Cancer of Vulva

Manidip  Pal; Soma  Bandyopadhyay

Cancer of VulvaChapter One

Manidip Pal,

Soma Bandyopadhyay

INTRODUCTION

Carcinoma of vulva accounts for approximately 5% of all female genital malignancies. Global incidence of vulvar carcinoma is not exactly known as it is rare and not under WHO monitoring. In developed countries the incidence is about 1.5 per 1,00,000 women years.¹ In India incidence rate varies in different parts (Table 1.1).

The disease is usually diagnosed in postmenopausal women (>65 years). Most of the time there is a late diagnosis as patient neglects treatment or the lesion is treated initially medically without biopsy. But young patient also can be affected. In a review, 15% of all vulval cancer patients are younger than 40 years of age.² In US incidence of younger and older patients are 19.3% and 80.7% respectively.³

Vulval cancer is of two types depending on neoplastic and nonneoplastic etiology (Table 1.2).⁴

Commonest site of occurrence is the medial aspect of the labia majora, though it can occur primarily in labia minora, clitoris and perineum. Rarely Bartholin gland is involved.

Vulval cancers are predominantly squamous cell carcinoma (SCC) (90%) followed by melanoma (5%) (Figs 1.1 and 1.2).

Table 1.1 Incidence of vulval cancer in various areas

Area	Percentage of vulval cancer
Mumbai	0.27
Chennai	0.33
Bangalore	0.41
Delhi	0.41
Bhopal	0.5
Barshi	0.28
Source: ICMR cancer registry 2001–03

Table 1.2 Comparison vulval cancer of type 1 and type 2

Characteristics	Type 1	Type 2
Age	Younger (35–65 years)	Older (55–85 years)
Cervical neoplasia	High association	Low association
Cofactors	Age, immune status, viral integration	Vulval atypia, possibly mutated host genes
Histopathology of tumor	Intraepithelial- like (basaloid), poorly	Keratinizing; squamous cell carcinoma, well
HPV DNA	differentiated	differentiated
Pre-existing lesion	Frequent (> 60 %)	Seldom (< 15 %)
	VIN	Vulval inflammation, lichen
History of condyloma		sclerosus, squamous cell
History of STD	Strong association	hyperplasia
Cigarette smoking	Strong association	Rare association
	High incidence	Rare association
		Low incidence
VIN – Vulval intraepithelial neoplasia

Fig. 1.1: Squamous cell carcinoma of the vulva with small “Kissing lesion” on contralateral site

Fig. 1.2: Invasive squamous cell carcinoma of nonhairy vulvar skin in a 79-year-old woman. The lesion arises in an area of lichen sclerous related to longstanding, untreated pruritus

Other rare types are adenocarcinoma, basal cell carcinoma, verrucous carcinoma, sarcoma, extramammary Paget's disease, endodermal sinus tumor (lymphoma), Merkel cell cancer, malignant Schwannoma, malignant fibrous histiocytoma, etc.

MOLECULAR BIOLOGY AND GENETICS

Genetic alterations are hallmarks of tumorigenesis. The main chromosomal imbalances were gains of, or from, chromosome arms 3q, 5p, 8q, 9q and 19q, and loss from 11q. Breakpoint clusters were seen in 11q 13–23, 2q 22–35, and 19q 13, as well as in the centromeres and pericentromeric bands of chromosomes 3,8,9,13,14 and 22.⁵

One study shows losses of 3p 14-cen, 8pter-p 11, 22q 13.1 −q 13.2, and the short arm of the inactive X; chromosome gains involving 3q 25-qter and 11 q21; and rearrangement breakpoints at 5cen-q 12. Loss of 18q 22-q23 and loss of 10q23-q25 may be associated with a poor prognosis.⁶

Mutation in TP53 tumor suppressor gene was found in SCC, lichen sclerosus and VIN.⁷ Genetic analysis of 12 SCC patients revealed loss of 1 copy TMSB10 in 11 patients, followed by loss of 1 copy of CTNNB1 and BCL2 in 7 patients. Frequent gains/amplifications included CCND1, observed in 8 of 12 patients and IL12A, in 7 of the 12 patients. Understanding the interplay of cancer genes and pathways they utilize can lead to the detection of novel molecular targets in the diagnosis, prognosis and treatment of SCC.⁸

