Vulva cancer is an uncommon cancer comprising 3-5% of gynaecological malignancies and less than 1% of all malignancies in women. The majority of lesions are squamous cell carcinomas (90%). Less common types include malignant melanoma (5%), adenocarcinoma, usually Bartholin’s gland (4%), basal cell carcinoma (2%) and sarcoma (1.5%).
Vulva cancer has 2 separate etiologic pathways. The first pathway is associated with HPV and affects a younger population group, less than 45 years of age. HPV is associated with 60% of vulvar cancers, most commonly HPV 16, 18 and 33. This type of vulva cancer is preceded by the usual type VIN and present with a warty of bowenoid lesion. The second pathway is associated with differentiated VIN or vulvar dystrophies like lichen sclerosis. This type most commonly affects older women with an average age 65 years.
Chronic vulval pruritis is the most common symptom, and may precede the presence of a mass, ulcer or lump. Localized vulvar complaints may include pain, burning and discomfort when voiding. It mostly affects the labia majora, labia minora, clitoris and perineum.
Associated factors include obesity, hypertension, diabetes, increased sexual partners and warts. Thirty percent will have an associated dysplasia elsewhere in the lower genital tract. A delay in diagnosis is not uncommon. Patients may present to local physicians with vulvar complaints and creams prescribed without proper assessment.
Lesions may be single or multifocal, unilateral or bilateral. They are divided into central and lateral lesions in view of different lymph drainage patterns. Spread patterns include local or direct extension, haematogenous or lymphatic. Lymphatic drainage initially lateral to superficial and deep inguinal-femoral nodes then pelvic nodes (usually medial external iliac group). The overall incidence of positive nodes is 30%. Lymphatic channels can become blocked resulting in aberrant or retrograde lymph drainage. Pelvic nodes are positive only with positive groin nodes. The risk of pelvic lymph node metastases is small in the absence of ipsilateral positive groin nodes with an overall risk 5%. If the groin nodes are positive then the risk of pelvic nodes being positive is 20%.
Predictors of positive groin nodes include: (i) tumour thickness (ii) histologic grade (iii) LVSI (iv) clitoral or perineal location and (v) clinically suspicious or fixed nodes.
Risk factors associated with pelvic lymph node metastasis include: (i) multiple positive groin nodes (ii) bilateral positive groin nodes (iii) palpable and positive groin nodes and (iv) positive deep inguinal nodes.
Advancing FIGO stage is associated with an increased risk of lymph node metastasis. The risk is 10% in Stage I, 30% in Stage II, 60% in Stage III and 75% in Stage IV cancers. Larger lesions are more likely to have nodal disease with 15% of T1 lesions (< 2cm) positive compared with 36% for lesions > 2 cm. Clitoral lesions may have increased risk of LNM. The presence of LVSI is associated with an increased risk of LNM with 25% without LVSI compared to 75% for patients with LVSI. Increasing tumour grade is associated with increasing LNM. Grade 1 lesions have 15%, grade 2 lesions have 35% and grade 3 lesions have 55% risk of LNM. Increasing tumour thickness and depth of invasion are significantly associated with lymph node metastases. The most common method used measures the distance from the most superficial dermal papilla adjacent to the tumour to the deepest focus of invasion. Many believe that an infiltrative growth is more aggressive than the papillary or exophytic type. The terminology and definitions are inconsistent and contradictory. The significance of the different growth patterns is controversial.
The tumour free margin after excision is a significant predictor of recurrence and lymph node status. A 1 cm tumour free surgical margin on the vulva results in a high rate of local control, whereas a margin < 8 mm is associated with a 50% chance of recurrence. Seventy five percent of tumours with surgical margins less than 2.5 mm had positive lymph nodes.
Diagnosis and investigations
Histological diagnosis prior to definitive treatment is imperative. Examination of the rest of the genital tract including colposcopy of vagina and cervix. Imaging must be arranged for the evaluation of inguinal and pelvic lymph nodes as well as possible bony erosion.
