FORUM 044 VULVAR DISEASE: WHAT DO YOU KNOW? AN OVERVIEW Vulvar Neoplasms: Benign and Malignant Jill Allbritton, MD March 2, 2019
NO DISCLOSURES WITH INDUSTRY Jill Allbritton, MD Forum 044 Vulvar Disease: What Do You Know? An Overview VULVAR NEOPLASMS: Benign and Malignant DISCLOSURES NONE
VULVAR PIGMENTED LESIONS Whats important? 10% of all pigmented lesions occur on genital skin Vulvar melanoma-late diagnosis-less than 50% 5 yr survival Avg depth 4.0 mm 2% of melanomas in women arise on vulva Genital melanoma Females>Males, Greatest in caucasians Only 4% of dermatologists include vulvar exam on FSE stirrups vs supine with feet on corners of table Seehusen DA et al. Improving women s experience during speculum examinations at routine gynecological visits: randomised clinical trial. BMJ 2006;333:171. Zikry J et al. Genital melanoma: are we adequately screening our patients? Dermatol Online J. 2017;23:1-2.
MELANOMA Average age 60-70 6% arise in preexisting nevi Most common labia minora, clitoris 5 year survival less than 50% (due to depth at detection) Often multifocal, unlike other sites 25% amelanotic German study - anogenital melanoma deeper Breslow depth than female genital tract Remember perianal area! Heppt et al. Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma. Eur J Cancer 2017:81:36-44.
GENITAL MELANOMAS Biopsy new or non resolving erythematous plaques as 25% of genital melanoma unpigmented multifocal sampling for large lesions
VULVAR MELANOMA Most common histology -acral lentiginous, then nodular BrafV600E mutations common in dysplastic nevi and common nevi of genital track (>90%) but not of vulvar melanomas Suggests that dysplastic nevi and common nevi are not melanoma precursor in genital tract C-Kit 28% (imatinib)(most common vulvar) NRAS 28% (most common vaginal) Recent study 9/13 vulvar melanomas as PD-L1 expression(nivolumab, pembrolizumab) Swedish study found decrease in rate (3% per yr over last 25yrs) of vulvar melanoma contrasted to increase in rate (6% per year) of cutaneous melanoma International Journal of Gynecological Pathology 37:477 481, Lippincott Williams & Wilkins, Baltimore Copyright 2017 by the International Society of Gynecological Pathologists Gadducci et al. Gynecologic Oncology 150 (2018) 180 189
AMELANOTIC MELANOMA
ATYPICAL NEVI OF GENITAL TYPE AND MIS
NODULAR MELANONA
VULVAR MELANOSIS Women in 40s rather than 70s Flat, asymmetric, tan to blue, black, irregular borders and size Most common on Labia minora Mucous membranes and modified mucous membranes rather than keratinized skin of vulva Indistinguishable from melanoma clinically Maybe post inflammatory Lichen sclerosus may be predisposing disease Unusual in older women (Suspect Melanoma) No increased risk of melanoma
MANAGEMENT OF VULVAR MELANOSIS Initial photographs Reassured if pt has lichen sclerosus Biopsy Follow up for clinical change Low threshold for biopsy for any clinical change as morphology not distinct in genital pigmented lesions Melanosis NOT premalignant
VULVAR SQUAMOUS CELL CARCINOMA Two common distinct pathways 1. Human Papilloma Virus (HPV) related young women often multifocal smokers 20% burden of invasive SCC better prognosis 2. Non HPV related elderly women often associated with lichen sclerosus 80% burden of invasive SCC
SQUAMOUS CELL CARCINOMAS HPV RELATED PRECURSORS/NONPRECURSORS A. Human Papilloma Virus (HPV) related 1. Low Grade Squamous Intraepithelial Lesion (LSIL) - (VIN1) 2. High Grade Squamous Intraepithelial Lesion (HSIL)-(VIN2/3) HSIL, VIN often thought to have low rate of progression to SCC 3%, this is in treated patients 10% risk of progression to SCC in untreated patients
LOW GRADE SQUAMOUS INTRAEPITHELIAL LESION (LSIL) - (VIN1) HIGH GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL)-(VIN2/3) LSIL- condyloma effect HSIL
VULVAR HSIL (HIGH GRADE SQUAMOUS INTRAEPITHELIAL LESION- HPV RELATED) 6.5-10% of HSIL progresses to SCC 1% regresses without treatment (usually within 10 months) Regression associated with young age, pregnancy, the presence of multiple pigmented lesions ISSVD refrains from using Bowenoid papulosis as it is impossible to know histologically if lesion will progress or regress
High risk HPV types,16 most frequent Stain with p16, Ki67(mitotic index), absence of p53 VULVAR HSIL (VIN)
VULVAR HSIL (VIN 3)
PERIANAL HSIL (PIN)
