Precancer and malignant disease of vulva MA International

Pre-cancer and malignant disease of vulva MA 張簡展照

International Society for the study of Vulvar Disease

Vulvar intraepithelial neoplasm

Epidemiology & Risk factor l l Premenopausal (75%) No racial predisposition l l l Similar to vulvar cancer HPV infection Cigarette smoking Immunodeficiency Immunosupression

HIV positive womem Vulvovaginal / perianal intraepithelial neoplasia is more prevalent in HIV infected women (9 % & 1 %) l 7% HIV positive with vulvovaginal or perianal condylomata acuminata highgrade intraepithelial lesions l

Histopathology l Table 2

Human papillomavirusvaginal intraepithelial neoplasia grade 1. Note the surface spicules with partial uptake of Lugol's stain.

(A) Vaginal intraepithelil neoplasia grade 2. (B) Vaginal intraepithelial neoplasia grade 3.

Carcinoma in situ of the vulva (vulvar intraepithelial neoplasia grade 3)

VIN III

Subtypes of VIN III l Basaloid– thickened epi. with flat, smooth surface, composed of atypical immature parabasal type cells with numerous mitotic figures and enlarged hyperchromatic nuclei l Warty(condyloma) – undulating or spiking surface, condyloma appearance, cellular proliferation with numerous mitotic figures and abnormal maturation l Differentiated (simplex) – thicked and parakeratotic epi. with elongated anastomosing rete ridges, abnormal cells confined to parabasal and basal portion of the rete pegs with little or no atypia above the basal layers, basal cell positive to P 53 which extend above the basal layers to epidermis, a precursor of HPVnegative vulvar cancer

Vulvar hyperkeratosis

Vulvar carcinoma in situ: carcinoma in situ extending into the hair follicle.

Overview of pathogenesis Embryonic cloaca anogenital epithelium (cervix, vagina, anus, lower 3 cm of rectal mucosa up to the dentate line) l Susceptible to similar exogenous factors HPV !! l CIN, VAIN, PAIN may multifocal !! l The risk of neoplastic progression of VIN to invasive cancer : lower than CIN !! l Genetic instability risk to invasive Dz. l

Distribution of VIN l 1. 2. 3. Unifocal Postmenopause No relationship to HPV Histology: differentiated type l 1. 2. 3. 4. 5. Multifocal Younger premenopausal Associated with HPV High grade & oncogenic HPV: 16, 18, 31 Interlabial grooves, post. fourchette, perineum 2/3 p’t of VIN

Clinical manifestations Pruritus l Altered appearance of the vulva l Palpable abnormality l Perineal pain or burning l Dysuria l 50% asymptomatic !! l

Diagnosis Physical examination --inspection & palpation (mass, color, ulcer) --most multifocal, non-hairy part --raised/verrucous white, red, brown, pink, gray, macular lesion l

Raised/verrucous white l Changes that appear infectious (eg, condyloma acuminata) should be treated with a course appropriate therapy and Bx. if refractory or not resolve !!

Red

Brown

Diagnosis-- Colposcopy Acetic acid -- 2 -5% acetic acid, several minutes, dense acetowhite, punctation or vascular abnormality (may be a sign of invasive cancer) l Toluidine blue -- 1% paint the vulva, wash with 1% acetic acid 2 mins later retained area -- False negative (infection, l nonneoplastic ulceration) -- False positive ( thick hyperkeratotic lesions, ulcerated or abraded area absort only small amount of dye) Identify subclinical lesions, define the extent of disease

Diagnosis Biopsy -- local anesthetic -- Punch Bx & Excisional Bx. l Differential diagnosis -- Invasive squamous cell cancer, lichen sclerosis, planus -- difficult to distinguish esp. occur concurrent l

Treatment—Goal Prevent development of invasive vulvar cancer and relieve symptoms l Preserve vulvar anatomy and function l Based on biopsy results, extent of disease and symptom l

Treatment Wide local excision -- individual lesion with a 1 cm margin -- removal of epidermis -- satisfactory cosmetic result # remove small amount of dermis to insure invasive disease l Skinning vulvectomy -- more extensive lesions -- removing the vascular skin along a avascular plane -- primary closure or use skin graft l

Treatment l Laser ablation -- multi-focal or extensive -- cosmetic advantages -- effective in multiple small lesions (VIN I, II) -- evaluate the coexistent invasive cancer previously -- use colposcopy to control depth (1 mm) -- cure rate: 70% (1 st), 1/3 need 2 nd, 3 rd l Topical 5 -FU -- conservative, preserve anatomy -- younger p’ts -- may result in buring pain, inflammation, edema and painful ulceration -- exclude invasive disease previously -- cure rate: 40 -75%

Treatment Imiquimod -- topical immune response modifier -- FDA-proved to treat anogenital warts -- treat multifocal VIN II or III… l l Topical immunotherapy, vaccines against HPV, photodynamic therapy, ultrasound surgical aspiration, chemopreventive agents…… Careful evaluation to exclude the presence of invasive squamous cell carcinoma is important prior to therapy !!

