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

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

Author Information
International Journal of Gynecological Pathology 41():p S8-S22, November 2022. | DOI: 10.1097/PGP.0000000000000900
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Abstract

INTRODUCTION AND BACKGROUND

The International Collaboration on Cancer Reporting (ICCR) was founded in 2011 by a quadripartite alliance [College of American Pathologists (CAP), Royal College of Pathologists in the United Kingdom (RCPath), Royal College of Pathologists of Australasia (RCPA), Canadian Partnership Against Cancer (CPAC)] to amalgamate efforts in the development of evidence-based data sets for cancer reporting. The ICCR vision is to reduce the global burden of cancer data set development and maintenance, benefit countries that lack sufficient resources to develop standardized cancer reporting protocols, and harmonize content and terminology that will augment international comparison, bench-marking, and epidemiological analyses.

Since its launch, the ICCR has successfully developed over 50 cancer reporting data sets spanning over 12 organ systems. All developed data sets have been developed through international consultation as detailed previously 1–3, and are freely available for worldwide use at the following website: http://www.iccr-cancer.org/datasets. Several data sets have also been translated into Spanish, Portuguese, and French languages. The field of female reproductive organs has seen successful development and updates to data sets for endometrial carcinoma 1, ovarian/fallopian tube/primary peritoneal carcinomas 2, and cervical carcinoma 3. The new vulval cancer data set, discussed herein, is accompanied by 3 other new data sets, addressing vaginal carcinomas, gestational trophoblastic neoplasms, and uterine malignant and potentially malignant mesenchymal tumors.

Vulval carcinoma is a rare cancer, with a worldwide incidence of 1.2/100,000 and a cumulative lifetime risk of 0.09% 4. In 2020, vulval cancer accounted for 45,240 newly diagnosed cancers and 17,247 deaths globally 4. This data set discusses the elements to be included in vulval carcinoma reporting, inclusive of clinical, macroscopic, microscopic, and ancillary testing considerations, as well as the evidence and/or consensus-based deliberations for their inclusion.

METHODS

The standard operating procedures for the process of ICCR data set development have been documented in earlier publications. This includes the selection process, roles and responsibilities of the chair, expert panel members, the ICCR Dataset Steering Committee representative/s on the panel, and the project manager. Each data set was produced by a panel of internationally recognized expert pathologists and a single clinician in each specific field.

After the expert panel (Dataset Authoring Committee; DAC) was established, a scope was defined (see below) and the project manager collated existing international data set elements for deliberation. A series of teleconferences took place to review and discuss each of the elements in the collated data set. Core elements were defined as those which were unanimously agreed by the panel to be essential for the histological diagnosis, clinical management, staging or prognosis. Noncore elements, defined as nonmandatory, are clinically important, recommended as good practice and should ideally be included in the data set, but are not yet validated or regularly used in patient management. The terms “core” and “noncore” replace the previous terminology “required” and “recommended” used in prior data sets. Evidentiary support at Level III-2 or above [based on prognostic factors in the National Health and Medical Research Council Methodology (NHMRC) levels of evidence document, defined as “Analysis of prognostic factors amongst persons in a single arm of a randomized controlled trial”] 5 was required to support core elements. In rare circumstances, where Level III-2 evidence was unavailable, an element could be categorized as core with the unanimous agreement of the DAC.

Once the elements were agreed upon by the expert panel, the next phase of the data set development process was to propose the value list or response to each element, for example, “present,” “not identified,” “indeterminate,” to avoid any ambiguity in the definition, assessment or meaning of the element. The Chair of the expert panel then assigned the writing of a commentary for each data element to different members of the DAC, based on a review of the current literature. The core elements and associated commentaries are presented first below, followed by the noncore elements and commentaries. The sum of the core elements constitutes the minimum information which should be included in the pathology report.

SCOPE OF THE DATA SET

The data set has been developed for the pathological reporting of resection specimens of primary carcinomas of the vulva. In some patients with a prior diagnosis of vulval carcinoma (especially squamous), it is not clear whether a “new” lesion is a recurrence or an independent neoplasm and the data set can also be used for such tumors, especially when these “arise” from the surface squamous epithelium. Molecular studies have shown that some of these “recurrent” neoplasms exhibit similar mutations and are clonally related to the original tumor and are likely to represent true recurrences while others are clonally unrelated with different mutations and are likely to represent new neoplasms 6. In those rare cases where more than one primary tumor is present, separate data sets should be completed for each neoplasm. These should include all the elements in this data set, except for lymph node status which does not need to be documented separately for each tumor.

The scope of this data set encompasses resection specimens of primary vulval carcinomas. Hematopoietic neoplasms, mesenchymal neoplasms, mixed epithelial and mesenchymal neoplasms, malignant melanomas, other nonepithelial malignancies, and metastatic tumors are excluded from this data set.

DATA ELEMENTS

A summary of the core and noncore elements for the reporting of vulval carcinomas is presented in Tables 1 and 2, respectively.

TABLE 1 - Core data elements for pathological reporting of resection specimens of primary carcinomas of the vulva
Clinical Macroscopic Microscopic Other
Clinical information Specimen dimensions Histologic tumor type Ancillary studies
 History of previous cancer Tumor site* Lymphovascular invasion  p16 immunohistochemistry and/or HPV testing for squamous cell carcinoma
 Prior neoadjuvant therapy Tumor dimensions Margin status
Operative procedure  Maximum horizontal tumor dimension  Margin status and distances for invasive tumor
 Depth of invasion Margin status for precursor lesion†
Lymph node status
 Sentinel and nonsentinel lymph nodes
 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
 Vulval intraepithelial neoplasia, HPV-independent
 Lichen sclerosus
Pathologically confirmed distant metastasis
Provisional pathologic staging
 FIGO or TNM staging (UICC/AJCC 8th edition)
*Specification of tumor site as left vulva, right vulva, midline, and extension into adjacent structures is considered core; subdivision of the right and left vulva into labium majus, labium minus and Bartholin gland is considered noncore (Table 2).
For the precursor lesion, status of the margin (involved vs. not involved) is a core element, the distance of the precursor to the margin is considered noncore (Table 2).
AJCC indicates American Joint Committee on Cancer; FIGO, International Federation of Obstetricians and Gynaecologists; HPV, human papillomavirus; UICC, Union for International Cancer Control.

