Fig. 3.1.
Histolopathologic Types of Carcinoma of the Vulva: SEER Data 1988–2001 [2]. Data source: Kosary CL. Cancer of the Vulva. In: Ries LAG, Young JL, Keel GE, Eisner MP, Lin YD, Horner M-J (editors). SEER Survival Monograph: Cancer Survival Among Adults: U.S. SEER Program, 1988–2001, Patient and Tumor Characteristics. National Cancer Institute, SEER Program, NIH Pub. No. 07-6215, Bethesda, MD, 2007 [2].
Peak incidence is between 65 and 75 years of age and the median age at diagnosis is 68.
Recent series suggest vulvar cancers etiologically related to human papillomavirus infection (HPV) infection present at a younger age than non-HPV related cancers [3].
Risk factors for invasive vulvar cancer depend on two distinct etiologic pathways:
Keratinizing, well-differentiated carcinomas arise in the background of vulvar dystrophy, such as lichen sclerosus or squamous hyperplasia.
Non-keratinizing carcinomas develop from malignant transformation of dysplastic conditions related to HPV infection, smoking, or immunosuppresion.
Quadrivalent HPV vaccination is effective against HPV types 16, 18, 6, and 11 and the expectation is that immunization will decrease the incidence of vulvar cancers related to HPV in the future.
Diagnosis/Screening
Screening: There is no screening test for vulvar cancer.
Patients with a history of cervical or vaginal cancer should be monitored closely with systematic inspection of the vulva with or without colposcopy.
Regular surveillance should also be standard practice for patients with lichen sclerosus or past history of vulvar intraepithelial neoplasia (VIN).
Natural History/Preinvasive lesions.
Tumors grow slowly over several years, resulting from either prolonged mucosal HPV infection or chronic inflammation due to vulvar dystrophies or autoimmune processes.
VIN is often a precursor lesion that precedes malignant transformation to invasive SCC of the vulva and as such the World Health Organization (WHO) prefers to grade VIN the same as cervical intraepithelial lesions according to the degree of abnormality (e.g., VIN 1, VIN2, and VIN3).
Current terminology was modified in 2004 by the International Society for the Study of Vulvar Diseases (ISSVD) [4] that introduced three different subcategories:
VIN, usual type (warty, basaloid, or mixed).
VIN, differentiated is now used to describe what was previously referred to as VIN simplex type (not HPV related).
VIN, unclassified encompasses VIN that cannot be classified into either of the above groups including pagetoid type cells.
The VIN 1 category was eliminated (because the diagnosis is not reliably reproducible and the findings are associated with HPV effect or reactive changes, not a precancerous lesion).
Thus, the term VIN is reserved for histologically high-grade squamous cell lesions.
VIN 2 and VIN 3 were combined since they are difficult to differentiate and would both be treated as high-grade preinvasive dysplasia.
Instead, VIN is divided into two diagnostic categories (usual and differentiated type) that more accurately reflect the etiology (+/− HPV) and clinical characteristics of the SCC variants they are associated with (see details in Sect. 1.4).
Clinical presentation.
Vulvar cancer may be asymptomatic but pruritis is the most common symptom.
Approximately 50 % present with a lump or ulcer on the vulva (or less commonly in the groin from metastases to lymph nodes).
Clinicians should have a low threshold to biopsy any suspicious vulvar abnormalities, because the appearance of malignant lesions is often similar to that of benign processes.
Frequently, this may result in delays in diagnosis from patients ignoring symptoms or physicians attempting topical therapy without definitive diagnosis.
Pretreatment evaluation.
Pathologic diagnosis is obtained using wedge or Keyes biopsy.
Clinical assessment with thorough history and physical exam including palpation of groin lymph nodes and complete pelvic with Pap smear if cervix remains in situ and colposcopy of the entire cervix, vagina, and vulva.
Imaging with PET or MRI for the evaluation of lymph nodes and soft tissues as appropriate.
Imaging is more sensitive than physical exam for detecting inguinal lymph node involvement; however, inflammatory processes may lead to false positive findings.
Prior to initiating treatment, it is important to disclose the risks and benefits of treatment with particular attention to counseling on sexual function after treatment.
Mode of spread.
The majority of vulvar cancers are confined to the vulva.
Initially local spread extends to contiguous skin and larger lesions can invade adjacent structures vagina, urethra, and rectum.