TREATMENT OF HSIL (USUAL TYPE VIN) Treatment recommended for everyone Surgery with 5mm to 1cm without damage to clitoris, urethra, anus or other critical structures Ablative laser therapy with margin of 5mm to 1cm of normal skin (2mm deep), if hair bearing need to treat to base of follicles (down into subcutis) Imiquimod 5% 3x week for 12-20 weeks, non responsive lesions are excised, close clinical followup after treatment 81% had complete or partial response
TREATMENTS HSIL Cidofovir 1% and 5FU are effective but have increased adverse effects Cidofovir trial in HIV+ patients Photodynamic therapy Sinecatechins - clinical trials nly
HSIL RECURRENCE Risk of recurrent disease increased Age>50 Multifocal disease Adjacent HPV or lichen sclerosus Immunosupression + excision margins Coexisting vaginal or cervical disease (VAIN or CIN) Satmary W. Gynecologic onc. 2018;148:126-131 (dvin and HSIL not differentiated)
NON HPV RELATED PRECURSOR LESIONS Differentiated VIN (dvin) Higher progression to SCC rate than HSIL (usual VIN) Elderly women Often associated with lichen sclerosus 1-3% of women with LS develop invasive SCC LS is present in 50% of women with SCC More than 50% of HPV unrelated SCC have adjacent dvin
DVIN IN LICHEN SCLEROSUS Rarely diagnosed except in excision specimens adjacent to invasive SCC
dvin in Lichen Sclerosus
B ASAL CELLS HYPERCHROMATIC PARAKERATOSIS DYSKERATOSIS PROMINENT INTERCELLULAR SPACES LOSS OF GRANULAR LAYER P53 STAINING MATCHES ADJACENT TUMOR
DVIN Enlarged vesicular nuclei Macro nucleoli Abundant eosinophilic cytoplasm
Invasive Squamous cell carcinoma (HPV related) HPV related SCC younger women (under age 60) 25% of invasive SCC HPV related 76% of HPV related SCC is warty or basaloid 33% well to moderately differentiated p16+ and HPV+ hallmark of HPV related SCC (HPV16-72%, HPV33-6%, HPV18-5%) (de Sanjose S et al. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer. 2013;49(16):3450-61.)
INVASIVE SCC (HPV RELATED) Incidence is increasing world wide mirroring increase in HPV prevalence Interval between HSIL (usual VIN) to invasive SCC, shortens with increasing age (50 months for 15-29 yrs, 25 months for age 70 yrs) No difference in time to progression to invasive SCC for multifocal vs unifocal disease
INVASIVE SQUAMOUS CELL CARCINOMA (HPV UNRELATED) HPV unrelated carcinomas, well to moderately differentiated SCC p53 mutation is the hallmark of HPV independent SCC 73% strong diffuse expression of p53 even above basal layer (mis sense mutation that leads to more stable protein) 27% of dvin and SCC have complete absence of p53 from nonsense mutation or deletion normal p53 staining - patchy p53 in basal layer More than 50% of HPV unrelated SCC have adjacent dvin Complete excision recommended of all hyperplastic vulvar lesions adjacent to SCC so p53 staining can be compared in lesional and nonlesional skin
LICHEN SCLEROSUS AND INVASIVE SCC Poorly controlled lichen sclerosus has much greater risk of progression to invasive SCC 507 women - observed 7 yrs, superpotent topical steroids 0 compliant pts, 7 partially compliant pts developed SCC manifested as treatment resistant hyperkeratotic plaques and nodules Incomplete disease control only risk for invasive SCC Even asymptomatic lichen sclerosus needs continuous maintenance therapy, such as mometasone furoate 0.1% (Lee A et al. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women. JAMA Dermatol. 2015;151(10):1061-7.) Unknown if lichen planus predisposes to vulvar SCC (Is vulvovaginal lichen planus associated with SCC? Day T et al. J of lower genital tract ds. 2018;22(2):159-165.) Looked at all non HPV SCC of of vulva 95% of excisions had ls next to it, other 5% had LS in subsequent biopsies No evidence of LP
SCC IN LICHEN SCLEROSUS Treatment resistant hyperkeratotic plaque
SCC IN POORLY CONTROLLED LICHEN SCLEROSUS
SCC (HPV NON RELATED) Younger women (<50 yrs) more likely to have local disease Older women (>50) more likely to have regional disease or metastases Survival longer in younger women than older women even with same disease stage (5yr survival 87% <50 yrs, 53% > 50yrs) Local disease recurrence - Pathological margins margins <3mm - local recurrence 17% margins 3-8mm - local recurrence 25% margins >8mm - local recurrence 22% margin distance did not effect overall survival, only perineurial invasion influenced survival
SCC (HPV UNRELATED) Tumor size important prognostic indicator even with negative lymph nodes 2.1-3.99cm 5yr OS 79%, 4-5.99cm 78%, 6-7.99cm 36% Prognosis significantly declines if size of tumor >6cm One positive LN did not effect survival Two or more positive nodes experienced greater than 5 times higher risk of death than node negative patients Extra- capsular growth in lymph node metastasis increased the risk of death 5.2 times.