TABLE 2 - Noncore data elements for pathologic reporting of resection specimens of primary carcinomas of the vulva
Macroscopic Microscopic Other
Tumor site* Perineural invasion Ancillary studies
Block identification key Margin status†  Ancillary studies other than p16 immunohistochemistry and HPV testing (such as p53 immunohistochemistry) for squamous cell carcinoma
 Distance from high grade precursor lesion to closest peripheral margin  p16 immunohistochemistry, HPV testing, and/or other ancillary studies for nonsquamous histological types
*Specification of tumor site as left vulva, right vulva, midline, and extension into adjacent structures is considered core; subdivision of the right and left vulva into labium majus, labium minus, and Bartholin gland is considered noncore (Table 1).
For the precursor lesion, status of the margin (involved vs. not involved) is a core element, the distance of the precursor to the margin is considered noncore (Table 1).
HPV indicates human papillomavirus.

Clinical Information (Core)

In most ICCR data sets, clinical information is a noncore element but the carcinoma of the vulva DAC felt that clinical information is vital in reporting vulval carcinomas and thus this is included as a core element. In reporting a vulval carcinoma, knowledge of a history of any prior vulval tumor (including the site), 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 important with vulval squamous carcinomas since tumor recurrence is common. In some patients with a prior vulval squamous carcinoma, it is not clear from a pathologic perspective whether a “new” lesion is a recurrence or an independent neoplasm and the data set can also be used for such tumors if an “origin” can be seen from the overlying squamous epithelium. Knowledge of a history of a prior precursor lesion or inflammatory dermatosis is also important. Information regarding a history of a prior malignancy is important in reporting those rare primary vulval adenocarcinomas since metastasis should always be excluded before rendering such a diagnosis. Knowledge of a history of any prior neoadjuvant therapy (chemotherapy, radiotherapy, chemoradiation) is important since this can have a marked effect on the pathologic appearances of the neoplasm (gross and morphologic).

Operative Procedure (Core)

The type of operative procedure is considered a core element for reporting. Wide local excision refers to the removal of the full thickness of vulval skin or mucosa with the preservation of subcutaneous fat and other deep tissues (older terminologies include partial vulvectomy, superficial vulvectomy, skinning vulvectomy) 7–9. Wide local excision is usually performed for preinvasive or nonmalignant lesions or for diagnostic purposes where cancer has not been ruled out. Radical vulvectomy (partial or total) is usually performed for biopsy confirmed invasive carcinoma and involves removing the vulval tissue down to the deep fascia. Radical vulvectomy may include removal of the clitoris with prepuce, the labia majora, labia minora, a portion the of vagina, urethra, and/or anus 7–9. It is desirable that orientation of the specimen is provided by the surgeon to enable evaluation of margin status; this may be achieved by the placing of sutures or by the provision of a diagram or photograph.

Wide local excision and radical vulvectomy procedures will be tailored depending on the tumor size, pathologic diagnosis, patient wishes/expectations, likely impact on psychosexual function and tumor location with respect to proximity to other vital structures.

Specimen Dimensions (Core)

Although not necessary for staging, clinical management or prognosis, it is recommended that the specimen dimensions be recorded on the pathology report 10–13. This gives clinicians dealing with the patient an indication as to how radical a resection has been undertaken.

Tumor Site (Core and Noncore)

Detailing the anatomic site of a vulval carcinoma is important for the following reasons: tumors located close to or in the midline can be associated with bilateral or contralateral lymph node involvement because the lymphatic vessels anastomose across the midline, particularly in the clitoral and the anterior labium minus regions and midline/clitoral involvement is associated with a worse prognosis which is possibly related to unfavorable histopathologic characteristics of the tumors [more likely to be human papillomavirus (HPV)-independent] 14–16.

The tumor site should be provided by the surgeon and, as discussed above, the placing of sutures or the provision of a diagram or photograph may be helpful. If the determination of the tumor site is not possible, it may be necessary to liaise with the surgeon.

The tumor laterality (right vulva, left vulva, midline, involvement of other structures) is regarded as a core item, while the involvement of the labium majus, labium minus and Bartholin gland is regarded as noncore.

Tumor Dimensions (Core)

Accurate measurement of tumor dimensions in vulval carcinomas is important for staging, patient management, and prognostication. Tumor dimensions should be measured in millimetres. The maximum horizontal dimension is the greatest tumor dimension measured parallel to the skin 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 in the histologic section. A second horizontal dimension taken perpendicular to the first and also parallel to the skin 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 and this is discussed in more detail below.

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 (largest) depth of invasion in the 2 different specimens.

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

Measurement of Depth of Invasion

As discussed, the maximum depth of tumor invasion should be measured in all cases since invasion >1 mm signifies greater than stage IA and typically results in inguinofemoral lymphadenectomy being undertaken. This measurement is taken from the most superficial dermal papilla adjacent to the tumor to the deepest point of invasion (conventional measurement) (Fig. 1). An alternative method of measuring the depth of invasion has been proposed whereby the depth of invasion is measured from the basement membrane of the deepest adjacent dysplastic (tumor free) rete ridge to the deepest point of invasion 17,18. This method of invasion results in “downstaging” of some stage IB tumors to IA. In one study, the downstaged patients developed less recurrences and had a higher disease-specific survival compared with the patients who remained at stage IB 17. Using the alternative method for measuring the depth of invasion would have resulted in 19% of patients with vulval squamous cell carcinoma (SCC) not undergoing lymphadenectomy with less treatment-related morbidity. In another study, all tumors which were downstaged using this method of measuring depth of invasion had no nodal metastasis, lymphovascular or perineural invasion 18. The DAC concluded “although the results of these studies are promising, more prospective data on a higher number of patients is necessary before this alternative method of measuring depth of invasion can be recommended and currently the conventional method is recommended.” However, not long after this data set was produced in 2021, the International Federation of Obstetricians and Gynaecologists (FIGO) published a new vulval carcinoma staging system which recommended using the alternative method of measuring the depth of invasion (see the Discussion section).

F1
FIG. 1:
Schematic diagram showing measurement of depth of invasion in vulval carcinomas. (A) Shows the traditional (recommended) method of measurement from the adjacent most superficial dermal papilla to the deepest point of invasion while (B) shows an alternative method from the basement membrane of the deepest adjacent dysplastic (tumor free) rete ridge to the deepest point of invasion. Permission courtesy of Mr Norm Cyr.

There is significant interobserver variability in assessment of superficial invasion, including disagreements about to whether or not there is invasion and whether the invasion is ≤1 or >1 mm (stage IA vs. stage IB) 19,20.

