1. Pre-cancer and malignant disease of vulva

2. International Society for the study of Vulvar Disease

3. Vulvar intraepithelial neoplasm

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

5. HIV positive womem
Vulvovaginal / perianal intraepithelial neoplasia is more prevalent in HIV infected women (9 % & 1 %)
7% HIV positive with vulvovaginal or perianal condylomata acuminata  high-grade intraepithelial lesions

6. Histopathology
Table 2

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

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

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

10. VIN III

11. Subtypes of VIN III
Basaloid– thickened epi. with flat, smooth surface, composed of atypical immature parabasal type cells with numerous mitotic figures and enlarged hyperchromatic nuclei
Warty(condyloma) – undulating or spiking surface, condyloma appearance, cellular proliferation with numerous mitotic figures and abnormal maturation
Differentiated (simplex) – thicked and parakeratotic epi. with elongated and 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 P53 which extend above the basal layers to epidermis, a precursor of HPV-negative vulvar cancer

12. Vulvar hyperkeratosis

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

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

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

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

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

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

19. Red

20. Brown

21. Diagnosis-- Colposcopy
Acetic acid
-- 2-5% acetic acid, several minutes, dense acetowhite, punctation or vascular abnormality (may be a sign of invasive cancer)
Toluidine blue
-- 1% paint the vulva, wash with 1% acetic acid 2 mins later retained area
-- False negative (infection, 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

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

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

24. 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
Skinning vulvectomy
-- more extensive lesions
-- removing the vascular skin along a avascular plane
-- primary closure or use skin graft

25. Treatment Laser ablation Topical 5-FU -- 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% (1st), 1/3 need 2nd, 3rd
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%

26. Treatment Imiquimod -- topical immune response modifier
-- FDA-proved to treat anogenital warts
-- treat multifocal VIN II or III…
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 the therapy !!

27. Prognosis Natural Hx. without Tx Recurrence after Tx.
-- high grade: varies from persistence, progression to remission
-- 9% untreated VIN III invasive cancer ( 8 yrs 內)
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

28. Vulvar Cancer

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

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

31. 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 !

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

33. 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
Classic, warty or Bowenoid type
-- HPV 16, 18, 33
-- Younger p’ts
-- Most present with early stage

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

35. 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.

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

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

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

39. 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).

40. Vulvar cancer Basal cell carcinoma Sarcoma -- 2% / 2% -- 1-2%
-- 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

41. Extramammary Paget’s disease
Intraepithelial adenocarcinoma
< 1%
60~70 y/o
Pruritus (70%), eczematoid appearance, well-demarcated, 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 !!

42. Paget's disease of the labium major

43. Paget's disease of vulva
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.

44. Bartholin gland adenocarcinoma
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)

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

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

47. 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

48. 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

50. 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 γ-detecting probe
(2)Peritumor injection of isosulfan blue dye
 Bilateral groin involvement is common in midline vulvar cancers  not suggest !!

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

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

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

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

55. Small (T1) vulvar carcinoma at the posterior fourchette.

56. 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 !!

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

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

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

60. Treatment Sarcomas -- Wide local excision
-- Lymphatic metastases: uncommon
# Exception: Rhabdomyosarcoma primary C/T + surgery
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 !!

61. Treatment– Vulvar Paget’s disease
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)

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

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

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

65. Recurrent disease Local, inguinal or distant
5-yr survival rate: according to location
-- Perineal : 60 %
-- Inguinal and pelvic : 27 %
-- Distant : 15 %
RT add to surgery or C/T or a sole modality
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

66. Treatment-- future
Anti-EGFR tyrosine kinase inhibitors…

67. Thank you for your attentions !!