Pattern of lymphatic spread is typically predictable and stepwise to ipsilateral superficial inguinal nodes followed by deep inguinal/femoral and pelvic nodes. Anatomic variations occur in a small percentage of women.
Metastatic sites including pelvic nodes (external, hypogastirc, obturator, and common iliac) are considered distant site involvement.
Hematogenous dissemination is rare except in malignant melanoma.
Staging
The International Federation of Gynecology and Obstetrics (FIGO) employ a surgical staging scheme that incorporates major determinants of prognosis such as primary tumor size and laterality, lymph-node metastasis, and distant spread to other organs (see Table 3.1) [5].
Table 3.1.
FIGO staging classification of vulvar cancer and 5-year overall survival.
Stagea (TNM)
Description
Treatment
5-Year survival (%)
I (T1)
Tumor confined to vulva or perineum
79–92
IA
Tumor confined to vulva or perineum; lesion ≤2 cm with stromal invasion ≤1 mm, no nodal metastasis
Radical local excision
IB
Tumor confined to vulva or perineum; lesion >2 cm or stromal invasion >1 mm, with negative nodes
Radical local excision with ipsilateral or bilateral inguinofemoral lymphadenectomy (IFLND)b
II (T2)
Tumor of any size with extension to adjacent perineal structures (lower 1/3 urethra, lower 1/3 vagina, anus) with negative nodes
Radical local excision with bilateral IFLND
58–78
III (T3)
Tumor of any size with or without extension to adjacent perineal structures with positive inguinofemoral lymph nodes
43–55
IIIA
(1) With 1 lymph node metastasis (≥5 mm) or
(2) One to two lymph node metastasis(es) (<5 mm)
Radical local excision with ipsilateral or bilateral IFLNDb
Adjuvant pelvic and bilateral groin RTc
IIIB
(1) With two or more lymph node metastases (≥5 mm) or
(2) Three or more lymph node metastases (<5 mm)
IIIC
With positive nodes with extracapsular spread
IVA (T4)
(1) Tumor invades upper urethra and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone fixed or
(2) Ulcerated inguinofemoral lymph nodes
Radical local excision with bilateral IFLND, remove all enlarged groin and pelvic nodes
Unresectable nodes should receive preoperative RT +/− chemotherapy
13–28
IVB
Spread to distant sites or pelvic lymph nodes
Supportive care +/− palliative chemotherapy or radiation
Depth of invasion is strictly measured from the epithelial-stromal junction of the most superficial dermal papillae to the deepest point of invasion.
Complete staging requires resection of the primary tumor and complete inguinofemoral and pelvic lymphadenectomy to accurately determine nodal status if lesions are >1 mm in depth.
However, excisional biopsy of sentinel lymph nodes is frequently used to assign stage and guide further treatment in an effort to avoid the morbidity associated with complete groin dissections (for detailed discussion see Sect. 1.5).
Accurate surgical staging is critical. Detecting the presence or absence of lymph node involvement at initial diagnosis is not only prognostic, but can also impact therapeutic efficacy by permitting modifications to the treatment plan and improving the probability of cure.
The prognostic significance of the number and size of nodal metastases are reflected in the recent revisions made to the FIGO staging system.
Depth of invasion and lymphovascular space involvement are prognostic measures for the risk of nodal disease.
The incidence of groin lymph node metastases are: 10, 26, 64, and 89 % for Stages I–IV, respectively.
Fifteen to 20 % of patients with positive groin nodes also have metastases to pelvic nodes; almost all patients with positive pelvic nodes will have clinically suspicious groin nodes and on pathology ≥3 positive groin nodes and invasion >4 mm [6, 7].
Overall, the incidence of metastasis to pelvic lymph nodes is less than 10 % and pelvic lymphadenectomy is no longer performed routinely, as this did not translate into improved survival outcomes.
Pathology/Histology
Squamous cell carcinomas (SCC) account for 80–90 % of vulvar malignancies.
Keratinizing subtype—represents more than 70 % of SCC; is not related to HPV and occurs in older women. These lesions tend to be unifocal, and a significant number are associated with atrophic lesions, such as lichen sclerosus. Precursor lesion is differentiated VIN (or VIN simplex type). Microscopically, it consists of invasive nests of malignant squamous epithelium and central keratin pearls.
Warty and basaloid carcinomas are associated with high-risk HPV types, predominantly HPV 16, 18, and 33. Precursor lesion is the classic or usual type of VIN. May be multifocal, occurs in younger women for whom the risk of progression to invasive carcinoma is approximately 6 % but the risk is higher in older women or immunosuppressed populations.