Squamous cell carcinomas account for about 80% of all invasive cervical cancers and adenocarcinomas and mixed tumours (adenosquamous) the bulk of the rest. Less frequently encountered cell types include small cell (neuroendocrine), adenoid basal, adenoid cystic, primary melanoma, sarcoma and primary lymphoma. Squamous and adenocarcinomas should be treated in a similar fashion.
Early lesions may be asymptomatic and are usually detected on routine Pap testing. Common symptoms include post coital, intermenstrual or post-menopausal bleeding. Offensive vaginal discharge may also be present. Pain, bladder and bowel symptoms, weight loss and bone pain may occur in advanced disease.
Confirmation of suspected cervical cancer is by way of cervical biopsy. For a small or occult lesion cone biopsy will be needed whereas for an obvious lesion a cone biopsy should be avoided, rather an incisional wedge biopsy should be performed.
Staging is by the clinically based FIGO system. A stage is assigned after a vaginal pelvic examination, cystoscopy, sigmoidoscopy and biopsy have been performed. Limited radiological examinations are allowed in the determination of the stage. The findings derived from a CT scan are not allowed to influence the assignment of stage. The value of the FIGO system is to compare results between institutions using either radiotherapy, radical surgery or a combination of both as primary therapy. The limitations of this system are obvious to those whose therapy is predominantly surgical.
Clinical assessment is a poor indicator of the presence of lymph node metastasis, with up to 30% of clinically negative nodes containing malignancy
Stage 1 – Tumor confined to the vulva
1A Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm*
1B Lesions >2 cm in size OR any size with stromal invasion >1.0 mm, confined to the vulva or perineum*
Stage 2 – Tumour of any size with extension to adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement)
Stage 3 – Tumour of any size with or without extension to adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement) with positive inguino-femoral lymph nodes
3Ai One lymph node metastasis, ≥5 mm
3Aii One to two lymph node metastases, <5 mm
3Bi One to two lymph node metastases, <5 mm
3Bii Three or more lymph node metastases, <5 mm
3C Lymph node metastasis with extracapsular spread
Stage 4 – Tumour invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures
4A Tumour invades any of the following: Upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa or fixed to pelvic bone, or fixed or ulcerated inguino-femoral lymph nodes
4B Any distant metastasis including pelvic lymph nodes
*The depth of invasion is defined as the measurement of the tumour from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion
Must be individualized with a trend toward organ preservation with consideration to age, post operative morbidity, psychosexual effects and lymph oedema. In the design of surgical therapy one must consider: (i) lesion size and location (ii) depth of invasion (iii) LVSI (iv) degree of histologic differentiation (v) clinical status of groin nodes (vi) health and wishes of patient (vii) condition of the vulvar skin not involved by the cancer (viii) presence of associated problems such as genital prolapse (ix) other sites of lower genital tract squamous neoplasia.
Has less than 1mm stromal invasion and is less than 2cm in size. The risk for nodal spread for stromal invasion less than 1 mm is nearly nil and groin dissection is not indicated. Radical local excision with a 1cm clear margin is usually adequate treatment with the depth of the incision down to the inferior fascia of urogenital diaphragm.
Stage 1B -III
Radical vulvectomy with a 1cm clear margin is indicated for T1 and T2tumours with lymph node dissection is the appropriate treatment. Ipsilateral groin dissection is acceptable if the cancer is stage I, lateralized and there are no suspicious contralateral nodes. Bilateral lymph node dissections should be done for central or midline tumours, large tumours and positive ipsilateral lymph nodes. The risk for bilateral LN involvement with a unilateral lesion if the stromal involvement is >3mm is 2.8% or greater. If there is no evidence of suspicious inguinal lymph nodes on CT or examination, bilateral inguinal LND can be done. Debulking of enlarged positive nodes can be considered prior to radiotherapy. Radiation is recommended if nodes are fixed or unrespectable because multimodality treatment (surgery followed by chemoradiation) causes severe lymphoedema that is best avoided.