HPV types 16, 18, 31, 33, 35, 45 and 54 are more likely to be associated with CIN (cervical intraepithelial neoplasia) and cervical cancer. They are also suspected to be associated with vulval intraepithelial neoplasia (VIN) and vulval cancer. In a review of 1379 invasive cancer, 1340 VIN 2/3, 71 VIN 1 (total 2790 cases) HPV prevalence was 40.1%, 80.4% and 77.5% respectively. HPV 16 was the most common type in 29.3% vulval cancer and 71.2% VIN 2/3 cases.⁹ Two third of the vulval cancer women aged <50 years are HPV positive.¹⁰

The mechanism of HPV transformation into dysplasia and cancer is not well understood. Two gene products from HPV are known to immortalize cells in culture and are probably responsible for malignant transformation.¹¹ The HPV E6 protein does have the ability to bind the host tumor suppressor protein p53 which causes proteolytic destruction and loss of regulated cell growth. The HPV E7 protein binds the pRB (Retinoblastoma protein) resulting in inactivation of cell cycle restriction function. This uncontrolled expression of E6 and E7 is related to the intregation mediated disruption of viral genome around E1/E2 region.¹²

STAGING

Revised FIGO staging¹³ 2008 and American Joint Commission on Cancer Staging (AJCC) 2010¹⁴ (Tables 1.3 to 1.6).4

Table 1.3 Revised FIGO staging

TNM Categories	FIGO	Definition
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
Tis^*		Carcinoma in situ (preinvasive carcinoma)
T1a	IA	Lesions ≤2 cm confined to the vulva or perineum and with stromal invasion ≤1 mm†
T1b	IB	Lesions >2 cm, or any size with stromal invasion more than 1 mm, confined to the vulva or perineum
T2‡	II	Tumor of any size with extension to adjacent perineal structures (lower/distal one third of urethra, lower/distal one third of vagina, anal involvement)
T3§	IVA	Tumor of any size with extension to any of the following: upper/proximal two thirds of urethra, upper/proximal two thirds of vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone
^* FIGO staging no longer includes Stage 0 (Tis).
+ The depth of invasion is defined as the measurement of the tumor from the epithelialstromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.
‡ FIGO uses the classification T2/T3. This is defined as T2 in TNM.
§ FIGO uses the classification T4. This is defined as T3 in TNM.

Table 1.4 Regional lymph nodes (N)^*

TNM categories	FIGO stages	Definition
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		1or 2 regional lymph nodes with the following features:
N1a	IIIA	1 lymph node metastasis each ≤5 mm
N1b	IIIA	1 lymph node metastasis ≥5 mm
N2	IIIB	Regional lymph node metastasis with the following features:
N2a	IIIB	≥3 lymph node metastases each <5 mm
N2b	IIIB	≥2 lymph node metastases ≥5 mm
N2c	IIIC	Lymph node metastasis with extracapsular spread
N3	IVA	Fixed or ulcerated regional lymph node metastasis

Table 1.5 Distant metastasis (M)

TNM categories	FIGO stages	Definition
M0		No distant metastasis
M1	IVB	Distant metastasis (including pelvic lymph node metastasis)

DIAGNOSIS

Biopsy is the mainstay of diagnosis. It may be punch biopsy or excisional biopsy. A punch biopsy down to the dermis is sufficient for pathologic evaluation.

Table 1.6 Anatomic stage/prognostic groups

Stage 0	Tis	N0	M0
Stage I	T1	N0	M0
Stage IA	T1a	N0	M0
Stage IB	T1b	N0	M0
Stage II	T2	N0	M0
Stage IIIA	T1, T2	N1a, N1b	M0
Stage IIIB	T1, T2	N2a, N2b	M0
Stage IIIC	T1, T2	N2c	M0
Stage IVA	T1, T2	N3	M0
	T3	Any N	M0
Stage IVB	Ant T	Any N	M1
^*An effort should be made to describe the site and laterality of lymph node metastases.

