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Clinicopathologic diagnosis of dVIN related vulvar squamous cell carcinoma: An extended appraisal from a tertiary women's hospital

Abstract

Background Differentiated vulvar intraepithelial neoplasia (dVIN) is a non-human papilloma virus (HPV)-related high-grade precursor lesion to vulvar squamous cell carcinoma (vSCCa). Although TP53 gene mutations have been identified in 80% of dVIN, its role in dVIN pathogenesis as well as malignant transformation is still being poorly understood. Poor reproducible diagnostic criteria and ambiguous p53 immunostaining patterns, along with morphologic discordance still pose a diagnostic challenge.

Methods A series of 60 cases of dVIN-related vSCCa along with adjacent dVIN were evaluated. Clinicopathological features as well as immunohistochemical results were recorded on the resection-confirmed dVIN-related vSCCa.

Results The average age of the patients was 71 years. Thirty-five cases (58.4%) of dVIN-related vSCCa were moderately differentiated, fourteen cases (23.3%) were poorly differentiated, and the remaining eleven cases (18.3%) were well-differentiated. Twenty-nine cases (48.3%) were found to have lichen sclerosus adjacent to dVIN. In terms of p53 and p16 expression in dVIN-related vSCCa and the adjacent dVIN, fifty-five (91.7%) dVIN showed mutant p53 immunostaining pattern with strong positive expression in 80% cases (basal/para-basal expression) and null pattern expression in 11.7% cases. Five (8.3%) dVIN showed p53 wild-type staining pattern. The wild-type pattern were seen in 5% of vSCCa and p53 null pattern were seen in 13.3% vSCCa. Six cases demonstrated atypical staining patterns: two cases showed p53 null expression in dVIN but p53 overexpression in invasive carcinoma; three cases exhibited p53 null expression in invasive carcinoma, with the adjacent dVIN showing basal and para-basal mutant (2 cases) and wild-type (1 case) p53 expression patterns. A single case demonstrated p53 wild-type pattern in dVIN and overexpression in invasive carcinoma. In addition, 65% dVIN were p16 negative and 31.7% dVIN had patchy p16 staining.

Conclusion Clinical and prognostic value of the ambiguous/inconsistent patterns are uncertain and molecular studies are needed for further characterization.

Highlights

  • p53 expression patterns are concordant in dVIN and the subsequent dVIN related vSCCa. However, there is a need for additional studies addressing the mutational profiles of dVIN and dVIN-related vSCCa with discordant or discrepant p53 expression patterns, especially in cases with unusual morphologic features.

  • An immunohistochemical panel including p53, Ki-67, and p16 should be utilized for a diagnosis of dVIN-related vSCCa.

1 Introduction

Differentiated vulvar intraepithelial neoplasia (dVIN) was initially described by Gosling et al in 1961 and called “intraepithelial carcinoma, simplex type”.1 This entity was further studied by Hart et al who coined the term “differentiated”’ to describe the specific morphologic features of dVIN in 1977.2 In 1986, the International Society for the Study of Vulvar Disease revised the classification, the term “VIN III, severe dysplasia, differentiated type” was recommended for the first time.3

Two main pathways, namely Human Papilloma virus (HPV)-related and HPV-independent processes, lead to the development of precursor lesions of vulvar squamous cell carcinoma (vSCCa).4 The HPV-related precursor lesion is the classic/usual vulvar intraepithelial neoplasia, (uVIN/VIN III) and HPV-independent lesions include dVIN and other vulvar aberrant maturation (VAM) conditions including differentiated exophytic vulvar intraepithelial lesion (DEVIL) and vulvar acanthosis with altered differentiation (VAAD). These HPV-independent lesions have been under-recognized in the past, leading to delays in treatment.5 The 2020 fifth edition of the World Health Organization (WHO) Classification of Female Genital Tumors classified VIN and vSCCa based on its association with HPV infection.6 This is a crucial distinction to make as the two groups are distinct in terms of prognosis and clinical management.