Verrucous Carcinoma is a distinct variant of squamous carcinoma that occurs in postmenopausal women that present as large, fungating masses that may be misidentified as condyloma.
Commonly associated with HPV 6 or 11.
The histologic appearance of verrucous carcinoma includes large nests of squamous cells with abundant cytoplasm, small bland nuclei, mitoses are rare but squamous pearls are common. This may be differentiated from condyloma acuminata by the absences of fibrovascular cores (connective tissues within the proliferating papillary masses of the tumor) that are typical of condyloma acuminata. To establish the diagnosis biopsies must be sufficiently deep to obtain underlying stroma.
Lymph node metastasis is exceedingly rare, but deep local invasion and local tumor recurrences are common.
Treatment consists of radical local excision. Lymphadenectomy is of limited value except with clinically suspicions lymph nodes. Radiation therapy is contraindicated because it is ineffective and may lead to increased aggressive behavior within this tumor.
Basal Cell Carcinoma constitutes <10 % of vulvar cancers.
Unlike other basal cell carcinomas of the skin ultraviolet light exposure plays no role in carcinogenesis, but histologically these lesions are identical.
Grossly, appears as flesh colored to pearly white nodules or plaques that are often ulcerated centrally.
They are usually local invasive and rarely metastasize, and wide local excision is the recommended treatment.
The prognosis is good despite a 20 % risk of local recurrence.
Bartholin’s Gland Carcinomas are rare representing less than 1 % of vulvar neoplasms
Cell types that give rise to Bartholin’s gland carcinomas include adenomatous, squamous, adenosquamous, and adenoid cystic.
Enlargement in the Bartholin gland in postmenopausal women is presumed to be a neoplasm until proved otherwise and biopsy of all suspicious lesions is recommended in women age 40 and older.
Unfortunately, given the extensive vascular and lymphatic supply in this area, metastatic disease is common
Malignant Melanoma of the vulva is uncommon, but is the second most common primary cancer of the vulva (5–10 %).
Melanomas are typically raised lesions, with irregular pigmentation and borders or ulcerations that probably arise from junctional or compound nevi. They usually occur on the labia majora or clitoris, but also on mucosal surfaces.
Histology is similar to melanomas of other skin areas but in difficult cases be confirmed in conjunction with immunohistochemisty staining for melanoma markers S-100 antigen and Melanoma specific (HMB) antibody.
There are several microstaging systems for vulvar melanoma that are summarized in Table 3.2.
Clark [8]
Chung [9]
Breslow [10]
I
Intraepithelial
Intraepithelial
<0.76 mm
II
Tumor extends into papillary dermis
Invasion ≤1 mm from granular layer
0.76–1.50 mm
III
Tumor filling dermal papillae
Invasion 1.1–2 mm from granular layer
1.51–2.25 mm
IV
Tumor extends into reticular dermis
Invasion >2 mm deeper than granular layer
2.26–3.0 mm
V
Tumor extends into subcutaneous fat
Into subcutaneous fat
>3.0 mm
Clark’s and Breslow systems are based on depth of invasion and tumor thickness, respectively. Chung modified Clark’s level to account for morphologic differences in the vulva and vagina [11].
Prognosis depends primarily on tumor size, thickness and on the presence or absence of lymph node involvement which is captured in the American Joint Committee on Cancer (AJCC) TNM criteria [12] that further subdivide staging of cutaneous melanomas by tumor ulceration, mitotic rate, microscopic tumor burden in lymph nodes, and lactate dehydrogenase (LDH) levels in metastatic disease (see Table 3.3).
Stage group
TNM clinical staging
Thickness (mm)
Ulceration
Mitotic rate
IA
T1a
N0
M0
<1.0
None
<1 mitoses/mm2
IB
T1b
N0
M0
<1.0
Present
>1 mitoses/mm2
T2a
N0
M0
1.01–2.0
None
IIA
T2b
N0
M0
1.01–2.0
Present
T3a
N0
M0
2.0–4.0
None
IIB
T3b
N0
M0
2.0–4.0
Present
T4
N0
M0
>4.0
None
IIC
T4
N0
M0
>4.0
Present
III
Any T
N1-3a
M0
IV
Any T
Any N
M1
Radical local excision is standard for the primary lesion [13] and if limited to the vulva with negative lymph nodes the survival is good. Although nodal status has prognostic significance, regional lymphadenectomy has a more prognostic role than therapeutic and sentinel lymph node biopsy should be considered.