The biopsy should include surrounding skin with underlying dermis and connective tissue so that the pathologist can evaluate the depth of stromal invasion. Cutting down to the subcutaneous fat layer assures that the proper depth has been reached. This can be accomplished with a cervical punch biopsy instrument or a toothed pick-up iris-scissors.¹⁵ Other tests that may aid in diagnosis and staging are colposcopy, cystoscopy, proctoscopy, X-ray, CT scan, MRI. Recently positron emission tomography (PET) using flurodeoxyglucose (FDG) as a tracer (FDG-PET) is been evaluated for vulval carcinoma. The positive predictive value of FDG-PET scans was 95% for squamous cell carcinoma and 71% for adenosquamous carcinoma and adenocarcinomas combined. In order to determine the impact of PET on management, patients were divided into 3 groups: preoperative scans (16; 31%), postoperative scans (19; 37%), and inoperable based on PET imaging (16; 31%). Of the 16 preoperative scans, 14 (88%) were positive for the primary and 6 (38%) were positive for inguinal lymph nodes. All 14 women with positive primaries had surgery to the primary. Of the 6 positive for inguinal lymph nodes, 5 had nodal surgery with disease identified. The 2 women with negative PET scans both had disease on surgery. Of the 19 preoperative scans, 16 (84%) had positive scans. In 13 (68%) of these patients, the vulva had residual disease. Within this group, 4 women had surgery followed by radiation, 1 had surgery alone, 1 declined surgery, and 7 had radiation alone. PET results changed management in 18 of these 19 patients. Eight (44%) patients received radiotherapy instead of surgery due to more extensive disease than anticipated. Four (22%) patients received more extensive surgery than planned, including 2 lymph node dissections, 1 with involvement of lymph node and primary, and 1 with a more extensive primary tumor. Five (28%) patients had additional radiotherapy and surgery, including >=4 extensive primary disease and 1 for more extensive primary plus lymph node involvement. It is particularly helpful in identifying patients with node-positive disease that may be 6clinically nonpalpable at presentation. PET imaging may also influence clinical management, including modification of both radiation and surgical interventions.¹⁶

TREATMENT (FIG. 1.3 TO 1.5)

Surgery is the gold standard of treatment. Usually radical vulvectomy or radical local excision is performed. The changing trends in surgical management are:

Triple incision technique (Fig. 1.5).
Unilateral inguinal node dissection for small ipsilateral tumors less than 2 cm as the chance of contralateral lymph node involvement is 0.4%.¹⁷
Preservation of Saphenous vein during groin node dissection to avoid acute and chronic lymphedema and wound cellulites.^{18, 19}

Fig. 1.3: Modified butterfly incision (schematic diagram)

Fig. 1.4: Modified butterfly incision after removal of structures

7

Fig. 1.5: Triple incision technique
Avoidance of extensive surgeries in microinvasive carcinoma.

Triple incision technique was found to be superior to single incision technique in relation to hospital stay, operative time, blood loss, wound breakdown, skin bridge metastasis. No difference was observed in overall survival or recurrence rate.²⁰

The only histologic feature for predicting concurrent lymph node metastasis is tumor depth invasion.

Invasion	Incidence of metastasis¹¹
≤ 1 mm	0 %
1.1–2 mm	10 %
2.1–3 mm	12 %
3.1–5 mm	14 %
> 5 mm	43 %

Early invasive vulval SCC with < 1 mm invasion (FIGO stage IA) has been shown to have a minimal risk of lymph node metastasis and is associated with an excellent prognosis.²¹

The most commonly performed surgical procedures regarding the extent of groin dissection for early vulval cancer by the gynecological oncologists are 1) lymph nodes above the cribriform fascia and those medial to the femoral vein (40%), 2) removal of lymph nodes above the cribriform fascia (34%), and 3) removal of all nodes above and below the cribriform fascia (22%).²²

The principle of less radical lymphadenectomy is that the superficial inguinal lymph node act as a sentinel node. Lymphatic mapping of sentinel node in early vulval cancer,²³ and it's removal may obviate the dissection of other nodes. In early stage cancer with a negative sentinel the groin recurrence arte is low, survival is excellent, and treatment related morbidity is minimal. In a 6 years study, sentinel node procedure was perfomed in 259 patients with unifocal vulval disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6 to 5%), and 3-year survival rate was 97% (95% CI, 91 to 899%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001).²⁴ The clinical implementation of the sentinel node procedure and the role of additional histopathological examination of the sentinel node have to be more investigated.