Clinically, lesions of dVIN are usually unifocal or unicentric, overlap with lichen sclerosus, and appear as grey-white discoloration with a rough surface, as a thick white plaque, or elevated nodule.7–9 vSCCa arising from an HPV-related process and an HPV-independent disease are distinct with different etiologies, characteristics, underlying oncogenesis, clinical management, and prognosis.5,10 A populational study by Joura et al. showed an increased incidence of both entities in the past few years ranging from 0.013 per 100,000 (1985–1988) to 0.121 per 100,000 (1994–1997).11 It is now known that uVIN is primarily associated with high-risk HPV (hrHPV) 16 and 18 infection and responds to multiple treatment regimens such as imiquimod, laser ablation, or surgical excision; whereas dVIN is typically seen in postmenopausal women and associated with chronic inflammatory dermatoses, such as lichen sclerosus and lichen simplex chronicus.11,12 dVIN demonstrates subtle clinicopathologic features with excision being the preferred management. As opposed to uVIN, dVIN is less radiosensitive, more likely to recur, progresses to vSCCa in a shorter period of time, and has higher disease related mortality than that in uVIN-related vSCCa.10,13-16

The rapid progression of dVIN to invasive carcinoma have made it imperative to establish a reproducible clinicopathologic diagnostic criteria for this entity. However, a diagnosis of dVIN remains challenging.4,5,17 Although TP53 gene mutations have been identified in 80% of dVIN, its role in dVIN pathogenesis as well as malignant transformation is still being understood. Poor reproducible diagnostic criteria and ambiguous p53 immunostaining patterns along with morphologic discordance still pose a diagnostic dilemma in daily practice. We specifically studied dVIN related vSCCa to establish/confirm the diagnostic criteria and p53/p16/Ki67 immunohistochemical expression patterns in dVIN and dVIN related vSCCa.

2 Materials and methods

2.1 Case selection

The study was approved by the Institutional Review Board Committee (IRB) at our institution. We retrospectively reviewed the archived pathology database to retrieve the cases with a diagnosis of dVIN related vSCCa at our institution from July 2014 to May 2020. The clinicopathological features were documented from the electronic medical records and analyzed.

2.2 Immunohistochemistry

The hematoxylin and eosin (H&E) slides of dVIN related vSCCa cases on biopsy and resections were reviewed by three subspecialty-trained gynecologic pathologists to confirm the diagnosis. The dVIN related vSCCa was diagnosed according to morphologic criteria and immunohistochemistry (IHC) combination in predominantly dVIN. All dVIN related vSCCa were accompanied with adjacent dVIN, which was the reason we call them dVIN related SCCa. Immunohistochemical stains for p53, Ki67, and p16 were performed on all cases. Formalin-fixed, paraffin-embedded tissue sections were deparaffinized, and immunohistochemical staining was performed using protocols optimized for each antibody. p16 (E6H4™ clone, Ventana, Tucson, AZ), Ki67 (30-9 clone, Ventana, Tucson, AZ) P53 (DO-7 clone, Ventana, Tucson, AZ) with appropriate positive and negative controls were used. In situ hybridization (ISH) for high-risk HPV (hrHPV) mRNA was performed (RNAscope® VS Universal Assay, Advanced Cell Diagnostics, Newark, CA). The probe set included the following HPV subtypes: 16, 18, 31, 33 with additional positive and negative control.

