Vulva & vagina
Squamous carcinoma & precursor lesions
HPV independent squamous cell carcinoma-vulva
Author: Matthias Choschzick, M.D.
Board of reviewers: C. Blake Gilks, M.D.
Deputy Editor-in-Chief: Gulisa Turashvili, M.D., Ph.D.
Last staff update: 11 July 2024 (update in progress)
Copyright: 2002-2024, PathologyOutlines.com, Inc.
PubMed Search: HPV independent squamous cell carcinoma - vulva
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Choschzick M. HPV independent squamous cell carcinoma-vulva. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/vulvaverrucous.html. Accessed July 15th, 2024.
Definition / general
- Stromal invasive squamous cell carcinoma with no evidence for association with human papillomavirus (HPV) infection
Essential features
- Stromal invasive squamous cell carcinoma
- p16 nonblock type positivity or aberrant p53 mutation type expression pattern
- Coincident HPV independent vulvar intraepithelial neoplasia (dVIN, vaVIN) (desirable)
Terminology
- No synonyms
ICD coding
Epidemiology
- ~67% of all vulvar squamous cell carcinomas (VSCC) independent of HPV prevalence in the population (Lancet Oncol 2023;24:403)
- Highest incidence in the eighth decade (Int J Cancer 2017;141:2517)
Sites
- All parts of the vulva including labia majora et minora, clitoris (midline carcinomas), vestibule, introitus
Etiology
- 30 - 80% of cases present with TP53 mutations (Semin Diagn Pathol 2021;38:50)
Clinical features
- Risk factors: lichen simplex chronicus, lichen sclerosus (5% with subsequent vulvar carcinoma), lichen planus (Surg Pathol Clin 2019;12:249)
Diagnosis
- Punch biopsy, vulvectomy specimen
Prognostic factors
- Prognosis of HPV independent VSCC is worse than HPV associated VSCC (Histopathology 2017;71:238, Int J Gynecol Pathol 2020;39:391)
- Higher local recurrence rate in HPV negative VSCC (Gynecol Oncol 2016;142:420)
- Stage (tumor size and invasion depth) and lymph node status are main prognostic factors (Semin Diagn Pathol 2021;38:37)
- Tumor margin plays a role in local recurrence (Eur J Cancer 2016;65:139)
Case reports
- 28 year old woman with VSCC and simplex VIN (Int J Gynecol Pathol 2008;27:591)
- 74 year old woman with HPV negative spindle cell carcinoma of the vulva (Am J Dermatopathol 2002;24:135)
- 79 year old woman with verrucous carcinoma and lichen planus (World J Surg Oncol 2017;15:7)
- 82 year old woman with acantholytic squamous cell carcinoma (Int J Gynecol Pathol 2022;41:122)
- 4 cases with spindle cell carcinoma of the vulva (Int J Gynecol Pathol 2014;33:203)
Treatment
- Wide local excision, partial or total vulvectomy, sentinel or inguinofemoral lymph node dissection depending on stage and patient condition (J Obstet Gynaecol Can 2019;41:89)
- Diminished response to radiotherapy (Int J Gynecol Cancer 2020;30:100)
Gross description
- Exophytic mass or ulcerated lesion, frequently multifocal
- Tumor diameter should be measured parallel to the skin surface in millimeters
Microscopic (histologic) description
- Frequently (up to 80%) keratinizing squamous cell carcinomas; other histological patterns: nonkeratinizing, basaloid, warty differentiation (Int J Cancer 2017;141:2517)
- Keratin pearl formation and high percentage of differentiated tumor cells are characteristic features
- Verrucous carcinomas and carcinomas with spindle cell differentiation are mostly HPV negative (Surg Pathol Clin 2019;12:249, Int J Gynecol Pathol 2023;42:207)
- Rare acantholytic morphology has been described (Int J Gynecol Pathol 2022;41:122)
- No established grading system
- Combined use of p16 and p53 immunohistochemistry (IHC) is recommended for demonstration of HPV independence (Mod Pathol 2023;36:100145)
Microscopic (histologic) images
Contributed by Matthias Choschzick, M.D.
Keratinizing squamous cells
Clear cells
p53 immunohistochemistry
p53 immunohistochemistry
Positive stains
- p53 mutation type pattern in the majority of HPV independent VSCC (Mod Pathol 2020;33:1595)
Negative stains
- p16 nonblock-like staining or negative in most cases (Int J Gynecol Pathol 2016;35:385)
Sample pathology report
- Vulva, biopsy:
- Keratinizing squamous cell carcinoma (HPV independent) (see comment)
- Comment: p16 IHC nonblock-like (negative)
Differential diagnosis
- HPV associated squamous cell carcinoma:
- Histomorphological overlapping with HPV associated carcinomas, which also show keratinizing morphology in up to 36% of cases (Int J Cancer 2017;141:2517)
- p16 and p53 immunohistochemistry for differential
- Condyloma acuminatum:
- Morphological similarities to verrucous carcinoma: postmenopausal woman, pushing border infiltration, mostly HPV negative but sometimes also positive for low risk HPV
Additional references
Board review style question #1
What are the most helpful auxiliary analysis methods for categorization of vulvar carcinomas in HPV associated and HPV independent carcinomas?
- HPV immunohistochemistry
- HPV RNA in situ hybridization
- p16 immunohistochemistry
- p16 and p53 immunohistochemistry
- TP53 next generation sequencing
Board review style answer #1
D. p16 and p53 immunohistochemistry (IHC). Combined IHC for p16 and p53 shows the highest specificity and sensitivity for HPV association. Answer B is incorrect because the sensitivity of HPV RNA in situ hybridization is lower than p16 IHC. Answer C is incorrect because there are rare vulvar carcinomas with p16 overexpression without HPV association and these can be recognized because they show mutant pattern p53 expression. Answer E is incorrect because rare HPV associated vulvar carcinomas harbor TP53 mutations. Answer A is incorrect because the sensitivity for verification of HPV association is very low.
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Reference: HPV independent squamous cell carcinoma-vulva
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Board review style question #2
Which staining pattern of p53 in HPV independent squamous cell carcinomas of the vulva is displayed in the picture above?
- Basal mutation type
- Diffuse mutation type
- Membranous
- Null-like
- Wild type
Board review style answer #2
E. Wild type. The p53 expression pattern is heterogeneous and described as scattered wild type pattern. Answer B is incorrect because the p53 staining pattern is heterogeneous, not diffuse. Answer A is incorrect because the p53 expression pattern is more scattered than basal. Answer D is incorrect because p53 is overexpressed. Answer C is incorrect because p53 expression is never membranous.
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Reference: HPV independent squamous cell carcinoma-vulva
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