C8_1_27 (1).ppt PRECANCEROUS NAD MALIGNANT DISEASE OF VULVA

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

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. 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
1. Postmenopause
2. No relationship to
HPV
3. Histology:
differentiated type
 Multifocal
1. Younger
premenopausal
2. Associated with HPV
3. High grade &
oncogenic HPV:
16,18,31
4. Interlabial grooves,
post. fourchette,
perineum
5. 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
-- 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
-- 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
 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
>90% of vulvar malignancy, 2 subtypes

34.  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
-- 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

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.
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 !!