Five-year survival is lower than for cutaneous melanomas and vulvar SCC at 36 % [11].
The prognosis is very poor with positive inguinal or pelvic nodes and most of these patients die as a result of their disease.
In high risk patients or recurrent settings, the use of radiation, chemotherapy, biologic agents and immunotherapies are tailored to the individual patient.
Extramammary Paget’s Disease of the Vulva is rare.
Well demarcated patches of erythematous thickened areas and islands of white epithelium with foci of excoriation and induration are apparent on gross examination.
On histology these lesions contain diagnostic cells (Paget cells) with copious pale cytoplasm that infiltrate the epithelium and are interspersed among normal keratinocytes and often mixed inflammatory infiltrates of lymphocytes and plasma cells are noted in the underlying dermis. If the disease is limited to the epithelium, its clinical course is usually prolonged and indolent but approximately one-third of patients will develop recurrences after surgery.
Rarely the disease may have an invasive component or secondary infiltration of the vulvar skin with pagetoid cells that can result from an underlying primary adenocarcinoma of the apocrine glands.
The prevalence of these conditions reported in the literature varies widely and the risk of concomitant carcinomas at other sites has become fairly controversial.
The largest series reviewed 100 cases of Paget’s disease of the vulva and the prevalence of invasive Paget’s disease was 12 % and concurrent adenocarcinoma was identified in 4 % of patients [14].
Invasive Paget’s disease in women can be associated with concomitant carcinoma at other sites (e.g., breast, colon, or genitourinary cancer); thus, the workup should include colonoscopy, cystoscopy, mammogram, and colposcopy.
Treatment includes wide local excision or simple vulvectomy with 2- to 3-cm borders of uninvolved tissue in most cases, however, if an underlying adenocarcinoma or invasive Paget’s disease is identified radical excision and inguinal lymphadenectomy is required.
Treatment Algorithm
Therapy for Early Vulvar Cancer Stage I and II
The management of all invasive vulvar cancers involves careful consideration of the most appropriate surgical procedure for (1) excision of the primary tumor and (2) assessment of regional lymph nodes.
Primary Tumor
Historically this involved en bloc radical vulvectomy and bilateral inguinofemoral lymphadenectomy using a butterfly-shaped incision (Fig. 3.2a) to remove vulva and groin lymph nodes with the intervening skin; results in high survival rates but unacceptable morbidity for many patients.
Fig. 3.2.
Incisions for resection of vulvar cancer [15]. (a) Incision for en bloc radical vulvectomy with inguinal femoral lymphadenectomy. (b) Three separate incisions for the vulva or hemi-vulvectomy and both sides of the groin. Reprinted with kind permission from Springer Science and Business Media. From Horowitz IR. Female Genital System. In: Wood WC, Skandalakis JE, Staley CA, editors. Berlin: Springer; 2010 pp 637–78. [15].
Radical local excision (modified radical vulvectomy) is favored in contemporary practice and involves excision of the entire lesion with clinical margins of 1–2 cm laterally and dissection down to the perineal membrane (deep fascia of the urogenital diaphragm). Separate groin incisions (Fig. 3.2b) allow the intervening skin bridges between the vulva and unilateral or bilateral groin dissection to remain intact for improved healing.
Treatment of Positive or Narrow Margins
Shrinkage of tissue margins occurs in formalin-fixated specimens for histopathologic sectioning (microscopic 8 mm margins in fixed tissue specimens correspond to 1 cm clinical margins).
Microscopic margins less than 8 mm are associated with significantly higher rates of local recurrence (48 %). None of the women in this study with negative surgical margins ≥8 mm experienced a local recurrence [18].
Re-excision is recommended to ensure complete resection of the primary lesion with adequate tumor-free margins.
Postoperative radiation may be used if re-excision is not possible or if further surgery is declined by the patient.
RT improves local control in high risk patients but local recurrences are frequently salvaged with additional surgery or radiation.
Management of Groin Lymph Nodes in Early Vulvar Cancer
Appropriate treatment of the groin is the single most important factor in reducing mortality from vulvar cancer.
The optimal approach is to determine the most appropriate operation for each individual patient—to maximize the likelihood of cure and minimize morbidity.
