Vulva, vagina & female urethra
Squamous carcinoma and precursor lesions
HPV associated squamous cell carcinoma
Author: Priya Nagarajan, M.D., Ph.D.
Last author update: 1 April 2015
Last staff update: 15 March 2022
Copyright: 2002-2023, PathologyOutlines.com, Inc.
PubMed Search: Squamous cell carcinoma [title] vulva "loattrfree full text"[sb]
Table of Contents
Definition / general | Epidemiology | Sites | Etiopathogenesis | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Additional referencesCite this page: Nagarajan P. HPV associated squamous cell carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/vulvascc.html. Accessed September 26th, 2023.
Definition / general
- Includes malignancies originating from keratinizing and nonkeratinizing squamous epithelia of vulva
- Comprise 90 - 95% of the estimated 5,150 cancers of vulva in 2015 (CA Cancer J Clin 2015;65:5)
- Overall 5 year survival rate is ~70% (~90% in node negative patients) (Int J Gynaecol Obstet 2014;125:97)
Epidemiology
- Annual incidence in developed countries: 2 - 3 per 100,000 women (Gynecol Oncol 2015;136:143)
- Peak incidence: age 60 - 70 years
Sites
- Labia majora are most common site but tumors that involve clitoris require extensive surgery
Etiopathogenesis
- Two distinct pathways: (J Skin Cancer 2011;2011:951250, J Low Genit Tract Dis 2013;17:267)
- Human papillomavirus (HPV) dependent:
- 20 - 40% of vulvar SCCs
- More common in younger women; associated with smoking, higher number of sexual partners and immune compromise
- Associated with usual type vulvar intraepithelial neoplasia (uVIN)
- May be associated with genital warts or abnormal Pap smear
- Progression to SCC in 9 - 16% of untreated and 3% of treated patients
- Human papillomavirus (HPV) independent:
- Common in older, postmenopausal women
- Associated with lichen sclerosus and differentiated type of vulvar intraepithelial neoplasia (dVIN)
- 3 - 6% of patients develop SCC (J Am Acad Dermatol 1995;32:393)
- Associated with p53 mutations
- Increased risk of recurrence and death (Obstet Gynecol 1995;85:709)
Diagrams / tables
Contributed by Priya Nagarajan, M.D., Ph.D.
Schematic for measuring invasion and depth
Clinical features
- Warty tumor, long standing ulcer, groin mass, plaque or rarely erythematous rash
- May be asymptomatic, painful or itchy, associated with burning or soreness
- May be associated with bleeding or discharge
Diagnosis
- Histologic examination is essential to determine type of carcinoma and depth of stromal invasion (most importantly)
- Therefore, an adequate biopsy is essential
Radiology description
- CT, PET / CT, MRI assess tumor extent and presence of inguinal lymph node metastasis (AJR Am J Roentgenol 2013;201:W147)
- MRI can assess involvement of adjacent organs (Am J Clin Oncol 2013;36:415)
Prognostic factors
- Clinical adverse prognostic factors include older age, advanced stage at presentation, smoking, ulcerated / matted inguinal lymph nodes (J Skin Cancer 2011;2011:951250)
- Also clitoral involvement (probably due to larger tumor size), increased depth of invasion, lymphovascular space involvement (associated with metastasis to inguinofemoral lymph nodes) (Eur J Surg Oncol 2015;41:592)
- Lymph node status: number of positive nodes, extracapsular extension, percentage of nodal replacement and size of nodal metastasis (Crit Rev Oncol Hematol 2012;83:71, Int J Gynecol Cancer 2012;22:503)
- Perineural invasion is an independent risk factor for recurrence (Am J Surg Pathol 2015;39:1070)
- Other published indicators of poor prognosis:
- Tumor size ≥ 6 - 7.9 cm and depth of stromal invasion > 4 mm
- Tumor size ≥ 8 cm irrespective of depth of stromal invasion
- Extranodal extension
- ≥ 2 positive lymph nodes irrespective of tumor size and depth of stromal invasion (Gynecol Oncol 2014;132:643)
- Tumor size ≥ 35 mm, 15 mm of tumor free surgical margin and depth of stromal invasion > 4 mm (J Gynecol Oncol 2013;24:242)
Case reports
- 12 and 16 year old girls (Pediatrics 2000;106:E57, J Gynecol Oncol 2011;22:207)
- 14 year old girl and 23 year old woman with coexisting Fanconi anemia (Int J Gynecol Cancer 2002;12:220, Int J Hematol 2010;91:498)
- 28 year old woman with coexisting Crohn's disease (Eur J Gynaecol Oncol 2008;29:651)
- 35 year old woman with vulvar SCC and coexisting Turner syndrome (J Gynecol Oncol 2011;22:211)
- 37 year old pregnant woman (Iran J Cancer Prev 2014;7:175)
- 41 year old woman with verrucous carcinoma of vulva and Turner syndrome (Gynecol Oncol 2004;92:380)