2.3 Interpretation and scoring of immunohistochemical preparations

The immunohistochemical staining patterns for p53, Ki67, and p16 were interpreted. Immunostaining composite scores of p53 in vSCCa (range: 1 to 12) were calculated based on a semi-quantitative system by evaluating the extent (based on the percentage of positive cells) and the intensity of the immunostaining. Extent was scored as 0 points: <5%; 1 point: 6–25%; 2 points: 26%–50%; 3 points: 51%–75%; 4 points: 76%–100%. Intensity was arbitrarily scored as weak (1 point), moderate (2 points), or strong (3 points). Intensity was designated as weak when immunostaining was present but only barely detectable. To correlate the extent and the intensity of immunostaining, these values in positive cases were converted into immunostaining composite scores by multiplying the individual scores of extents by intensity (possible range of values from 1 to 12).18 For example, a case with 26–50% staining (2 points) and strong intensity of immunostaining (3 points) would have an immunohistochemical composite score of 2 ​× ​3 ​= ​6. p53 expression in dVIN was categorized into four patterns: pattern 1: basal staining (strongly positive), pattern 2: basal and para-basal staining (strongly positive), pattern 3: null pattern (completely negative), pattern 4: wild-type pattern. The Ki67 proliferative index in dVIN was categorized into two patterns: pattern 1: basal, pattern 2: basal and para-basal. The percentage of Ki67 positive cells per 100 consecutive cells was recorded in vSCCa. p16 immunostaining in both dVIN and dVIN vSCCa was categorized into three categories: negative, patchy staining, and strong block positive.

2.4 Statistical analysis

The differences of the immunohistochemical composite scores and patterns of dVIN-related vSCCa and the adjacent dVIN were documented and analyzed. The Pearson χ2 test was used for statistical analysis, conducted on an SAS 9.3 software (SAS Institute, Cary, NC). A P value of less than 0.05 was considered statistically significant.

3 Results

A total of 210 cases of vSCCa were retrieved during the study period. Seventy-one cases of dVIN related vSCCa were identified and consisted of biopsies, excisions, or vulvectomy specimens. Five cases with superficial stromal invasion and six cases from outside consultation were excluded from the study due lack of tissue blocks for immunohistochemical study.

3.1 Clinical and demographic findings of dVIN-related vSCCa

Overall, 60 cases of dVIN-related vSCCa were suitable for analysis. The age distribution of 210 cases of vSCCa and 60 cases of dVIN-related vSCCa is demonstrated in Fig. 1. The average age of the 60 patients was 71.2 years (34–92 years) with a median age of 57 years. dVIN-related vSCCa accounted for 38.3% vSCCa (36/94) in patients aged 70 years and older, which was significantly higher than 20.7% (24/116) in patients younger than 70 years of age (p ​< ​0.01).

Fig. 1
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Age distribution of women with dVIN-related vSCCa and total vSCCa.

The International Federation of Gynecology and Obstetrics system (FIGO) clinical stages were re-assigned for each case of dVIN related vSCCa based on the American Joint Committee on Cancer (AJCC) 8th edition. Forty-three cases (71.7%) were classified as FIGO stage 1B, twelve cases (20%) were classified as FIGO stage IIIA, three cases were FIGO stage IIIC, and stages IA and IIA had one case in each category, respectively. The depth of invasion for each case correlated with FIGO stage, as seen in Fig. 2.

Fig. 2
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Depth of invasion and FIGO stage of dVIN-related vSCCa.

FIGO clinical stages were re-assigned for each case of dVIN related vSCCa based on the AJCC 8th edition. Forty-three cases (71.7%) were classified as FIGO stage 1B, twelve cases (20%) were classified as FIGO stage IIIA, three cases were FIGO stage IIIC, and stages IA and IIA had one case in each category, respectively. The depth of invasion for each case correlated with FIGO stage.

3.2 Morphological characteristics of dVIN-related vSCCa

Of sixty cases, thirty-five cases (58.3%) of vSCCa were histologically moderately differentiated, fourteen cases (23.3%) were poorly differentiated, and the remaining eleven cases (18.3%) were well differentiated. Lichen sclerosus was found in the adjacent surface epithelium in 29 cases (48.3%) (Table 1.). Fourteen cases (23.3%) showed lymphovascular invasion either on biopsy or on the resection specimen. Eighteen cases (30%) had lymph node metastasis, with two of them showing extranodal extension.

Table 1
•
Clinicopathologic characteristics of dVIN-related vSCCa.

