Junzo P. Chino, Laura J. Havrilesky, and Gustavo S. Montana
ANATOMY
Vulva
The vulva is composed of the mons pubis, clitoris, labia majora and minora, vaginal vestibule, and their supporting subcutaneous tissues. The vulva blends with the urinary meatus anteriorly and with the perineum and anus posteriorly. The mons pubis consists of prominent tissue located anteriorly to the pubic symphysis. The labia majora are two elongated skin folds that course posteriorly from the mons pubis and blend into the perineal body. The skin of the labia majora is pigmented and contains hair follicles and sebaceous glands. The labia minora are a smaller pair of skin folds located between the labia majora. Anteriorly the labia minora separates into two components that course above and below the clitoris, fusing with those of the opposite side to form the prepuce and frenulum, respectively. The skin of the labia minora contains numerous sebaceous glands but no hair follicles and has no underlying adipose tissue. The clitoris is 2 to 3 cm anterior to the urethral meatus and is supported externally by the fusion of the labia minora.
The vaginal introitus is demarcated laterally by the labia minora and posteriorly by the perineal body. Anteriorly numerous small vestibular glands are located beneath the mucosa and open onto its surface adjacent to the urethral meatus. The Bartholin’s glands (or greater vestibular glands) are two small mucous-secreting glands situated within the subcutaneous tissue in the posterior aspect of the labia majora. The ducts of the Bartholin’s glands open onto the posterolateral portion of the introitus. The Skene’s glands (or paraurethral glands) open in the anterior aspect of the introitus but can be variable in location. The perineal body is a 3- to 4-cm band of skin that separates the vaginal introitus from the anus and forms the posterior margin of the vulva with the fusion of the labia minora, or the fourchette.
Lymphatic Drainage
The inguinofemoral nodes are located within the triangle formed by the inguinal ligament superiorly, the border of the sartorius muscle laterally, and the border of the adductor longus muscle medially. There are superficial inguinal lymph nodes that lie along the saphenous vein and its branches between Camper’s fascia and the cribriform fascia overlying the femoral vessels. There are usually three to five deep nodes, the most superior of which is located under the inguinal ligament and is known as Cloquet’s node. Lymph drains from these nodes into the external and common iliac pelvic lymph nodes.
Lymphatic drainage is specific to the location of a vulvar lesion. Labial lesions drain into the superficial inguinal and femoral lymph nodes, then penetrate the cribriform fascia and reach the deep femoral nodes. Lesions of the fourchette and perineum follow the lymphatics of the labia. Lymphatic drainage from the glans clitoris or perineal body enter either unilateral or bilateral superficial femoral nodes or the deep femoral and pelvic lymph nodes. Some lymphatics originating in the clitoris enter the pelvis directly, bypassing the femoral nodes to connect with the obturator and external iliac lymph nodes, though in practice, the pelvic lymph nodes are rarely involved without synchronous involvement of the inguinal nodes (Fig. 74.1).
EPIDEMIOLOGY
Vulvar cancer is a rare malignancy that represents < 1% of all the cancers diagnosed in women and <5% of all gynecologic neoplasms. In the United States, it is estimated that there were 3,900 new cases in 2010, with 920 deaths due to the disease.1 The incidence is 2 cases per 100,000 women; however, this incidence increases to 13 per 100,000 in women of age >75 years.2 The incidence is slightly lower in Black women (1.6 per 100,000) and Hispanics (1.5 per 100,000) compared with Whites (2.4 per 100,000), and Asians/Pacific Islanders have the lowest incidence (0.9 per 100,000).
There are two primary mechanisms believed to be involved in the carcinogenesis of this disease: human papillomavirus (HPV) and vulvar dystrophy, including lichen sclerosus and squamous hyperplasia. HPV DNA can be identified in 40% of invasive vulvar cancers, with 16, 18, and 33 being the predominant subtypes.3,4 This is in contrast to vulvar intraepithelial neoplasia (VIN), from which HPV can be isolated in 70% to 90% of lesions.5 Because HPV infection is related to numerous other cancers of the anogenital region (e.g., cervical cancer and anal canal cancer), the risk factors are similar: previous diagnosis of genital warts, multiple sexual partners, smoking history, previous abnormal Papanicolaou test, and immune suppression.6,7 Lichen sclerosus (LS) has been found to be associated with vulvar cancer in 30% to 60% of cases in some series,8,9 although there is no histopathologic evidence of direct transformation.10 Women with existing LS have a 5% risk of developing invasive disease.11 The evidence for VIN as an obligate precursor to invasive vulvar disease is much less compelling than that established between cervical intraepithelial neoplasia and cervical cancer. Only one-third of vulvar cancers have an associated VIN-3 lesion,12 and <5% of women with an existing VIN lesion will subsequently be diagnosed with invasive disease.13,14
These findings have led to the hypothesis that squamous carcinoma of the vulvar can be broadly classified into two clinicopathologic entities: keratinizing squamous carcinomas (KSCs) and basaloid squamous carcinomas (BSCs).15 KSC is more common (80% of cases), is found in older women with vulvar dystrophy, and is rarely associated with other neoplasia, HPV, or VIN.16 p53 may or may not stain positive in KSC, because p53 mutations may play a role in pathogenesis in a subset of these neoplasms; p16 is rarely positive.17 BSC, in contrast, is less common (20% of cases), is found in younger women, and is associated with multifocality, other anogenital neoplasia, HPV infection, and VIN. In BSC, staining for p53 is often negative, whereas p16 is often positive due to HPV infection.