- 54 and 85 year old women with primary subepithelial squamous cell carcinomas of vulva (J Low Genit Tract Dis 2013;17:e8)
- 92 year old woman with plasmacytoid squamous cell carcinoma (Int J Gynecol Pathol 2008;27:601)
- Spindle cell carcinoma of vulva (Int J Gynecol Pathol 2014;33:203)
Treatment
- Surgery:
- Wide local excision is mainstay treatment for early stage vulvar carcinoma and includes radical / modified radical vulvectomy en bloc with bilateral inguinofemoral lymphadenectomy or at least sentinel lymph node sampling (Gynecol Oncol 2000;76:24, Ther Adv Med Oncol 2013;5:183, Eur J Gynaecol Oncol 2011;32:505, Gynecol Oncol 2015;136:300)
- Pelvic exenteration is usually reserved for locally advanced disease (Gynecol Oncol 2012;124:87)
- Radiotherapy:
- Primary radiation therapy is often used for unresectable disease (Am J Clin Oncol 2013;36:415, Cochrane Database Syst Rev 2011;(5):CD00222)
- Adjuvant radiation therapy is used for high risk primary tumors (tumor size > 4 cm, lymphovascular invasion, close or positive surgical margins, metastasis to lymph nodes)
- Chemotherapy:
- Primary chemoradiation is used for unresectable tumors, to avoid significant postoperative morbidity (Wien Klin Wochenschr 2013;125:119, Gynecol Oncol 2014;132:780, J Natl Cancer Inst 2015;107:dju426)
- Neoadjuvant chemotherapy (Curr Oncol Rep 2013;15:573)
Clinical images
Images hosted on other servers:
Ulcerative lesion, upper labia minor
Gross description
- Warty tumor, ulcer, plaque or rarely erythematous rash
Superficially invasive squamous cell carcinoma (SISCCA):
- Previously called microinvasive squamous cell carcinoma but terminology changed based on Lower Anogenital Squamous Terminology (LAST) criteria (Int J Gynecol Pathol 2013;32:76)
- SISCCA terminology recommended for minimally invasive squamous cell carcinomas of vulva that has been completely excised and can be safely treated with conservative surgical therapy alone
- SISCCA refers to AJCC T1a (FIGO IA) vulvar cancer:
- Tumor size ≤ 2 cm, confined to the vulva AND
- Stromal invasion of ≤ 1 mm
- No metastasis to lymph nodes
Microscopic (histologic) description
- Similar to squamous cell carcinoma at other sites
- However, due to its association with human papillomavirus (HPV), malignant squamous cells may be well differentiated (abundant eosinophilic cytoplasm with low nuclear to cytoplasmic ratio), moderately differentiated (with nuclear pleomorphism) or poorly differentiated (high grade features such as basophilic cytoplasm and increased nuclear to cytoplasmic ratio)
- For detailed histologic prognostic parameters to be included in the pathology report, please refer to CAP synoptic report: CAP: Cancer Protocol Templates [Accessed 10 October 2017]
- See also FIGO staging: Int J Gynaecol Obstet 2014;125:97
Microscopic (histologic) images
Contributed by Priya Nagarajan, M.D., Ph.D.
Ulcerated
Sqamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma
Sarcomatoid carcinoma
Superficially invasive squamous cell carcinoma (SISCCA):
With VIN
Microinvasive
Images hosted on other servers:
Sarcoma-like stroma, various images
Cytology description
- Performed infrequently (Br J Cancer 2012;106:269, Acta Cytol 1993;37:871)
- HPV+ neoplasms: clusters or single cells with increased nuclear to cytoplasmic ratio, irregular nuclear contours, coarse chromatin and perinuclear clearing
- HPV- neoplasms: large cells with round / ovoid nuclei, prominent nucleoli, open / vesicular chromatin, no perinuclear halo
Molecular / cytogenetics description
- Allelic imbalances: gains at 3q, loss of 3p, 4p and 11q are common in HPV 16+ SCC (Gynecol Oncol 2015;136:143, Eur J Cancer 2014;50:85)
- See Eur J Gynaecol Oncol 2007;28:442:
- HPV+ : gain of 3q and 12q
- HPV- : gain of 8q
- HPV+ and HPV- : loss of 4p and 3p
- Hypermethylation of RAS association domain family RASSF2A gene seen in lichen sclerosis associated SCC (Int J Cancer 2011;128:2853)
- Somatic mutations of p53 identified in > 80% of vulvar SCC
Differential diagnosis
- Autoimmune and bullous disorders (Am Fam Physician 2008;77:321)
- Bowen disease
- Giant condyloma acuminatum (Buschke-Löwenstein tumor) (Oncol Lett 2013;5:541, Int J Infect Dis 2010;14:e455)
- Hypertrophic herpes simplex genitalis / pseudoepitheliomatous hyperplasia (Int J Gynecol Pathol 2012;31:286, J Low Genit Tract Dis 2011;15:66)
- Hypertrophic / erosive lichen planus (Am Fam Physician 2008;77:321)
- Other carcinomas / benign tumors of vulva
- Prurigo nodularis (Pathology 2012;44:565)
Additional references