3.3 Immunostaining patterns of dVIN-related vSCCa and adjacent dVIN

In the majority of cases, the adjacent dVIN exhibited a basal and para-basal p53 staining pattern (66.7%; 40/60), with 13.3% (8/60) showing a basal pattern, 11.7% (7/60) showing a null pattern, and 8.3% (5/60) showing a wild-type pattern. Most cases showed Ki67 expression in a basal pattern of distribution (61.7%; 37/60), with 38.3% (23/60) of cases showing a basal and para-basal pattern. In vSCCa, most cases showed a strong and diffuse positivity of p53 with score 12 (61.7%; 38/60), with one case having a positive score of 9, five cases with a positive score of 8 and five cases with a positive score of 6. Eight cases showed a null pattern of p53 expression, and three cases demonstrated wild-type expression patterns. Immunostaining for p16 was negative with patchy-type stain in 31.7% (19/60) of dVIN and 18.3% (11/60) in vSCCa. In addition, two of the five p53 wild-type cases of dVIN showed strongly positive staining for p53 in vSCCa (one case had a score of 12 and the other one showed null pattern staining). The remaining three cases showed a consistently p53 wild-type pattern in vSCCa. Four of five p53 wild-type cases in dVIN were p16 completely negative. Three p53 null vSCCa cases showed a basal and para-basal staining pattern in dVIN areas (Table 2).

Table 2
•
Summary of p53, p16, and Ki67immunostaining in dVIN and dVIN-related vSCCa.

Figs. 3–9 depict the common staining pattern of mutant p53 and patchy positive p16 in dVIN and dVIN related vSCCa, as well as all atypical staining patterns. Overall, there were 44 cases with a mutant p53 and negative p16 staining in both dVIN and invasive carcinoma areas. A total of five type of p53/p16 staining patterns in dVIN and vSCCa areas were summarized: A. The most common mutant p53 expression pattern in dVIN was basal and para-basal strongly expression (40 cases), with only 8 cases showing a basal-only p53 expression. Most cases showed entirely negative p16 staining in this pattern, with 19 cases showing patchy positive staining. B. Three cases fit into the second pattern with p53 wild-type pattern and an entirely negative p16 expression. C. The third pattern, showing mutant p53 staining (basal or basal and para-basal strongly positive) and block positive p16 expression, was seen in two cases, both in invasive carcinoma and the adjacent dVIN. D. The fourth pattern was seen in five cases and showed null expression of p53 and completely negative p16 staining. E. Atypical p53 staining patterns were identified in six cases: two cases showed a null p53 pattern in dVIN with p53 overexpression in invasive carcinoma; three cases demonstrated a null p53 pattern in invasive carcinoma with dVIN showing either a basal and para-basal p53 expression (2 cases) or p53 wild-type pattern (1 case). One case demonstrated p53 wild-type pattern in dVIN but overexpression in the invasive carcinoma.

Fig. 9
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Example of atypical case reported as dVIN and dVIN related vSCCa, Clinical Stage IIIA.

Fig. 8
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Example of atypical case reported as dVIN and dVIN related vSCCa, Clinical Stage IB.

Fig. 7
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Example of atypical case reported as dVIN and dVIN related vSCCa, Clinical Stage IB.

Fig. 6
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Example of case reported as “wild-type p53 and negative p16” in dVIN and dVIN related vSCCa. Clinical Stage IIIA.

Fig. 5
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Example of case reported as “mutant p53 and block positive p16,” Clinical Stage IB

Fig. 4
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Examples of case reported as “Null p53 and negative p16” in dVIN and dVIN related vSCCa, Clinical Stage IB.

Fig. 3
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Example of case reported as “Mutant p53 and negative p16” in dVIN and dVIN related vSCCa, Clinical Stage IB.