Inguinal lymph node dissection should be superficial and medial to the femoral vein. Dissection should be individualised. There is controversy regarding the recommended depth of dissection. The rate of complications after superficial and deep groin dissection has been reported to be as high as 50%. Infection, hemorrhage, wound dehiscence, paresthesia and lymphocele with chronic lymphoedema have been the most commonly reported short and longterm complications.
Pelvic nodal metastases occur infrequently, unless the patient has (i) clinically suspicious (N2) groin nodes or (ii) 3 or more positive unilateral groin nodes.
2. Sentinel lymph node mapping and biopsy
Sentinel lymph node assessment has been used more frequently in recent years as it incurs less morbidity (lymphoedema and wound breakdown). The sentinel lymph node for vulva cancer is the superficial inguinofemoral lymph nodes. Detection rates are very high (nearly 100%) and it has a very low rates of false negatives. If these nodes are negative for malignancy, the risk for metastases to the deep lymph nodes is insignificant. Current practice use isosulfan blue dye and same day preoperative lymphoscintgraphy. The best candidates for this procedure is patients with uninfected, smaller than 4cm vulva tumours, limited to the lateral vulva, no palpable or enlarged inguinofemoral lymph nodes and no previous vulvar surgery. If the sentinel lymph node is positive or not detected, a complete LND must be done. Ultrastaging of the negative sentinel node is mandatory.
3. Adjuvant Radiotherapy
Patients with negative nodes and margin free resections do not require further therapy. Adjuvant radiotherapy has been shown to improve prognosis for patients with positive LN. In some instances various features such as poorly differentiated cancers, large bulky tumours, those with diffusely infiltrative growth patterns, those with lymph-vascular space invasion or those with very small surgical margins (<1cm) may be selected for postoperative therapy based on concern for local relapse. Radiation therapy options would include whole pelvic irradiation centered low to include the vulva and soft tissues of the medial groins or vulva irradiation alone. Groin radiation is indicated for one macrometastases, presence of extracapsular spread and two or more micrometastases. If a unilateral dissection has been carried out, the contralateral groin may be dissected, radiated or observed. Radiation of the intact groins has been thought as inferior to surgically dissected groins followed by irradiation. It has been realized that those that failed were obese and probably received inadequate dose of irradiation at the level of the femoral vessels. Also at least half of the dose was given as electrons. When there is concern over the adequacy of excision (close margins) or the presence of LVSI after radical local excision, vulvar irradiation may be considered or in the unusual situation where patients are unsuitable for surgery.
As primary treatment chemoradiation can be an alternative for locally advanced primary lesions, stage III or IV where the tumour is either unresectable or require exenteration (GOG 205). Cisplatin and 5-FU can be used with similar no differences in survival or recurrence rates. Neoadjuvant chemoradiation can be used to decrease tumour bulk, lesions close to the urethra and anus and to lessen the risk of local recurrence. This allows a smaller resection, usually with reconstruction. Radiation is given with concurrent cisplatin and/or 5-fluorouracil. Concurrent chemotherapy with radiotherapy improves response rates compared to RT alone. Complete lymph node dissection post radiation is not recommended as this increased the risk for severe lymphoedema. Role of chemoradiation as adjuvant therapy has not been well studied.
5. Primary radiotherapy
In young patients with small primary tumours, especially clitoral lesions in young and middle-aged women where surgical resection would have significant psychological consequences primary irradiation therapy instead of surgery may be considered
6. Neo adjuvant chemotherapy
Currently not standard of care
Operative morbidity, nodal metastases requiring adjuvant concurrent therapy and psychosocial impact is high with advanced stage disease. Primary chemoradiation, consisting of Cisplatin,5-FU and radiation is a good alternative to exenterative surgery. This can be followed by surgery in selected cases. The presence of distance metastases requires individualized treatment and the aim is palliation.