Microinvasive or Stage IA tumors have an extremely low incidence of lymphatic involvement (<1 %) therefore inguinofemoral lymphadenectomy (IFLND) may be omitted [19].
Patients with Stage IB and Stage II should undergo at least ipsilateral IFLND (with lateralized lesion >1 cm from midline) but the incidence of positive nodes in the contralateral groin is minimal and therefore unilateral dissection is acceptable.
Bilateral dissection is required for tumors that are <2 cm from midline or large (>4 cm), and for clinically suspicious lymph nodes.
If a positive unilateral lymph node is identified then dissection of the contralateral side is recommended as the risk of metastasis in this setting is as high as 18 %.
If all nodes are negative, no further treatment is necessary.
There is a high incidence of complications related to complete groin dissection and radiation but unexpected groin failures are universally fatal.
Adjuvant pelvic and bilateral groin RT is recommended for patients with affected groin lymph nodes after IFLND with more than two micrometastases (<5 mm), one macrometastasis (>5 mm) or extracapsular spread given the evidence to date. However, there is significant morbidity associated with complete lymphadenectomy and RT.
Radiation fields should include inguinal and femoral nodes as well as pelvic nodes distal to and including the bifurcation of the common iliac vessels using various methods.
The recommended dose is dependent on the size and extent of nodal disease, approximate range is 50–60 Gy. Primary radiation of advanced gross vulvar disease requires 60–70 Gy for local control.
Intensity-modulated radiotherapy (IMRT) may be used to reduce the dose to the femoral head and neck, pelvic bone, bladder, and rectum.
Alternative Methods for Approaching Lymph Nodes
Post-treatment complications related to the treatment of vulvar cancer have prompted investigators to study alternative methods to selectively identify patients who benefit from complete inguinofemoral lymphadenectomy versus those who may be spared unnecessary morbidity without compromising survival.
Primary Groin Radiation (without groin dissection) after radical vulvectomy is less morbid acutely but is associated with significantly higher rates of groin recurrence and inferior survival compared to primary groin lymphadenectomy [20]. Investigators had hypothesized that prophylactic radiation of intact groins could be used to avoid lymph node dissection in low risk patients (to treat occult metastasis) but it is not recommended based on the results of GOG 88 that closed prematurely due to the number of groin recurrences with RT compared to surgical dissection.
Superficial Lymphadenectomy has been studied in an effort to reduce the extent of groin dissection.
GOG 74.
Prospective study of ipsilateral superficial lymphadenectomy and radical local excision for Stage I disease.
The rate of recurrence diagnosed in the groin after negative superficial lymphadenectomy was 7 %. Significantly higher than historical controls in which groin relapse occurred in less than 1 % following en bloc radical vulvectomy and bilateral inguinofemoral lymphadenectomy.
The number of patients who experienced recurrence in the operated groin may be attributed to anatomic variation in lymphatic drainage of the vulva and suggests the sentinel node is not always an ipsilateral superficial inguinal node and may actually be located in the deep femoral nodes or contralateral groin in 15 % of women.
Sentinel Lymph Node Biopsy
The use of sentinel lymph node biopsy (SLNB) is based on the concept that the sentinel node is the first node to receive lymphatic drainage from the primary tumor and will be the first node to develop metastasis and can therefore be used to patients who do not need full regional lymphadenectomy.
The practice of SLNB in early-stage vulvar cancer has increased in Europe and the U.S. following the publication of two landmark trials discussed below:
GOG 173.
Patients with primary tumor with >1 mm invasion and 2–6 cm in size underwent intraoperative lymphatic mapping and SLNB followed by unilateral or bilateral lymphadenectomy [21].
Protocol: Intradermal injection of isosulfan blue (or 1 % methylene blue) is made at the leading edge of the primary tumor closest to the ipsilateral groin or on both sides for midline tumors; multiple peri-tumoral injections up to 2.5 ml on each side are permitted. Massage injection sites gently. The groin incision should be made a minimum of 5 min following injection, and if afferent lymphatic channel cannot be located in the groin a second injection of the primary site is permitted. Intraoperative radiolocalization can be performed after preoperative lymphoscintigraphy (LSG) with 0.5–1.0 ml of radiolabeled Tc99 microsulfur colloid, if done on the day of surgery, or the radionuclide is injected 1–6 h prior to the operation.
Sentinel nodes were identified in 418 women out of 452 total subjects.Related posts:
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