4 Discussion

Poor reproducible diagnostic criteria and ambiguous immunostaining patterns, along with morphologic discordance still affects the accurate diagnosis and classification of vulvar precancer lesions, especially dVIN and dVIN related vSCCa. To address this issue, we studied a series of 60 first-time diagnosed dVIN-related vSCCa from our archived pathologic records. The majority of our cases (80%) are morphologically moderately to poorly differentiated. dVIN-related vSCCa usually occurred in postmenopausal women with peak age of 70–80 years. Forty-six cases (77%) were classified as FIGO stage 1B and above according to the AJCC 8th Edition.

One of the most important morphologic features of dVIN is vulvar basal layer atypia and the high degree of differentiation. By histology, the basal layer of vulvar skin show “cytologic atypia” with vesicular nuclei with thickened, irregular nuclear membranes, coarse chromatin/hyperchromasia, and prominent nucleoli. Other histologic features of dVIN include the increased mitosis, particularly atypical mitosis in the basal cell layer, elongation and anastomoses of rete ridges, dyskeratosis, and prominent acantholysis or spongiosis. Abnormal keratinization and reverse maturation along with basal cell proliferation may also be identified. These features can be extremely subtle, which results in low interobserver agreement even among experienced gynecologic pathologists.4,19,20 There are some occasions where it can be challenging to distinguish between dVIN and uVIN, especially when dVIN presents with a more basaloid appearance extending beyond the basal layer, architectural disorganization, and undifferentiated keratinocytes.4,21 In these instances, ancillary immunohistochemical studies can be helpful, such as the hrHPV surrogate marker, p16. In our study, all of the p16 positive cases had negative HPV RNA in-situ hybridization results, regardless of whether p16 was positive in dVIN or vSCCa.

TP53 gene mutation has been reported in up to 80% of dVIN, however its role in dVIN pathogenesis as well as malignant transformation is still being understood. Recently, six p53 immunohistochemical staining patterns have been described, in which the authors have shown its strong correlation with TP53 mutation status.22 In this study, the authors identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) para-basal/diffuse overexpression, (5) absent expression, and (6) cytoplasmic expression. These patterns were consistent with TP53 mutation status in 95% vSCCa and 93% in-situ lesions. They concluded that those exhibited scattered p53 staining and those with a p53 weak basal overexpression could be easily confused. Rakislova et al23 compared patterns of p53 positivity and identified a new six-pattern framework between invasive vSCCa and an adjacent skin lesion. They found that approximately 74% invasive vSCCa showed abnormal p53 staining and 47% vSCCa with associated skin lesions showed an abnormal p53 stain, with an identical staining pattern between the vSCCa and the adjacent skin lesion in 80% of the cases.

In the present study, we identified four major staining patterns with respect to p53 and p16 expression in dVIN related vSCCa: 1) pattern of “mutant p53 and negative p16” in dVIN and invasive carcinoma (44/60); 2) “wild-type p53 and negative p16” (3/60); 3) “mutant p53 and block positive p16” (2/60); 4) “null p53 and negative p16” (5/60). Additionally, we identified atypical staining patterns in six cases in our cohort: null p53 in dVIN but overexpression in invasive carcinoma (2/60); null p53 in invasive carcinoma with two showing basal and para-basal p53 in dVIN (3/60); wild-type p53 pattern in dVIN (1/60). Only one case demonstrated p53 wild-type pattern in dVIN but overexpression in invasive carcinoma.

TP53 mutations are widely accepted as supportive of a diagnosis of dVIN. Somatic missense, deletion, or truncating mutations of the TP53 tumor suppressor gene are commonly found in HPV-negative vulvar carcinogenesis, although a subset of them may develop through TP53-independent routes. Petitjean et al have reported that strong and diffuse p53 expression is a surrogate for TP53 missense mutation, whereas TP53 deletion or truncating mutations are associated with a null phenotype,24 although the null phenotype of p53 has not been well studied in the vulva yet.