FIGURE 74.1. A: The lymphatic drainage of the vulva initially flows to the superficial inguinal nodes and then to the deep femoral and iliac group. Drainage from midline structures may flow directly beneath the symphysis to the pelvic nodes. (Modified from Plentl AA, Friedman EA, eds. Lymphatic system of the female genitalia. Philadelphia: WB Saunders, 1971.) B: The superficial inguinal lymph nodes comprise 8 to 10 subcutaneous nodes located between Camper’s fascia and the cribriform fascia. These nodes are immediately adjacent to the saphenous vein and its branches. (Modified from DiSaia PJ, Creasman WT, Rich WM. An alternative approach to early cancer of the vulva. Am J Obstet Gynecol 1979;133:825.)
FIGURE 74.2. Squamous cell carcinoma of the vulva. A: Squamous cell carcinoma with ulceration, arising from the right labia minora. This elderly woman had no apparent predisposing disease. B: Photomicrograph of invasive keratinizing squamous cell carcinoma of the vulva. Note the keratin pearls. (Courtesy of Dr. Stanley Robboy, Duke University Medical Center, Durham, NC.)
PATHOLOGY
Squamous Carcinoma
Eighty-five percent of invasive disease of the vulva is squamous cell carcinoma (Fig. 74.2).18 As noted earlier, these arise within squamous epithelium, often in or adjacent to areas of epithelial abnormalities or of premalignant conditions such as lichen sclerosus, erythroplasia of Queyrat, and Bowen’s disease.19 The depth of invasion, critical for appropriate staging and management, is defined as the distance from the epithelial stromal junction of the most superficial adjacent dermal papillae to the deepest point of invasion. Tumor thickness is measured from the overlying surface epithelium, or the bottom of the granular layer if the surface is keratinized, to the deepest point of invasion as specified by the International Society of Gynecological Pathologists.20
There are three recognizable types of growth pattern of squamous carcinoma: confluent, compact, and spray or finger-like growth. Confluent growth is defined as a tumor mass composed of interconnected tumor >1 mm in dimension. This type of growth is characteristic for being deeply invasive with associated stromal desmoplasia. Compact growth is associated with well-differentiated tumors, which maintain continuity with the overlying epithelium, infiltrating as a well-defined and circumscribed tumor mass, which rarely invades the vascular space. Histologically, the tumor cells resemble squamous cells of adjacent and overlaying epithelium. The spray or finger-like growth pattern is characterized by a trabecular appearance with small islands of poorly differentiated tumor cells found within the dermis or submucosa, deeper than the main tumor mass. This growth pattern is often associated with desmoplastic stromal response and a lymphocytic inflammatory infiltrate. Vascular space involvement is seen more commonly with this pattern of growth than with tumors with a compact pattern of growth.21
FIGURE 74.3. Melanoma of the vulva. A: A nodular, elevated, and darkly pigmented lesion arising from the right labia majora. B: Photomicrograph of invasive melanoma, with melanin apparent in portions of the tumor. (Courtesy of Dr. Stanley Robboy, Duke University Medical Center, Durham, NC.)