There are some reports of unexpected groin failure after negative superficial inguinal lymphadenectomy. In stage I/II groin recurrence is 4.6%.²⁵ The median time to recurrence is 22 months. Groin relapse is due to metastasic disease in unresected inguinal nodes.²⁶

In order to reduce wound dehiscence, vaginal stenosis, sexual dysfunction, urinary problems and for cosmesis different vulval and perineal reconstructive surgeries using rhomboid flaps, rotational skin flaps and V-Y flaps are performed. This procedures are simple and can be done by trained gynecological oncologist.^27–29 When defects are more, then rectus abdominis or gracilis musculocutaneous flaps are used which require plastic surgeon's assistance.^30–32 Vulval field resection (VFR) combined with anatomic reconstruction (AR) is a new surgical approach to the treatment of vulval cancer. VFR is based on ontogenetic anatomy and on the concept of local tumor spread within permissive compartments. Patients would benefit from this new approach as local tumor control is high and the preserved tissue can be successfully used for restoration of vulval form and function.³³

Chemoradiation

Though surgery is the mainstay of the treatment there is a role for chemoradiation in advanced stage vulval cancer. In this category neoadjuvant chemotherapy is considered to be the better modality of treatment. In locoregionally advanced or recurrent SCC overall response rate is 56% with bleomycin (B), methotrexate (M), and CCNU (C) regimen.³⁴ In another study of 25 patients {10 patients bleomycin (Group A); 5 patients paclitaxel (Group B); and 10 patients a combination of 5-fluorouracil/cisplatin (Group C)} bleomycin was found to be superior. In Group A, there was a 60% response rate. Mortality was 70%, with an overall survival rate of 70%, 40%, and 30% at 12, 24, and 60 months, respectively. The mean (SD) survival was 46.7 (15.4) months. In Group B, the response rate was 40%, with an 80% mortality rate and a survival rate of 60 and 20% at 12 and 24 months, respectively. The mean (SD) survival was 17.0 (3.8) months. In Group C, 20% of the responses were observed and the mortality was 90%, with an overall survival rate of 10% at 12 and 24 months and a mean (SD) survival of 7.6 (2.0) months.³⁵9

Whereas Cochrane database system review on neoadjuvant chemoradiation state that operability could be achieved in 63–92% of patients, using 5FU and CDDP or 5FU and MMC. In contrast, only 20% of the patients who received bleomycin were operable after chemoradiation.³⁶

5-Fluorouracil [5-FU] or 5-FU- and cisplatin-based chemotherapy concurrent with irradiation followed by tailored surgery represents an attractive therapeutic option for advanced disease, planned to avoid such ultra-radical surgical procedures and, hopefully, to improve patient outcome. Primary chemoradiation can be also used for advanced carcinoma of the Bartholin gland or for advanced adenocarcinoma associated with extramammary Paget's disease.³⁷

In locally advanced vulval cancer when surgery cannot be done due to multiple medical co-morbidities and stage of disease, Erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, can be given. This new therapeutic approach deserves further evaluation.³⁸

HPV Vaccine

Among the cell mediated immunity and humoral immunity, humoral responses are more important in the context of HPV vaccine.³⁹ Immunization with virus like particles (VLPs) of L1 protein of papilloma viruses has shown to induce serum anti-L1 neutralizing antibodies, thereby resulting in protection against HPV infection.⁴⁰ Quadrivalent vaccine protects not only against HPV 16 and 18 related cervical cancers but also protects against HPV types 6, 11, 16 and 18 related genital warts, vaginal intraepithelial neoplasia (VaIN) and VIN.⁴¹

5-year Survival

The 5-year survival rates in relation to different parameters (Table 1.7).

Table 1.7 5-year survival rates in relation to different parameters

Parameters	5-year Survival Rate (%)
Overall	70.1
Younger patients	87.5
Older patients	52.5
Lymph node positive	53.8
Lymph node negative	79.7
Unifocal lesion	76
Multifocal lesion	50
Posterolateral lesion	79.5
Anterior central lesion	54.4
Saphenous vein excision	66.7
Saphenous vein preservation	68
References ^18,42,43

Stage of the disease	5-year survival rate¹¹
I	90%
II	81%
III	68%
IV	20%

Fig. 1.6: The surgical defect after removal of radical vulvectomy specimen

Special Situation

Pregnancy and vulvar carcinoma: Radical or modified radical vulvectomy with or without groin node dissection can be performed safely during second trimester (Fig. 1.6). Delivery should be done by cesarean section.⁴⁴ Hiv infection And vulvar Carcinoma: HIV is associated with a decrease in cellular immunity which allows for persistence of high-risk HPV types and this can predispose the woman to dysplasia or cancer of the genital tract.⁴⁵

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Chapter Notes

Cancer of VulvaChapter One