Advanced or Recurrent Disease
Local recurrence follows definitive surgery in up to 40% and is most common in the first year after treatment. Long term follow up is needed. The majority are on the vulva (60%) compared to the groin region (40%). Groin recurrences tend to occur earlier and are ultimately lethal, while central or vulval recurrences tend to occur later and can be adequately managed with repeated surgical excision. The most active chemotherapeutic agents for patients with advanced and recurrent tumour are: cisplatin, 5-FU and mitomycin C, but response rates are modest.
Overall 5-year survival for operable cases is about 70% and the corrected 5-year survival rates are 90,80, 50 and 15% for stages I to IV. Extracapsular growth of lymph node metastases, two or more positive lymph nodes and greater than 50% replacement of lymph nodes by tumour were predictors of poor survival. Patients with negative nodes have a 5-year survival of about 90%; but this falls to about 50% for patients with positive nodes.
Is the second most common vulval malignancy comprising 5-10% of all vulval cancers. While vulval melanomas account for 3-7% of all melanomas, the skin of vulva accounts for only 1-2% of total surface area of body. They arise from junctional nevi or epidermal melanocytes and are considered an APUD-derived tumour since melanocytes originate from the neural crest anlage (neuroectodermal origin). Therefore gynaecological melanomas arise at the vulvovaginal junction where melanocytes concentrate. They tend to occur in older age patients, average age 60 years (whereas cutaneous melanomas age is much younger). Most are polypoid tumours, many may be amelanotic. The commonest sites are clitoral area and labia majora. The FIGO staging system for vulva cancer is not helpful with vulvar melanoma. In this disease, prognosis is significantly influenced by 2 micro staging techniques. The Breslow System that measures the thickness of the invasive portion of the neoplasm and the Clarke scheme which measures the depth of invasion in terms of descriptive histology of the skin. Both systems including that of Chung are outlined in the table below. The microscopic differential diagnosis is Paget’s disease which can be differentiated by immunoperoxidase staining. Melanoma does not contain CEA but does contain S-100 antigen and melanoma antigen.
Groin node metastasis occurs in 25% of patients. The risk of lymph node metastasis is <1% for lesions less than 0.76 mm thick but rises sharply to about 25% for lesions 0.76 to 1.5 mm thick
Micro staging of Vulvar Melanomas
|II||Into papillary dermis||<1mm from granular layer||0.76-1.50 mm||100%|
|III||Filling dermal papillae||>1-2 mm from granular layer||1.51-2.25 mm||80%|
|IV||Into reticular dermis||> 2mm from granular layer||2.26-3.0 mm||65%|
|V||Into subcutaneous fat||Into subcutaneous fat||>3 mm||25%|
Superficial spreading melanoma (SSM)
Characterized by initial horizontal growth, but once vertical growth occurs, progression is rapid. Accounts for 66% of vulvar melanomas.
Nodular melanoma (NM)
Are aggressive tumours with early vertical growth phase, accounting for approximately 30% tumours
Lentigo maligna melanoma (LMM) or Mucosal Lentiginous Melanoma (MLM)
Occur in sun exposed regions and hence not usually seen on the vulva. Are slowly growing tumours and of low grade malignancy. Have a predominant horizontal growth phase.
Optimal management is WLE for lesions <1mm thick and no LVSI. The lesion should be excised with a 1cm margin. If the melanoma is intraepithelial or superficial, WLE is probably adequate. If any lymph-vascular space invasion is noted, groin dissection may be considered. If the lesion is thicker or more infiltrative, radical wide local excision with bilateral groin dissection or radical wide local excision and ipsilateral groin dissection could be employed in most instances. The prognosis with metastatic disease in the nodes is poor.
The role of elective lymph node dissection (ELND) is controversial. Whether data from other cutaneous sites can be extrapolated to the vulva is unclear.
Radiation therapy may be useful in patients with close or positive surgical margins.
Chemotherapy agents with some (albeit minor) activity include: DTIC, CTLA-4 monoclonal antibodies and BRAF inhibitors.