Block Identification Key (Noncore)

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 Type (Core)

All tumors should be typed according to most recent edition of the World Health Organization (WHO) Classification of Tumours of Female Genital Tumours, 5th edition, 2020 (Table 3) 21,22. The ICCR data set includes 5th edition Corrigenda, June 2021 23. SCC is by far the most common carcinoma to arise on the vulva. Traditional histologic subtyping of SCC, using terms such as keratinizing, nonkeratinizing, basaloid and warty, has been superseded by HPV status as the major determinant of classification. Vulval SCC is divided into HPV-associated and HPV-independent types. HPV-independent SCC have a worse prognosis with significantly worse recurrence free and overall survival compared with HPV-associated SCC 24–27. There is also growing evidence that HPV-independent SCC are less responsive to radiotherapy 28,29. HPV-associated SCC are secondary to persistent infection by oncogenic high-risk HPV (most commonly types 16 and 18) and are associated with smoking, immunosuppression and often multifocal disease including HPV-associated lesions in other areas of the lower female genital tract (vagina, cervix) and anal/perianal regions. HPV-independent SCC often arises in the setting of lichen sclerosus and chronic inflammation 30. Verrucous carcinoma falls under the umbrella of HPV-independent SCC. The majority of HPV-associated SCC exhibit basaloid or warty morphology, while HPV-independent SCC tend to be keratinizing; however, a significant percentage of cases (15%–20%) will show overlapping morphologic features 31,32. The nature of any adjacent precursor lesion may be useful in helping to determine the HPV status. However, in practice, ancillary testing is necessary to determine the HPV status given the overlap in morphology in some cases (see the Ancillary studies section). When HPV status cannot be confidently determined or resources are not available to undertake ancillary testing, a morphologic diagnosis of SCC, not otherwise specified (NOS) is acceptable, although this is not recommended.

TABLE 3 - World Health Organization classification of malignant epithelial tumors of the vulva21
Descriptor ICD-O codes*
Squamous cell carcinoma, HPV-associated 8085/3
Squamous cell carcinoma, HPV-independent 8086/3
Squamous cell carcinoma NOS 8070/3
Basal cell carcinoma NOS 8090/3
Adenocarcinoma of anogenital mammary-like glands 8500/3
Bartholin gland lesions
 Squamous cell carcinoma NOS 8070/3
 Adenoid cystic carcinoma 8200/3
 Carcinoma, poorly differentiated, NOS 8020/3
 Adenosquamous carcinoma 8560/3
 Neuroendocrine tumor NOS 8240/3
 Myoepithelial carcinoma 8982/3
 Epithelial–myoepithelial carcinoma 8562/3
 Paget disease, extramammary 8542/3
 Sweat gland adenocarcinoma 8400/3
  Apocrine adenocarcinoma 8401/3
  Eccrine adenocarcinoma 8413/3
  Porocarcinoma NOS 8409/3
  Adenoid cystic carcinoma 8200/3
 Adenocarcinoma, intestinal type 8144/3
*These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) 22. 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.
World Health Organization/International Agency for Research on Cancer. Reproduced with permission.
HPV indicates human papillomavirus; NOS, not otherwise specified.

Most, but not all, HPV-independent vulval SCC are associated with TP53 mutations. However, a proportion are TP53 wild-type and there is growing evidence that these may have an intermediate prognosis between HPV-associated SCC and HPV-independent TP53 mutated neoplasms 33.

Grading of vulval SCC is not recommended and is not included in this data set. Grading has not been shown to consistently correlate with clinical outcome 34. In fact, there is a paradox in that HPV-independent SCC, which tend to be keratinising 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 vulval SCC.

Basal cell carcinomas are histologically identical to their counterparts occurring in other cutaneous locations. A variety of adenocarcinomas rarely arise in the vulva and these should be diagnosed using the 2020 WHO Classification 21. These may be of mammary gland type (various types as in the breast), of sweat gland origin (various types), intestinal type or arise from Paget disease (invasive Paget) 35,36. Before diagnosing a primary vulval adenocarcinoma, a metastasis from elsewhere should always be considered, and correlation of the clinical picture (including the past history) with pathologic features, including immunohistochemical studies, may assist.

A variety of carcinomas (squamous, glandular, “salivary-type,” and other) can arise from the Bartholin gland 37. To be considered a Bartholin gland primary, the tumor should involve the anatomic region of the Bartholin gland and be histologically compatible with an origin in Bartholin gland with no alternative primary site identified elsewhere; preferably normal Bartholin gland tissue should be present in the vicinity of the neoplasm.

Neuroendocrine neoplasia is classified according to the 2020 WHO Classification (neuroendocrine tumor, small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, mixed neuroendocrine-non-neuroendocrine carcinoma, Merkel cell carcinoma) 21. Some vulval neuroendocrine carcinomas are driven by HPV-infection, while some Merkel cell carcinomas are driven by polyomavirus 38,39.

Lymphovascular Invasion (Core)

Lymphovascular invasion is an adverse prognostic factor associated with increased risk of local recurrence, lymph node metastasis, and poorer survival in vulval SCC 40–43. Two recent systematic reviews have highlighted some conflicting data on the prognostic significance of lymphovascular invasion from different studies 34,44, but it should be noted that the criteria for lymphovascular invasion were often not specified and there might be substantial variability in terms of diagnostic thresholds. The published studies also did not distinguish between focal or extensive lymphovascular invasion 34,44.

Caution is needed when distinguishing genuine lymphovascular invasion from mimickers, such as “carry-over” of tumor cells into lymphovascular spaces or retraction artefacts. In one study of vulval carcinomas, the use of D2-40 immunohistochemistry as a marker of lymphatic vessels demonstrated improved detection of lymphovascular invasion as compared with morphology alone 45.

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 or cauterization artefacts. 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.

Perineural Invasion (Noncore)

Perineural invasion has been specifically evaluated by several retrospective studies, which demonstrated an association with significantly shorter overall survival and disease-free survival in patients with vulval SCC 46–48. Perineural invasion is also an independent predictor of local recurrence based on multivariate analysis in 2 studies 48,49.

Immunohistochemistry was used as an adjunct to identify perineural invasion in several studies which showed its prognostic value 47–49, either by S100 alone or dual immunohistochemistry with S100 and AE1/3. Immunohistochemistry may be useful to assist with cases that are morphologically inconclusive or suspicious for perineural invasion.

Margin Status (Core and Noncore)

Appropriate sections need to be taken to include the nearest peripheral epithelial/mucosal margin and the deep margin.