Noojj et al demonstrated that the TP53 mutations were much more common in HPV-independent precancer lesions than those related with HPV infection.25 They further identified a novel, third genetically distinct group of tumors that were HPV-independent but p53 wild-type (so-called p53 ​wt VIN) but were enriched for somatic mutations in the NOTCH1 and HRAS genes. However, they found no difference in rates of local recurrence or 5-year survival between HPV negative/p53 ​wt and HPV negative/p53 mutant vSCCa in their study.26–28

It may be difficult to interpret p53 expression patterns in some cases. Leigl et al have reported the p53 overexpression in lichen sclerosus, therefore p53 is not specific for a diagnosis of dVIN.28 They also proposed that wild-type p53 protein may accumulate following cell stress or DNA damage, a mechanism postulated to occur in lichen sclerosus where ischemic stress results from the poor oxygenation, further resulting in vasculitis and inflammation.29 In addition, wild-type and mutant p53 staining pattern may overlap, further complicating interpretation.

This is an observational clinical study with an inclusion of a large number of dVIN-related vSCCa cases from a single academic women's hospital. Both in-situ and invasive carcinoma components along with an immunohistochemical stain panel including p16, p53, and Ki67 were clinicopathologically reviewed. All strongly positive p16 IHC cases were confirmed hrHPV status by RNA in-situ hybridization. Studies have shown that p53 IHC pattern has an excellent correlation with TP53 sequencing, albeit it was not performed in current study.24 This study corroborates previous findings that the p53 expression patterns are concordant in dVIN and the subsequent dVIN related vSCCa.24 However, there is a need for additional studies addressing the mutational profiles of dVIN and dVIN-related vSCCa with discordant or discrepant p53 expression patterns, especially in cases with unusual morphologic features. In this regard, we recommend the clinical correlation and morphologic re-evaluation. An immunohistochemical panel including p53, Ki67, and p16 should be utilized for a diagnosis of dVIN-related vSCCa.

Author contributions

WT: conceptualization, slide review, investigation, data analysis, writing the original draft; VB: slide review, investigation, data analysis, writing the original draft; LH: data analysis, review and edit of the manuscript; TJ: data analysis, review and edit of the manuscript; ZHN: data analysis, review and edit of the manuscript; RB: review of selective slides, data analysis, review and edit of the manuscript; ZCQ: project supervision and conceptualization, review of the slides, data analysis, review and editing of the manuscript.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.

Ethics approval and consentment

The study was approved by the Institutional Review Board Committee (IRB) of University of Pittsburgh Medical Center. Informed consent was exempt for retrospectively retrieved data from pathology database.

Declaration of competing interest

All authors have no conflict of interests.

  • ^ 1: Co-first author

  • This abstract was presented at the 2020 USCAP Annual meeting in Los Angeles, CA.