Uncommon Histologic Types
Malignant melanoma of the vulva accounts for approximately 10% of all primary tumors of the vulva, occurs predominately in White women, and has a peak incidence in the sixth and seventh decades (Fig. 74.3).22 Sometimes the tumor arises in a pre-existing pigmented lesion, and in these cases the differential diagnosis includes benign vulvar melanosis and pigmented VIN. Vulvar melanomas can be subclassified into three specific categories: superficial spreading malignant melanoma; nodular melanoma; and acral lentiginous melanoma.23 As is the case for melanomas arising in other sites, the level of invasion and tumor thickness dictate the therapy and determine the prognosis.24
Adenocarcinomas of the vulva arise predominantly in the Bartholin’s glands, although apocrine, eccrine, and Skene’s glands can also be the site of origin. In the rare instances when adenocarcinomas arise in the absence of glandular tissue, they may be of cloacogenic origin. Carcinoma of Bartholin’s gland is seen more frequently in older women and is often solid and deeply infiltrative. The overlying epidermis may remain intact, leading to misinterpretation as a benign process. Other histopathologic types are mucinous, papillary, mucoepidermoid, adenosquamous, and transitional. The transition from normal to malignant glandular tissue can be recognized in some cases. Adenocarcinomas often present with more locally advanced disease with metastases to the inguinal-femoral lymph nodes.
Paget’s disease of the vulva (intraepithelial adenocarcinoma) is seen most often in postmenopausal, older White women. The disease varies in appearance, but most often it presents as an eczematoid, red can or weeping lesion, and it can be mistakenly diagnosed as eczema or contact dermatitis (Fig. 74.4). The lesion may be flat, raised, or ulcerated and may appear whitish (leukoplakia), red (erythroplastic), or hyperpigmented. This condition has a typical histologic pattern and often stains positive for carcinoembryonic antigen. Vulvar Paget’s disease is associated with invasive carcinoma in 10% to 20% of the cases.25,26,27 The invasive disease may be an underlying adenocarcinoma of the apocrine or Bartholin’s glands, or it may be an adenocarcinoma arising elsewhere in the anogenital region.
Verrucous carcinomas of the vulva are uncommon, usually diagnosed in the fifth or sixth decade of life. Histologically these tumors are often well differentiated and have a low incidence of metastasis to the lymph node. In instances when the lesion is in early stage, excellent results are obtained with radical wide excision.28 Other vulvar malignancies arising from epidermal cell types are rare. Merkel cell tumors (neuroendocrine carcinomas) of the vulva are aggressive locally, have a high incidence of distant metastasis, and carry a poor prognosis. Basal cell carcinomas, on the other hand, seldom spread to lymph nodes and are appropriately treated with wide excision alone.29Transitional cell carcinomas may arise from the Bartholin’s glands or may also represent metastasis from the bladder and/or lower urinary tract.
The most common subtypes of vulvar sarcoma are leiomyosarcomas, malignant fibrous histocytomas, epithelioid sarcomas, and rhabdomyosarcomas. Rhabdomyosarcomas of the vulva require combination therapy, chemotherapy, and radiation, as per rhabdomyosarcoma protocols of other sites. Results of treatment with other sarcomas of the vulva are unpredictable, and wide resection and/or radical radiotherapy should be considered, given the relative inactivity of chemotherapy.
FIGURE 74.4. Paget’s disease of the vulva. A: Photo of extensive perineal disease, extending to the perianal skin. B: Photomicrograph of intraepithelial Paget cells, with copious pale cytoplasm, occurring singly or in small clusters, and appearing slightly larger than neighboring squamous cells. (Courtesy of Dr. Stanley Robboy, Duke University Medical Center, Durham, NC.)
TABLE 74.1 INCIDENCE OF LYMPH NODE INVOLVEMENT CORRELATED WITH PRIMARY TUMOR SIZE AND EXTENT
CLINICAL PRESENTATION
Vulvar pruritus is the most common presenting symptom, although women may also complain of bleeding, pain, or discharge. If there is a visible lesion on physical examination, a biopsy is required to distinguish it from other vulvar lesions such as dystrophia, benign condylomata, and VIN. Unfortunately, many women have a long delay in diagnosis due to denial or minimization of symptoms and may present with a locally advanced tumor by the time of initial evaluation. These lesions may also present with symptoms related to the invasion of regional structures, including difficulty with urination or defecation. Metastatic disease is an uncommon presenting symptom because the primary lesion is usually much more problematic, although consequences of groin and distant disease may also be seen at presentation.