Vulval cancer patients with positive or “close” surgical margins are at high risk of local recurrence. A clearance of at least 8 mm from the tumor has been suggested as the distance required to significantly reduce this risk of local recurrence. Recent studies, however, show no difference in recurrence between <8 and ≥8 mm tumor free surgical margin 50,51. It is also likely that the risk of recurrence with regard to tumor distance to the nearest margin differs between HPV-associated and HPV-independent SCC 24. It is clear that there are multiple problems in measuring the distance to surgical margins with no clear guidelines as to how measurements should be undertaken. 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 vulval carcinomas, it is recommended that surgical margins should be inked and the following recommendations adhered to 52:

  • Involvement of a peripheral (skin, 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.
  • This peripheral surgical margin should be roughly perpendicular to the skin/mucosal surface; this includes the epithelial surface and deeper soft tissue.
  • The peripheral margin should be measured toward the peripheral stromal edge or surface-epithelial edge, whichever is shorter.
  • The minimum peripheral margin should be measured through tissue and preferably in a straight uninterrupted line; however, in some situations (collarette), a composite measurement including separate linear measurements joined at an angle may be required.
  • Measuring the distance to the margin by a curved line in the context of an irregular surface, which is now possible due to the increased use of digital pathology, is not recommended, unless this is felt to represent a truer measurement, for example, when a length of uninvolved skin is embedded curved/folded in order to fit into a paraffin block.
  • Involvement of a peripheral margin by a high-grade precursor lesion [HPV-associated high-grade squamous intraepithelial lesion (HSIL) or HPV-independent vulval intraepithelial neoplasia (VIN)] should be recorded and the margin specified if possible; p53 immunohistochemical staining may be of value in assessing margin involvement by HPV-independent VIN (see the Ancillary studies section). Margin involvement by a low-grade precursor lesion [low-grade squamous intraepithelial lesion (LSIL)] does not need to be recorded.
  • Although there is no clear evidence to support the value of recording the distance of high-grade precursor lesions from the nearest peripheral margin and thus this cannot be considered a core element, 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. This measurement is made along the epithelial surface. The distance from the margin of a LSIL does not need to be recorded.
  • The minimum distance of invasive tumor to the deep soft tissue margin should also be recorded. In general, this should be measured from the deepest infiltrating tumor nest to the deep soft tissue margin. However, if the deep margin is irregular, the closest deep margin may not necessarily be at the point of deepest invasion; in such cases, this should be taken into account when providing this measurement.

Lymph Node Status (Core)

Lymph node involvement in vulval cancer is one of the most important adverse prognostic parameters 34, and the appropriate management and pathologic assessment of regional (inguinofemoral) lymph nodes is considered the most important factor in reducing mortality from early vulval cancer 53. Regional nodal assessment is therefore typically indicated in all carcinomas (with the exception of basal cell carcinomas) that are greater than International Federation of Gynecology and Obstetrics (FIGO) Stage IA (pT1A) on clinicopathologic assessment, that is, those that exceed 20 mm in maximum size, those with >1 mm depth of invasion and those of any size that involve adjacent structures (lower third of urethra, lower third of vagina or anus) 54,55. Clinically suspicious/palpable inguinal nodes should be biopsied. Tumors that are <40 mm in size and ≥20 mm from the midline are usually managed by an ipsilateral inguinofemoral lymphadenectomy. Bilateral inguinofemoral lymphadenectomy is typically undertaken in tumors larger than 40 mm, those that cross or are located within 20 mm of the midline, or those that clinically or radiologically are felt to have positive ipsilateral lymph nodes 56. Significant changes in surgical practice in the last decades, both in terms of vulvar excision and nodal assessment have led to publication of algorithms to help direct surgical procedure.

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. Ultrastaging does not need to be performed for lymphadenectomies [see discussion on sentinel lymph node biopsy (SLNB) below].

Lymph node status is a powerful indicator of local recurrence and survival. The site, size, and nature of nodal metastasis all influence prognosis and are integral to tumor stage. Involvement of regional lymph nodes represents FIGO stage III, and this is further subdivided according to the number of involved nodes, the maximum size of the deposit and the presence or absence of extracapsular spread. It has been shown in multivariate analysis that extracapsular lymph node spread is an independent prognostic factor for earlier recurrence and overall survival 48. The presence of fixed or ulcerated inguinofemoral lymph nodes as determined by clinical examination, or of involvement of nonregional, including pelvic, lymph nodes, upstages the carcinoma to FIGO stage IVA or IVB, respectively. The anatomic location and number of lymph nodes dissected, the number containing tumor and the size of the largest tumor deposit should be accurately documented in the pathology report. As already discussed, FIGO published a new vulval carcinoma staging system in 2021 which made some changes to the substaging of stage III based on nodal involvement (see the Discussion section).

In recent years, owing to the high morbidity of groin dissection, SLNB has become the standard of care in some vulval cancers 57–59. SLNB can be performed for unifocal lesions which are confined to the vulva and <40 mm in size, with no prior vulval or groin surgery or radiation, and in the absence of clinically palpable or radiologically suspicious nodes. The evaluation of sentinel lymph nodes should follow an established locally agreed protocol. It should be documented whether or not an ultrastaging procedure has been carried out and whether nodal metastases have been detected on routine histologic examination (without ultrastaging) or by ultrastaging, including cytokeratin immunohistochemistry. Sentinel (and nonsentinel) nodal involvement should be recorded as presence of isolated tumor cells (ITC), micrometastases (MIC) or macrometastases (MAC). An ideal ultrastaging protocol used should detect almost all MIC (0.2–2 mm). 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 60, nodal involvement should be recorded as the presence ITC (<0.2 mm), MIC (0.2–2 mm) or MAC (>2 mm). MAC are regarded as pN1, MIC as pN1 (mi) and ITCs are pN0 (i+); ITCs do not upstage a carcinoma. The possibility of performing radiologically guided fine-needle aspiration cytology of suspicious lymph nodes should be considered. A positive result enables the surgeon to immediately perform a bilateral inguinofemoral lymphadenectomy, thus avoiding an unnecessary SLNB.

Coexistent Pathology/Precursor Lesions (Core)

Recording the presence of precursor lesions and coexistent pathology is important for vulval SCC since this gives insight into the pathogenesis of the tumor, specifically whether it is HPV-associated or HPV-independent 25. Margin involvement by a high grade precursor lesion is also important.

A variety of noninvasive lesions may be present in association with SCC. Some are considered to be precursor lesions while others, such as lichen sclerosus, are not considered to be a precursor lesion but rather a chronic inflammatory condition that increases the risk of HPV-independent SCC and cancer recurrence when present at surgical margins 61,62.