SQUAMOUS CELL CARCINOMA Re-excision of adjacent VIN (HSIL or dvin) in vulvar SCC did not change disease free survival Perhaps due second primaries due to existing risk factors for SCC (HPV or Lichen sclerosus) Impact of re-excision of residual adjacent VIN and histological tumor free margin on survival in primary SCC of vulva. Gasimli K et al. Archives Gyn and OB. 2018;298:945-950.
VULVAR PAGETS DISEASE (EXTRAMAMMARY) Average age 64 yrs Vulva (labia)most common site of extramammary Pagets disease Erythematous to hyperkeratotic plaques Symptom - pruritus Multifocal Median size 6.5cm Only 30% associated with underlying neoplasm Recurrence very common
PAGETS
PAGETS DISEASE Histology Pagets cells sit on top of basal layer Large cells with ample cytoplasm Vacuolated to clear cytoplasm Prominent nuclei and nucleoli PAS+ CEA+ EMA+ Cytokeratin 7+
EXTRAMAMMARY PAGETS DISEASE
OVERVIEW - TREATMENT OF PAGETS DISEASE Standard treatment - wide local excision (WLE) (2-3 cm margins) with XRT if LN+ (40-70% + resection margins) Laser - high rate of recurrence as may not reach adnexal extension Photodynamic (5 aminolevulinic acid) - high recurrence Radiation - appropriate dose unknown - 0-35% recur, skin complications Imiquimod - recurrence 19%?????
TREATMENT OF PAGETS DISEASE Often do not recur (50% without further therapy) even with positive margins Could not predict invasive disease even with multiple scouting biopsies Recurrence most common in surgical scar from excision Increased recurrence if invasive disease present No evidence that microinvasive disease (invasion<1mm) decreases survival Risk of developing invasive disease is 8%
MOH S SURGERY VS WIDE LOCAL EXCISION MMS 12% 5 yr recurrence rate as opposed to 50% WLE recurrence rate, Wollina et al. Surgical treatment of extramammary Paget s disease. Curr ent Treatmetn Options in Oncol.2018;19:27. WLE 2.5x higher recurrence rate even with negative margins than MMS, Long et al. A matter of margins: surgical and pathological risk factors for recurrence in extramammary Paget s disease. Gynecologic oncology 2017;147:358-363. Damavandy A et al. CK7 immunostain during MMS decreases local recurrence from 26% to 3% (combined initial recurrent dx and disease with first treatment)
IMIQUIMOD ADVERSE EFFECTS Targets Toll like receptor 7 (TLR7) of dendritic and Langerhan cells Release INF, TNF, IL-12 which activates CD8+ cells Apoptosis of transformed cells Application 5-7x week - 82% adverse effects causing frequency reduction 3-4x week - 2 % adverse effects causing frequency reduction 1-2x week - 0 % adverse effects causing frequency reduction Treatment duration 4 months 73% CR 27% PR or stable disease 0% progression
IMIQUIMOD RESULTS Complete response versus Partial response No difference in age No difference in primary vs recurrent disease No difference in tumor size No difference in treatment duration
PAGETS THERAPY - TAKE HOME MESSAGE Surgery often mutilating with significant decrease in quality of life Recurrence rate for all therapies HIGH (perhaps less with MMS) Use imiquimod 3-4 x week as sole therapy If using surgery, consider imiquimod prior to surgery to decrease size of tumor Life long follow up Low threshold to biopsy for recurrent disease
TAKE HOME MESSAGES Many pigmented vulvar lesions are indistinguishable clinically Low threshold for biopsy LONG TERM MONITORING ESSENTIAL Lichen sclerosus Vulvar melanosis Pagets disease
TAKE HOME MESSAGES Lichen Sclerosus requires maintenance therapy to reduce risk of SCC Paget s disease and Lichen Sclerosus Low threshold to biopsy - new or non responsive areas Baseline photographs Vulvar melanosis Low threshold to biopsy - new or non responsive areas Baseline photographs
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