Prognosis l Natural Hx. without Tx -- high grade: varies from persistence, progression to remission -- 9% untreated VIN III invasive cancer ( 8 yrs 內) l Recurrence after Tx. -- at least 1/3 -- regardless to Tx. Modality -- Risk factors: high grade VIN, multiple focal or multicentric, positive margin on Bx. -- Long term F/U: 6 ms for 2 yrs 1 yr

Vulvar Cancer

Epidemiology & risk factor l l l 4 th common GYN cancer Postmenopause 65 y/o l l l l Cigarette smoking Vulvar dystrophy (eg, lichen sclerosis) VIN or CIN HPV infection Immunodeficiency Cx. cancer Hx. Northern European ancestry

Clinical manifestations Unifocal vulvar plaque, ulcer or mass (most labia majora) l 5% multifocal (evaluate vulvar and perianal skin, cervix, vagina) l Synchromous second neoplasm (most cervical neoplasm): 22% l Pruritus (vulvar bleeding, discharge, dysuria, enlarged l groin LN…)

Diagnosis Biopsy !! -- Determine the depth and nature of stromal invasion -- Taken from the center of the lesion -- If multiple abnormal areas: multiple biopsies to map -- Use acetic acid & colposcopy if not sure ! l

Histopathology l Squamous cell carcinoma -- Variant: verrucous carcinoma l Melanoma l Basal cell carcinoma l Sarcoma l Extramammary Paget’s disease l Bartholin gland adenocarcinoma

Squamous cell carcinoma >90% of vulvar malignancy, 2 subtypes Keratizing, differenrtiated or simplex type -- More common -- Older p’ts -- No related to HPV infection -- Associated with vulvar dystrophy l Classic, warty or Bowenoid type -- HPV 16, 18, 33 -- Younger p’ts -- Most present with early stage l

l Squamous cell carcinoma of the vulva, keratinizing type. The multiple pearl formations consist of laminated keratin.

l Early invasive carcinoma of vulva originating from vulvar intraepithelial neoplasia. An irregular nest of malignant cells extend from the base of rete pegs. Desmoplastic stromal reaction and chronic inflammation are useful diagnostic signs of stromal invasion. The depth of stromal invasion is measured from the base of the most superficial dermal papilla vertically to the deepest tumor cells.

Cervical cancer: also strongly linked to persistent HPV infection… There is evidance that some high grade VIN and VAIN is a monoclonal lesion derived from high grade or malignant cervical disease !!

Verrucous carcinoma—a variant of SCC l l Verrous configuration Papillary fronds without central connective tissue core (typical of condyloma acuminata) Rarely metastasis to LN May local destructive l Verrucous carcinoma of the vulva. Note the exophytic hyperkeratotic papillary fronds and endophytic bulky rete pegs with smooth borders.

Melanoma l l l 2 nd common, 5% of primary, 3~7% of all melanomas Postmenopause, white, non. Hispanic 68 y/o Pigmented lesion Most clitoris or labia minora Melanoma of the vulva involving the right labium minus.

l Vulvar melanoma. Spindle-shaped melanoma cells form interlacing bundles, and some contain melanin pigment (right upper corner). Epidermal invasion is evident in the form of Pagetoid migration (left upper corner).

Vulvar cancer l Basal cell carcinoma -- 2% / 2% -- postmenopausal Caucasian women -- locally invasive -- rodent ulcer with rolled edges and central ulceration -- high incidence of antecedent or concomitant malignancy Sarcoma -- 1 -2% -- poor prognosis l

Extramammary Paget’s disease l l l l Intraepithelial adenocarcinoma < 1% 60~70 y/o Pruritus (70%), eczematoid appearance, welldemarcated, slightly raised edges with a red background, dotted with small pale islands Dx. : Bx. Histopathology ! Persistent pruritus with no response to antieczema therapy within 6 weeks Bx. !! Invasive adenocarcinoma may be beneath or within the surface lesion synchronous neoplasm !!

Paget's disease of the labium major

l Paget's disease of vulva. The epidermis is permeated by abnormal cells with vacuolated cytoplasm and atypical nuclei. This heavy concentration of abnormal cells in the parabasal layers is typical of Paget's disease.