The presence of the following should be noted in the setting of vulval SCC: HPV-associated squamous intraepithelial lesion, HPV-independent VIN, and lichen sclerosus.

Vulval squamous precursor lesions are classified into HPV-associated and HPV-independent. The HPV-associated lesions predominantly comprise HSIL (VIN 2/3). LSIL in the vulva is uncommon aside from condylomatous lesions. HPV-associated precursor lesions are associated with smoking, immunosuppression and often multifocal disease including HPV-associated lesions in other areas of the lower female genital tract (vagina, cervix) and anal/perianal regions. HPV-independent precursor lesions, collectively termed “VIN, HPV-independent”, include differentiated VIN (dVIN) and 2 uncommon lesions termed vulvar acanthosis with altered differentiation and differentiated exophytic vulvar intraepithelial lesion 63–66. The latter 2 lesions show significant morphologic overlap and are likely part of a spectrum of HPV-independent precursor lesions. dVIN is typically associated with TP53 mutations while vulvar acanthosis with altered differentiation and differentiated exophytic vulvar intraepithelial lesion usually do not contain mutations.

Biomarkers may be useful for appropriate classification of precursor lesions given that both HPV-independent premalignant lesions morphologically indistinguishable from HSIL and HPV-associated intraepithelial precursors simulating dVIN have been described (see the Ancillary studies section) 67–70.

Ancillary Studies (Core and Noncore)

As discussed (see the—Histologic tumor type section), the 2020 WHO Classification categorizes vulval SCC into 2 main types, HPV-associated and HPV-independent 71, with prognostic implications which have already been discussed 25,27–29,72. This new diagnostic approach has consequences since, as discussed, morphology is not always reliable in distinguishing between the 2 types 31,73. It implies that the use of ancillary techniques, namely p16 immunohistochemistry and/or HPV molecular testing, are considered as essential to correctly classify vulval SCC 71. Similarly, although the HPV-associated and HPV-independent intraepithelial precursors of SCC have distinctive features (see the—Coexistent pathology/precursor lesions section), both HPV-independent premalignant lesions morphologically indistinguishable from HSIL and HPV-associated intraepithelial precursors simulating dVIN have been described 67–70. Therefore, p16 staining and/or molecular testing (see below) are also highly desirable in classifying precursor lesions. p16 immunohistochemistry and/or HPV testing is considered a core element in cases of vulval 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 morphologic diagnosis of SCC, NOS is acceptable, although this is not recommended. This is especially likely in laboratories in middle- and low-income areas 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.

As discussed, the 2 accepted tools for confirming an HPV-association are the direct identification of HPV products (DNA or mRNA) and block-type staining for 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 74, discrepancies are observed in a small number of cases when the two techniques are applied 31. Moreover, most laboratories are not likely to 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 vulval 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 73. Thus, highly sensitive methods, such as SPF10 polymerase chain reaction testing are the most used tests, but large series have reported both false positive and false negative results with this test 31,73,74. In situ hybridization for HPV E7 mRNA, one of the oncogenic HPV genes has shown good results in tumors of the uterine cervix 75, but the experience in vulval lesions is limited.

p16 immunohistochemical staining has shown a good correlation with HPV testing 27,28,31,72–74. Although isolated cases of HPV-associated tumors with “negative” p16 staining have been reported in the cervix and vulva 76, 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 31. It has also been shown that p16 expression alone is closely associated with prognosis 25,27–29,72. 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 typically nuclear and cytoplasmic (less frequently only nuclear) immunoreactivity 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 77. 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 also needs to be 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 vulval SCC contain TP53 mutations. Almost all HPV-associated vulval SCC and high grade precursor lesions exhibit a “wild-type” pattern of p53 immunoreactivity while many, but importantly not all, HPV-independent SCC and precursor lesions exhibit “mutation-type” immunoreactivity. Classification of p53 staining in such lesions as “wild-type” or “mutation-type” is not always straightforward with different patterns of both types of staining being described 78,79. In addition, there is emerging evidence that not all HPV-independent SCC and precursor lesions are associated with TP53 mutations and that TP53 wild-type tumors may have a better prognosis than those harboring TP53 mutations. p53 staining may be helpful in assessing margin involvement by HPV-independent dVIN; this may be subtle histologically and mutation-type p53 staining at a margin may be useful in confirming margin involvement.

Additional biomarkers, such as PD-L1, may become useful in the future as the role of immune checkpoint inhibitor therapy in vulval squamous carcinomas becomes established through ongoing clinical trials 80.

Pathologically Confirmed Distant Metastasis (Core)

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 (Core)

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 tumor board meeting where all the pathologic, clinical, and radiologic features are available 53,60,81,82.

The latest version of either FIGO or TNM staging, or both, can be used depending on local preferences 53,60,81,82. 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 60,82. 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, the amendments are 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 posttherapy stage.

In cases where more than 1 primary tumor is present, a separate pathologic stage should be provided for each tumor and, as stated in the scope, separate data sets should be completed for each neoplasm.

The reference document TNM Supplement: A commentary on uniform use, 5th edition (C Wittekind et al. editors) may be of assistance when staging 83.

DISCUSSION

Each data element in the vulval carcinoma data set was excogitated by the DAC and reflects a culmination of literature review and practice-based expertise. The vulval carcinoma data set provides up-to-date and critical commentary that is intended to reduce variability in vulval carcinoma reporting and ensure the inclusion of all pathology data elements that will impact patient care. The commentary also discusses items for which there is emerging evidence (for example, vulvar cancer precursors, distance of high-grade precursor lesion to the nearest peripheral margin, use of p53 immunohistochemistry) that may assume greater importance in the future, as more studies accrue. There are several elements in this data set that do warrant further elaboration and emphasis; these are discussed below.