The behavior of vulval melanomas is unpredictable, and overall the prognosis is poor with 32% 5-year survival. Prognosis is related to tumour thickness and disease spread. Invasion past the papillary dermis (Clarkes’s level 2 or Breslow’s 0.76-1.5 mm) portends a poor prognosis. Other prognostic factors include (i) tumour thickness (ii) ulceration (iii) macroscopic amelanosis (iv) clinical stage (v) high mitotic rate (>4/10hpf) (vi) epithelioid cell type (vii) age > 65 (viii) nodular.
Presents at a more advanced staged, and has higher incidence of lymph node metastases. Have a poor prognosis.
Are rare representing 1-2% of vulvar malignancies. Usually occur in younger age group (about 40 years). Many histologic types described including: LMS; rhabdomyosarcomas; fibrosarcoma, neurofibrosarcoma; liposarcoma, angiosarcomas and epithelioid sarcomas. Diagnosis: >10 mitoses per high power field. Recurrence of vulvar sarcomas is associated with (i) lesion size > 5 cm, (ii) infiltrating margins and (iii) > 5 mitoses/10hpf. While treatment recommendations cannot be supported by medical evidence, it is recommended that patients undergo radical WLE and groin dissection with consideration for adjuvant radiation and/or chemotherapy. Prognosis is poor.
Is a rare intraepithelial neoplasm that comprises 1-2% of vulvar malignancies. It most commonly is seen in postmenopausal Caucasian females and clinically appears as a red, eczematoid lesion. Histological disease may exceed far beyond the visible lesion. Surgical evaluation of these lesions is important since 20-30% may have an underlying malignancy. Patients with invasive Paget’s or with an underlying adenocarcinoma or coexisting cancer have a poor prognosis. Wide local excision is the treatment of choice. Negative permanent margin status is not predictive of disease recurrence. Compared to radical resection, WLE is associated with an increased local recurrence risk but survive longer than those treated more radically.
Basal Cell Carcinoma
Usually occurs in postmenopausal white women. While they are locally invasive, but rarely metastasize. It typical presents as a rodent ulcer with rolled edges and central ulceration. Mostly asymptomatic, but can present with pruritis, bleeding or pain. Can also be associated with malignancy elsewhere in the body. Treatment is by WLE except if >4cm diameter which warrant LND.
Bartholin Gland Tumours
Are uncommon vulval tumours comprising 1-3% all vulval tumours. The mean age at presentation is 52 years (range 18-91 years), approximately 10 years younger than patients with squamous cell cancers. Enlargement of the Bartholin gland in a post menopausal women is always concerning. Histologically they are usually adenocarcinoma (45%), SCC (40%), sarcoma (5%), melanoma (1%). Diagnostic criteria needed to make the diagnosis (Honan’s criteria) (i) correct anatomical position (ii) located deep in the labia majora (iii) the overlying skin is intact (iv) some recognizable normal gland is present (v) histologically documented transition from normal Bartholin’s gland to the malignant element (vi) absence of another primary cancer. Recommended treatment is radical vulvectomy and bilateral groin dissection. Post op vulval irradiation can reduce vulval recurrence and if nodes are positive pelvic and groin irradiation. Survival is usually a function of clinical stage. Overall prognosis is poor with a 5-year survival < 10%.
Are slowly growing, locally invasive, and rarely metastatic. Is considered a variant of a well differentiated squamous cell carcinoma. While the etiology is unknown, a history of genital warts, syphilis and gonorrhea has been reported as has a history of immune suppression. They may be associated with infection with HPV-6. The histological features include (i) papillary projections with no fibrovascular cores (ii) very little mitotic figures and mild epithelial atypia (iii) “pushing” deep borders but no infiltration of cells into stroma . They can occur at other sites including cervix, endometrium, vagina. Treatment is radical local excision. Radiation therapy may be unsuccessful and it has been suggested it may transform verrucous carcinoma into highly malignant tumour. Chemotherapy appears to be of little benefit.