–83.
    36. Nicolás I, Saco A, Barnadas E, et al. Prognostic implications of genotyping and p16 immunostaining in HPV-positive tumors of the uterine cervix. Mod Pathol 2020;33:128–37.
    37. Singh N, Gilks CB, Wong RWC, et al. Interpretation of p16 immunohistochemistry in lower anogenital tract neoplasia. 2018. Available at: https://www.bgcs.org.uk/wp-content/uploads/2019/05/BAGP-UKNEQAS-cIQC-project-p16-interpretation-guide-2018.pdf. Accessed February 14, 2021.
    38. Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.
    39. Wittekind C, Brierley JD, Lee A, et al. TNM Supplement: A Commentary on Uniform Use, 5th ed. USA: Wiley; 2019.
    40. Frumovitz M, Gayed IW, Jhingran A, et al. Lymphatic mapping and sentinel lymph node detection in women with vaginal cancer. Gynecol Oncol 2008;108:478–81.
    41. Hacker NF, Eifel PJ, van der Velden J. Cancer of the vagina. Int J Gynaecol Obstet 2015;131(suppl 2):S84–87.
    42. Jesinghaus M, Strehl J, Boxberg M, et al. Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix. J Pathol Clin Res 2018;4:93–102.
    43. Zare SY, Aisagbonhi O, Hasteh F, et al. Independent validation of tumor budding activity and cell nest size as determinants of patient outcome in squamous cell carcinoma of the uterine cervix. Am J Surg Pathol 2020;44:1151–60.
    44. McCluggage WG. Towards developing a meaningful grading system for cervical squamous cell carcinoma. J Pathol Clin Res 2018;4:81–5.
    Keywords:

    Vagina; Vaginal carcinoma; Datasets; Protocols; Tumor classification; Standardized reporting; Staging

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