The ICCR vulval carcinoma data set was finalized in mid-2021, before the publication of an updated FIGO staging system for cancers of the vulva 84. The FIGO Committee for Gynecologic Oncology reviewed data from the United States National Cancer Database (US NCDB) to prospectively analyse 12,063 vulval cancer cases treated over a 7-yr period (2010–2017). From this data reservoir, characteristics associated with similar survivals were identified and reorganized into the same stages/substages, and then Kaplan-Meier overall survival curves were created to view the prognostic differences in the revised staging system. Several changes were made as summarized in Figure 2. The first change modifies the method used to measure depth of invasion (see the Tumor dimensions section). The traditional method (measurement taken from the most superficial dermal papilla adjacent to the tumor to the deepest point of invasion) was replaced by the alternative method [measured from the basement membrane of the deepest adjacent dysplastic (tumor free) rete ridge to the deepest point of invasion] 17,18. This decision was based on the results of the 2 studies (n=148 and n=100, respectively) discussed earlier 17,18 and FIGO acknowledges that the US NCDB data used to inform the revisions actually used the conventional method. The alternate method parallels the approach used in carcinomas of the uterine cervix and will potentially reduce overtreatment of early-stage patients. It was the opinion of the DAC that more prospective data on a higher number of patients was needed before implementation of this change. With the movement from FIGO, it will be incumbent on the clinical and research community to amass larger data sets for analysis and validation of the oncological safety of this method.

F2
FIG. 2:
Changes between FIGO 2018 and 2021 staging systems. FIGO indicates International Federation of Obstetricians and Gynaecologists.

The second change was moving involvement of the upper perineal structures (upper two-thirds of vagina and urethra), bladder mucosa and rectal mucosa from stage IV to IIIA. The third change was removal of the number of lymph nodes as a parameter for substaging of stage III. These changes were prompted by the findings that “stage IIB is defined by lymph node metastasis >5 mm and combining this with disease extension to upper two-thirds of perineal structures did not change the prognosis.” Similarly, stage IIIC is defined by lymph node metastasis with extracapsular extension, and combining this with lymph node metastases that are >5 mm without extracapsular extension and tumor extension to the upper two-thirds of adjacent perineal structures did not alter the prognosis” 84. The fourth change is the same as the FIGO update to cervical cancer staging, allowing for the incorporation of cross-sectional imaging to change staging which is designated by the prefix (r).

This data set has removed the necessity to grade vulval SCC and grading of SCC is not included as a core or noncore element. SCC of the vulva, like other lower anogenital sites, suffers from a paradox, in that HPV-independent SCC tend to be keratinising and well-differentiated but have poor outcomes, while HPV-associated SCC tend to be nonkeratinizing, basaloid and poorly differentiated but have favorable outcomes. In a recent review, only 5 of 19 studies found a correlation between tumor grade and prognosis, and in only 1 study did this remain significant on multivariate analysis 34. In addition, there is no validated grading system for vulval SCC. For these reasons, grading was removed from the data set for SCC. While most guidelines at present retain the tradition of tumor grading, the American Society of Clinical Oncology (ASCO) has also removed tumor grade for HPV/p16 positive oropharyngeal SCC. The new ICCR vaginal cancer data set and the update of the cervical cancer data set also do not include grading of SCC as a core or noncore element. Other histologic characteristics, such as tumor budding as proposed in the cervix 85,86, pattern of invasion 87, and fibromyxoid stromal response 87–89, are potential prognosticators, but further studies are needed for validation and these are not included in the data set.

This data set considers p16 immunohistochemistry and/or HPV molecular testing (in practice, most laboratories will undertake p16 immunohistochemistry alone) as a core element for vulval SCC classification. This stance is in unison with guidelines for oropharyngeal SCC, where p16 immunohistochemistry and/or HPV testing is required by the National Cancer Comprehensive Network (NCCN) 90 and is strongly recommended by other bodies (TNM8, ASCO, and CAP) 60,86,91. TNM8 even provides separate staging systems for p16 positive and p16 negative oropharyngeal SCC 60.

CONCLUSIONS

This review describes the development of the ICCR data set for the reporting of resection specimens of primary vulval carcinomas and identifies several areas worthy of further study. 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. It is anticipated 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 and this will ultimately improve patients care and clinical outcome.

