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

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. Carcinomain situof 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 carcinomain situ: carcinomain situextending 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. 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 Distribution 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. Changes that appear infectious (eg, condyloma acuminata) should be treated with a course appropriate therapy and Bx. if refractory or not resolve !! Raised/verrucous white

19. Red

20. Brown

21. 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) Diagnosis-- Colposcopy 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. 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 Treatment

25. 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% Treatment

26. 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…… Treatment Careful evaluation to exclude the presence of invasive squamous cell carcinoma is important prior to the therapy !!

27. 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 Prognosis

28. Vulvar Cancer

29. 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 Epidemiology & risk factor

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. 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 Squamous cell carcinoma >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. 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. Verrucous carcinoma—a variant of SCC

38. 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. Melanoma

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. 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 Vulvar cancer

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