Bartholin gland adenocarcinoma l l l Rare, 57 y/o Duct lined by stratified squamous epi. which changes to transitional epi. as the terminal ducts are reached If squamous lesion related to HPV infection !! Bartholin gland tumor in a postmenopausal women or > 40 y/o Bx. to survey the malignancy !! Metastasis is common (due to rich vascular and lymphatic network)

Mode of spread l Direction extension to adjacent structure l Lymphatic embolization: may occur early, begins at superficial inguinal LN drainage to deep inguinal and femoral LN pelvic lymphatics Inguinal-femoral lymph nodes

Mode of spread Hematogenous dissemination -- typically late in the course -- rare in p’ts without inguinofemoral LN involvement l

Staging Clinical staging -- PE (palpate LN: inguinal, axillary, supraclavicular ) -- PV (Cx. Cytology, colposcopy of Cx, vagina & vulva due to multifocal lesions) -- Radiographic and endoscopic studied in large tumor or suspected metastasis l

Staging Surgical staging—FIGO -- Inguinofemoral LN status: the most important predictor of overall prognosis (clinical assessment of groin LN: false negative) -- Inguinofemoral lymphadenctomy (except stage IA) # Unilateral: unilateral lesion, distant from the midline # Bilateral: midline or bilateral lesions or unilateral lesion with positive ipsilateral LN l

Staging Less invasive means to assess LN status Sentinel node biopsy (unilateral) Reduce acute and long-term complications (1)Lymphoscintigraphy using radiolabeled human albumin and an intraoperative γdetecting probe (2)Peritumor injection of isosulfan blue dye Bilateral groin involvement is common in midline vulvar cancers not suggest !! l

Treatment l Goal -- Cure the cancer -- Minimize perioperative morbidity -- Maximize long-term psychosexual and physical well-being

Treatment--SCC ü Stage IA l Radical local excision without LN dissection l Inguinofemoral LN metastases : <1 % l Wide, deep excision of the lesion down to the inf. fascia of the urogenital diaphragm l Clear margin: 2 cm (at least 1 cm)

Treatment--SCC ü Stage IB l Inguinofemoral LN metastases : >8 % l Radical local excision + ipslateral inguinofemoral LN dissection ( lateralized lesion) or bilateral inguinofemoral LN dissection (central lesions)

Treatment--SCC ü Stage II l Modified radical vulvectomy + ipslateral / bilateral inguinofemoral lymphadenectomy l Clear margin: at least 1 cm

Small (T 1) vulvar carcinoma at the posterior fourchette.

Treatment--SCC Adjuvant R/T ? -- appears benefit those with two or more positive inguinal LN or positive/closes surgical margin -- The minimum number of nodes that should be examined is unclear !! -- GOG study: adjuvant R/T to high risk p’ts (> 4. 1 cm tumor, positive margins, lymphovascular space invasion) with negative LN reasonable to consider !! l

Treatment--SCC ü Stage III and IV l Radical vulvectomy combined with pelvic exenteration high morbidity !! l Preoperative radiation therapy: downstage the tumor, allow a more conservative surgery l Chemoradiotherapy: locally advanced vulvar cancer (cisplatin + 5 -FU, Mitomycin + 5 -FU

Treatment--SCC ü Stage III and IV l Neoadjuvant chemotherapy—for recurrent or locally advanced disease --Decreased tumor bulk and permit later resection --Result is inf. to chemoradiotherapy

Treatment—Verrucous carcinoma Radical local excision l Bx. suspicious LN, if positive inguinofemoral lymphadenectomy l RT: contraindication !! (induce anaplastic transformation and increase the likehood of metastases) l Recurrence: surgical excision l

Treatment Sarcomas -- Wide local excision -- Lymphatic metastases: uncommon # Exception: Rhabdomyosarcoma primary C/T + surgery l l Melanoma --10% vulvar cancer -- Wide local excision or radical vulvectomy -- depth /clear margin # < 1 mm 1 cm # 1~ 4 mm 2 cm # > 1 cm and extend to muscular fascia local recurrent rate of local or radical vulvectomy is similar -- if central lesion groin LN dissection !!

Treatment– Vulvar Paget’s disease l l l Local excision or vulvectomy depend upon the extent of disease Poor prognostic markers: greater depth of invasion and lymphovascular involvement Moh’s micrographic surgery: lower recurrence rate RT or C/T ? Long-term F/U (high risk of recurrence) Annually inspection of vulva & survey tumors at other site (breast, lung, colorectum, gastric, pancreas, ovary)

Treatment Bartholin gland cancer l Basal cell carcinoma -- radical vulvectomy + -- locally aggressive but bilateral groin & pelvic rarely metastasis LN dissection -- Radical local excision --Extensive deep without LN dissection l

Prognosis l stage, tumor size, depth of invasion, capillary lymphatic space, older age, degree of nodal involvement

Follow up Twice yearly l Inspection, palpation of vulva, skin bridge and inguinal nodes l Colposcopy & Bx. If suspicious l

Recurrent disease Local, inguinal or distant l 5 -yr survival rate: according to location -- Perineal : 60 % -- Inguinal and pelvic : 27 % -- Distant : 15 % l RT add to surgery or C/T or a sole modality l Salvage cytotoxic C/T: for distant metastases -- most active agents: those against squamous cell tumors at other sites ( Cisplatin, MTX, bleomycin, mitomycin C, cyclophosphamide) --duration of response usually low and short l

Treatment-- future l Anti-EGFR tyrosine kinase inhibitors…

Thank you for your attentions !!