Acknowledgments

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

REFERENCES

1. 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.
2. 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.
3. 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.
4. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.
5. 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.
6. Pors J, Tessier-Cloutier B, Thompson E, et al. Targeted molecular sequencing of recurrent and multifocal non-HPV-associated squamous cell carcinoma of the vulva. Int J Gynecol Pathol 2021;40:391–9.
7. de Hullu JA, van der Avoort IA, Oonk MH, et al. Management of vulvar cancers. Eur J Surg Oncol 2006;32:825–31.
8. American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice and the American Society for Colposcopy and Cervical Pathology. Management of vulvar intraepithelial neoplasia. 2016. Available at: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2016/10/management-of-vulvar-intraepithelial-neoplasia. Accessed February 19, 2021.
9. Morrow CP, Curtin JP. Gynecologic Cancer Surgery. New York, NY: Churchill Livingstone; 1996.
10. Heatley MK. Dissection and reporting of the organs of the female genital tract. J Clin Pathol 2008;61:241–57.
11. College of American Pathologists. Protocol for the examination of specimens from patients with primary carcinoma of the vulva. 2021. Available at: https://documents.cap.org/protocols/Vulva_4.2.0.2.REL_CAPCP.pdf. Accessed November 21, 2021.
12. Royal College of Pathologists. Dataset for histopathological reporting of vulval carcinomas. 2018. Available at: https://www.rcpath.org/uploads/assets/79003d03-8e27-4bf9-9732d2f3ffc5291d/G070-Dataset-for-histopathological-reporting-of-vulval-carcinomas.pdf. Accessed February 19, 2021.
13. Royal College of Pathologists of Australasia. Vulva Cancer Structured Reporting Protocol. 2013. Available at: https://www.rcpa.edu.au/getattachment/9cdcbca0-6523-4a13-b716-370d5bc945c3/Protocol-vulva-cancer.aspx. Accessed February 19, 2021.
14. Hinten F, Molijn A, Eckhardt L, et al. Vulvar cancer: two pathways with different localization and prognosis. Gynecol Oncol 2018;149:310–7.
15. Iversen T, Aas M. Lymph drainage from the vulva. Gynecol Oncol 1983;16:179–89.
16. Hinten F, van den Einden LC, Cissen M, et al. Clitoral involvement of squamous cell carcinoma of the vulva: localization with the worst prognosis. Eur J Surg Oncol 2015;41:592–8.
17. van den Einden LC, Massuger LF, Jonkman JK, et al. An alternative way to measure the depth of invasion of vulvar squamous cell carcinoma in relation to prognosis. Mod Pathol 2015;28:295–302.
18. Skala SL, Ebott JA, Zhao L, et al. Predictive value of an alternative strategy for measuring depth and size of stage 1 vulvar squamous cell carcinoma. J Low Genit Tract Dis 2020;24:265–71.
19. Abdel-Mesih A, Daya D, Onuma K, et al. Interobserver agreement for assessing invasion in stage 1A vulvar squamous cell carcinoma. Am J Surg Pathol 2013;37:1336–41.
20. Pouwer AW, Bult P, Otte I, et al. Measuring the depth of invasion in vulvar squamous cell carcinoma: interobserver agreement and pitfalls. Histopathology 2019;75:413–20.
21. WHO Classification of Tumours Editorial Board. Female Genital Tumours, WHO Classification of Tumours, 5th ed. Lyon: IARC Press; 2020:4.
22. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S, eds. International Classification of Diseases for Oncology, Third edition, Second revision ICD-O-32. Lyon: International Agency for Research on Cancer; 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.
23. WHO Classification of Tumours Editorial Board. Female Genital Tumours, WHO Classification of Tumours, 5th Edition, Volume 4—Corrigenda June 2021. Geneva: World Health Organization; 2021. Available at: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Female-Genital-Tumours-2020. Accessed June 16, 2021.
24. McAlpine JN, Leung SCY, Cheng A, et al. Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis than HPV-associated disease: a retrospective cohort study. Histopathology 2017;71:238–46.
25. Nooij LS, Ter Haar NT, Ruano D, et al. Genomic characterization of vulvar (pre)cancers identifies distinct molecular subtypes with prognostic significance. Clin Cancer Res 2017;23:6781–9.
26. Allo G, Yap ML, Cuartero J, et al. HPV-independent vulvar squamous cell carcinoma is associated with significantly worse prognosis compared with HPV-associated tumors. Int J Gynecol Pathol 2020;39:391–9.
27. Lee LJ, Howitt B, Catalano P, et al. Prognostic importance of human papillomavirus (HPV) and p16 positivity in squamous cell carcinoma of the vulva treated with radiotherapy. Gynecol Oncol 2016;142:293–8.
28. Proctor L, Hoang L, Moore J, et al. Association of human papilloma virus status and response to radiotherapy in vulvar squamous cell carcinoma. Int J Gynecol Cancer 2020;30:100–6.
29. Horne ZD, Dohopolski MJ, Pradhan D, et al. Human papillomavirus infection mediates response and outcome of vulvar squamous cell carcinomas treated with radiation therapy. Gynecol Oncol 2018;151:96–101.
30. McCluggage WG. Recent developments in vulvovaginal pathology. Histopathology 2009;54:156–73.
31. 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.
32. Dong F, Kojiro S, Borger DR, et al. Squamous cell carcinoma of the vulva: a subclassification of 97 cases by clinicopathologic, immunohistochemical, and molecular features (p16, p53, and EGFR). Am J Surg Pathol 2015;39:1045–53.
33. Kortekaas KE, Bastiaannet E, van Doorn HC, et al. Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes. Gynecol Oncol 2020;159:649–56.
34. Chen J, Ln H. A review of prognostic factors in squamous cell carcinoma of the vulva: evidence from the last decade. Semin Diagn Pathol 2020;38:37–49.
35. Tessier-Cloutier B, Asleh-Aburaya K, Shah V, et al. Molecular subtyping of mammary-like adenocarcinoma of the vulva shows molecular similarity to breast carcinomas. Histopathology 2017;71:446–52.
36. He SR, Deng WH, Yang L, et al. Cloacogenic adenocarcinoma of the vulva: one new case and literature review. Eur J Gynaecol Oncol 2017;38:296–302.
37. Nazeran T, Cheng AS, Karnezis AN, et al. Bartholin gland carcinoma: clinicopathologic features, including p16 expression and clinical outcome. Int J Gynecol Pathol 2019;38:189–95.
38. Chen PP, Ramalingam P, Alvarado-Cabrero I, et al. High-grade neuroendocrine carcinomas of the vulva: a clinicopathologic study of 16 cases. Am J Surg Pathol 2021;45:304–16.
39. Coggshall K, Tello TL, North JP, et al. Merkel cell carcinoma: an update and review: pathogenesis, diagnosis, and staging. J Am Acad Dermatol 2018;78:433–42.
40. Raspagliesi F, Hanozet F, Ditto A, et al. Clinical and pathological prognostic factors in squamous cell carcinoma of the vulva. Gynecol Oncol 2006;102:333–7.
41. Chan JK, Sugiyama V, Pham H, et al. Margin distance and other clinico-pathologic prognostic factors in vulvar carcinoma: a multivariate analysis. Gynecol Oncol 2007;104:636–41.
42. Aragona AM, Cuneo NA, Soderini AH, et al. An analysis of reported independent prognostic factors for survival in squamous cell carcinoma of the vulva: is tumor size significance being underrated? Gynecol Oncol 2014;132:643–8.
43. Dabi Y, Gosset M, Bastuji-Garin S, et al. Associated lichen sclerosis increases the risk of lymph node metastases of vulvar cancer. J Clin Med 2020;9:250.
44. Te Grootenhuis NC, Pouwer AW, de Bock GH, et al. Prognostic factors for local recurrence of squamous cell carcinoma of the vulva: a systematic review. Gynecol Oncol 2018;148:622–31.