  1. close Gosling J.R.G., Abell M.R., Drolette B.M., et al. Infiltrative squamous cell (epidermoid) carcinoma of vulvar. Cancer 1961; 14:330–343.
    Google Scholar
  2. close Hart W.R.. Cutaneous vulvar diseases. Contemp Ob/Gyn 1977; 9:45–50.
    Google Scholar
  3. close Wilkinson E.J., Kneale B., Lynch P.J., et al. Report of the ISSVD terminology committee. J Reprod Med 1986; 31:973–974.
    Google Scholar
  4. close Jin C., Liang S.. Differentiated vulvar intraepithelial neoplasia: a brief review of clinicopathologic features. Arch Pathol Lab Med 2019; 143:768–771.
    Google Scholar
  5. close Singh N., Gilks C.B.. Vulvar squamous cell carcinoma and its precursors. Histopathology 2020; 76:128–138.
    Google Scholar
  6. close Moch H.. Female Genital Tumours: WHO Classification of Tumours. Lyon, France, International Agency for Research on Cancer 2020;
    Google Scholar
  7. close Hart W.R.. Vulvar intraepithelial neoplasia: historical aspects and current status. Int J Gynecol Pathol 2001; 20:16–30.
    Google Scholar
  8. close Bornstein J., Bogliatto F., Haefner H.K., et al. The 2015 International society for the study of vulvovaginal disease (ISSVD) terminology of vulvar squamous intraepithelial lesions. J Low Genit Tract Dis 2016; 20:11–14.
    Google Scholar
  9. close Eva L.J., Ganesan R., Chan K.K., et al. Differentiated-type vulval intraepithelial neoplasia has a high-risk association with vulval squamous cell carcinoma. Int J Gynecol Cancer 2009; 19:741–744.
    Google Scholar
  10. close Day T., Marzol A., Pagano R., et al. Clinicopathologic diagnosis of differentiated vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Low Genit Tract Dis 2020; 24:392–398.
    Google Scholar
  11. close Joura E.A., Lösch A., Haider-Angeler M.G., et al. Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulvar in young women. J Reprod Med 2000; 45:613–615.
    Google Scholar
  12. close 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 Care 2013; 49:3450–3461.
    Google Scholar
  13. close Reyes M.C., Cooper K.. An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis. J Clin Pathol 2014; 67:290–294.
    Google Scholar
  14. close McAlpine J.N., Kim S.Y., Akbari A., et al. HPV-independent differentiated vulvar intraepithelial neoplasia (dVIN) is associated with an aggressive clinical course. Int J Gynecol Pathol 2017; 36:507–516.
    Google Scholar
  15. close McAlpine J.N., Leung S.C.Y., 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; 71:238–246.
    Google Scholar
  16. close Horne Z.D., Dohopolski M.J., 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.
    Google Scholar
  17. close Hoang L.N., Park K.J., Soslow R.A., et al. Squamous precursor lesions of the vulva: current classification and diagnostic challenges. Pathology 2016; 48:291–302.
    Google Scholar
  18. close Zhao C., Vinh T.N., McManus K., et al. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol 2009; 33:354–366.
    Google Scholar
  19. close Reutter J.C., Walters R.A., Selim M.A., et al. Differentiated vulvar intraepithelial neoplasia: what criteria do we use in practice? J Low Genit Tract Dis 2016; 20:261–266.
    Google Scholar
  20. close Van Den Einden L.C.G., De Hullu J.A., Massuger L.F.A.G., et al. Interobserver variability and the effect of education in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia. Mod Pathol 2013; 26:874–880.
    Google Scholar
  21. close 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; 33:1659–1665.
    Google Scholar
  22. close Tessier-Cloutier B., Kortekaas K.E., 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; 33:1595–1605.
    Google Scholar
  23. close Rakislova N., Alemany L., Clavero O., et al. p53 immunohistochemical patterns in HPV-independent squamous cell carcinomas of the vulva and the associated skin lesions: a study of 779 cases. Int J Mol Sci 2020; 21:1–15.
    Google Scholar
  24. close Petitjean A., Achatz M.I.W., Borresen-Dale A.L., et al. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 2007; 26:2157–2165.
    Google Scholar
  25. close Nooij L.S., Ter Haar N.T., Ruano D., et al. Genomic characterization of vulvar (Pre) cancers identifies distinct molecular subtypes with prognosticsignificance. Clin Cancer Res 2017; 23:6781–6789.
    Google Scholar
  26. close Han M.R., Shin S., Park H.C., et al. Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva. Exp Mol Med 2018; 50:e442.
    Google Scholar
  27. close Cohen P.A., Anderson L., Eva L., et al. Clinical and molecular classification of vulvar squamous pre-cancers. Int J Gynecol Cancer 2019; 29:821–828.
    Google Scholar
  28. close Liegl B., Regauer S.. p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulvar intraepithelial neoplasia (d-VIN). Histopathology 2006; 48:268–274.
    Google Scholar
  29. close Junttila M.R., Evan G.I.. p53-a Jack of all trades but master of none. Nat Rev Cancer 2009; 9:821–829.
    Google Scholar

  • Received: 15 September 2022
  • Accepted: 18 January 2023
  • First published: 1 March 2023

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