45. Braun M, Wardelmann E, Debald M, et al. Detection of lymphovascular invasion in vulvar cancer by D2-40 (podoplanin) as a predictor for inguinal lymph node metastases. Onkologie 2009;32:732–8.
46. Salcedo MP, Sood AK, Dos Reis R, et al. Perineural invasion (PNI) in vulvar carcinoma: a review of 421 cases. Gynecol Oncol 2019;152:101–5.
47. Long Y, Yao DS, Wei YS, et al. Prognostic significance of perineural invasion in vulvar squamous cell carcinoma. Cancer Manag Res 2019;11:4461–9.
48. Ferrari F, Forte S, Ardighieri L, et al. Multivariate analysis of prognostic factors in primary squamous cell vulvar cancer: the role of perineural invasion in recurrence and survival. Eur J Surg Oncol 2019;45:2115–9.
49. Holthoff ER, Jeffus SK, Gehlot A, et al. Perineural invasion is an independent pathologic indicator of recurrence in vulvar squamous cell carcinoma. Am J Surg Pathol 2015;39:1070–4.
50. Woelber L, Griebel LF, Eulenburg C, et al. Role of tumour-free margin distance for loco-regional control in vulvar cancer-a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study. Eur J Cancer 2016;69:180–8.
51. Nooij LS, van der Slot MA, Dekkers OM, et al. Tumour-free margins in vulvar squamous cell carcinoma: does distance really matter? Eur J Cancer 2016;65:139–49.
52. Kortekaas KE, Van de Vijver KK, van Poelgeest MIE, et al. Practical guidance for measuring and reporting surgical margins in vulvar cancer. Int J Gynecol Pathol 2020;39:420–7.
53. Rogers LJ, Cuello MA. Cancer of the vulva. Int J Gynaecol Obstet 2018;143(suppl 2):4–13.
54. Koh WJ, Greer BE, Abu-Rustum NR, et al. Vulvar cancer, version 1.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017;15:92–120.
55. Dellinger TH, Hakim AA, Lee SJ, et al. Surgical management of vulvar cancer. J Natl Compr Canc Netw 2017;15:121–8.
56. Stehman FB, Look KY. Carcinoma of the vulva. Obstet Gynecol 2006;107:719–33.
57. Coleman RL, Ali S, Levenback CF, et al. Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173. Gynecol Oncol 2013;128:155–9.
58. Van der Zee AG, Oonk MH, De Hullu JA, et al. Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 2008;26:884–9.
59. Fotopoulou C, Ind T, Baldwin P, Crawford R, et al. Sentinel lymph node consensus document of the British Gynaecological Cancer Society for endometrial, vulvar, and cervical cancers. Int J Gynecol Cancer 2019;29:1348–50.
60. Brierley JD, Gospodarowicz MK, Wittekind C. Union for International Cancer Control TNM Classification of Malignant Tumours, 8th ed. USA: Wiley; 2016.
61. Satmary W, Holschneider CH, Brunette LL, et al. Vulvar intraepithelial neoplasia: risk factors for recurrence. Gynecol Oncol 2018;148:126–31.
62. Te Grootenhuis NC, Pouwer AW, de Bock GH, et al. Margin status revisited in vulvar squamous cell carcinoma. Gynecol Oncol 2019;154:266–75.
63. Watkins JC, Howitt BE, Horowitz NS, et al. Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA. Mod Pathol 2017;30:448–58.
64. Akbari A, Pinto A, Amemiya Y, et al. Differentiated exophytic vulvar intraepithelial lesion: Clinicopathologic and molecular analysis documenting its relationship with verrucous carcinoma of the vulva. Mod Pathol 2020;33:2011–8.
65. Singh N, Gilks CB. Vulval squamous cell carcinoma and its precursors. Histopathology 2020;76:128–38.
66. McCluggage WG. Premalignant lesions of the lower female genital tract: cervix, vagina and vulva. Pathology 2013;45:214–28.
67. Ordi J, Alejo M, Fusté V, et al. HPV-negative vulvar intraepithelial neoplasia (VIN) with basaloid histologic pattern: an unrecognized variant of simplex (differentiated) VIN. Am J Surg Pathol 2009;33:1659–65.
68. Rakislova N, Alemany L, Clavero O, et al. HPV-independent precursors mimicking high-grade squamous intraepithelial lesions (HSIL) of the Vulva. Am J Surg Pathol 2020;44:1506–14.
69. Rakislova N, Alemany L, Clavero O, et al. Differentiated vulvar intraepithelial neoplasia-like and lichen sclerosus-like lesions in HPV-associated squamous cell carcinomas of the vulva. Am J Surg Pathol 2018;42:828–35.
70. Griesinger LM, Walline H, Wang GY, et al. Expanding the morphologic, immunohistochemical, and HPV genotypic features of high-grade squamous intraepithelial lesions of the vulva with morphology mimicking differentiated vulvar intraepithelial neoplasia and/or lichen sclerosus. Int J Gynecol Pathol 2021;40:205–13.
71. Herrington CS, Kim KR, Mccluggage WG, et al. WHO Classification of Tumours Editorial Board. Tumours of the vulva. Female Genital Tumours, WHO Classification of Tumours (Vol 4), 5th ed. IARC Press, Lyon. 2020.
72. Hay CM, Lachance JA, Lucas FL, et al. Biomarkers p16, human papillomavirus and p53 predict recurrence and survival in early stage squamous cell carcinoma of the vulva. J Low Genit Tract Dis 2016;20:252–6.
73. 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.
74. 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.
75. 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.
76. 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.
77. Singh N, Gilks CB, Wing-Cheuk Wong R, 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.
78. Tessier-Cloutier B, Kortekaas KE, Thompson E, et al. Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status. Mod Pathol 2020;33:1595–605.
79. Kortekaas KE, Solleveld-Westerink N, Tessier-Cloutier B, et al. Performance of the pattern-based interpretation of p53 immunohistochemistry as a surrogate for TP53 mutations in vulvar squamous cell carcinoma. Histopathology 2020;77:92–99.
80. Borella F, Preti M, Bertero L, Collemi G, et al. Is there a place for immune checkpoint inhibitors in vulvar neoplasms? A state of the art review. Int J Mol Sci 2020;22:190.
81. Hacker NF. Revised FIGO staging for carcinoma of the vulva. Int J Gynaecol Obstet 2009;105:105–6.
82. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR, eds. AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.
83. Wittekind C, Brierley JD, Lee A, van Eycken E. TNM Supplement: A Commentary on Uniform Use, 5th Edition. USA: Wiley; 2019.
84. Olawaiye AB, Cotler J, Cuello MA, et al. FIGO staging for carcinoma of the vulva: 2021 revision. Int J Gynaecol Obstet 2021;155:43–47.
85. 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.
86. 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.
87. Jeffus SK, Gehlot A, Holthoff E, et al. 2015 A fibromyxoid stromal response is associated with an infiltrative tumor morphology, perineural invasion, and lymph node metastasis in squamous cell carcinoma of the vulva. Am J Surg Pathol, 39:1226–33.
88. Ambros RA, Malfetano JH, Mihm MC Jr. Clinicopathologic features of vulvar squamous cell carcinomas exhibiting prominent fibromyxoid stromal response. Int J Gynecol Pathol 1996;15:137–45.
89. Pinto AP, Signorello LB, Crum CP, et al. Squamous cell carcinoma of the vulva in Brazil: prognostic importance of host and viral variables. Gynecol Oncol 1999;74:61–67.
90. Fakhry C, Lacchetti C, Rooper LM, et al. Human papillomavirus testing in head and neck carcinomas: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists Guideline. J Clin Oncol 2018;36:3152–61.
91. College of American Pathologists. Human Papillomavirus Testing in Head and Neck Carcinomas. 2021. Available at: https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-guidelines/human-papillomavirus-testing-in-head-and-neck-carcinomas. Accessed August 1, 2021.
Keywords:

Vulval cancer; Data sets; Protocols; Tumour classification; Grading; Measurement; Staging

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