PATTERNS OF DISEASE AND SPREAD
Primary Site
Approximately 70% of vulvar malignancies arise in the labia majora and minora, 15% in the clitoris, 5% in the perineum and fourchette, 5% in the prepuce Bartholin’s glands and urethra, and 5% are too extensive at presentation to classify.30
Lymphatic Spread
High-grade tumors with “spray” growth pattern and lymphatic space invasion have a proclivity to spread to the regional lymphatic nodes. The superficial inguinofemoral lymph nodes are the first echelon, followed by the deep inguinofemoral nodes. For well-lateralized lesions, metastasis to the contralateral inguinal or pelvic lymph nodes is unusual in the absence of ipsilateral inguinofemoral node involvement. Lesions of the clitoris or urethra can spread directly to pelvic lymph nodes, although this is rare without involvement of the inguinal nodes.31,32
The frequency of inguinal lymph node metastasis in surgically staged patients ranges from 6% to 50%, depending on tumor invasion and extent of disease (Table 74.1).33–37 Physical examination alone is inaccurate to assess lymph node involvement: Plentl and Friedman30 reported a 62% incidence of lymph node metastases in patients with clinically palpable adenopathy and 35% involvement in patients without clinically palpable adenopathy. In a review of clinical staging, Franklin38 noted that approximately 75% of patients with clinically suspicious lymph nodes had nodal metastasis, and 11% to 43% of patients with clinically negative nodes had metastasis to the nodes. In a Gynecologic Oncology Group (GOG) study reported by Homesley et al.39 23.9% of the patients with clinically negative inguinal nodes were found to have nodal metastasis on final pathology. When the lymph nodes were clinically suspicious, 76.2% of the patients had histologically positive nodes. In patients that have histologically positive inguinal nodes, the probability of having positive pelvic nodes is 30%.39
Multiple clinical and histologic features of the primary tumor are associated with nodal metastasis, including tumor thickness, histologic grade, capillary-like space involvement, depth of invasion, location of the tumor, and tumor size.40,41 Rutledge et al.42 also described the adverse effect on local control and survival of tumor size, clinical stage, positive inguinal or pelvic nodes, and positive margins at the primary site. When the tumor thickness is ≤1 mm, the probability of nodal metastasis is ≤3%, but with tumor a tumor thickness ≥5 mm, the probability increases to 33.3%. Depth of invasion of 1, 2, and 3 mm corresponds to a 4.3%, 7.8%, and 17% incidence of nodal involvement, respectively. It should be noted that in the vulva the thickness of the epithelium varies significantly from one area to another, in some areas being >0.8 mm thick, which can influence the relative value given to tumor thickness and depth of invasion. Measuring tumor thickness in superficially ulcerated tumors can be misleading and may lead to underestimating the depth of invasion. Perineural invasion correlates strongly with lymph node metastasis.43
In analysis of the Gynecologic Oncology Group (GOG) database on carcinoma of the vulva, several clinical and histologic tumor characteristics were identified as predictors of nodal involvement. In order of importance these are clinical node status (palpable vs. nonpalpable), grade, capillary-lymphatic space involvement, tumor thickness, and patient’s age.39,41,44 There is also a correlation between the size of the primary tumor and involvement of the lymph nodes. In Donaldson et al.’s34 series of 66 patients, the probability of having positive inguinal nodes rose from 18.9% for patients with lesions <3 cm to 72.4% for patients with primary tumors ≥3 cm. In a GOG study of 267 patients with superficial vulvar cancer reported by Sedlis et al.,41 the frequency of positive inguinal nodes was 18.1% for patients with lesions up to 3 cm in size and 29.3% for patients with lesions ≥3 cm. Extension of the primary tumor to the urethra, vagina, and anal area is associated with an increased incidence of nodal involvement and worsening of prognosis. The significance of this is reflected in the stage assignment of the patients.
Curry et al.45 noted that pelvic nodes were not involved if three or fewer inguinal nodes were positive. Similar findings have been reported by Hacker et al.46 In the GOG study reported by Homesley et al.47 of patients with positive inguinal nodes, the incidence of pelvic node involvement was 28.3% (15 of 23). In this study, there was a correlation of pelvic node involvement with the extent of inguinal node involvement. Due to the rarity of isolated pelvic nodal metastasis, the status of the inguinal nodes determines the management of the pelvic nodes. Although deep pelvic node involvement is an ominous sign, one-fourth to one-third of the patients are still potentially curable, particularly if only a few nodes are involved.31,33,45
Distant Metastases
Hematogenous dissemination generally occurs late in the natural history of the disease, with the most common sites being the lungs, liver, and bones. The development of distant metastasis portends a very poor outlook.
PROGNOSTIC FACTORS
Lymph node metastasis is the most important prognostic factor in patients with vulvar cancer. The presence of inguinal node metastases is accompanied by a 50% reduction in long-term survival.48,49 Pelvic nodal metastasis has an even more profound negative effect on survival.31,33,45 Kurzl and Masserer50 analyzed 124 patients with various stages of vulvar carcinoma treated with simple vulvectomy alone and local/inguinal irradiation. They found that age, disassociated growth, lymphatic spread, thickness, and ulceration of the primary tumor were important prognostic factors. In a detailed analysis of a GOG clinicopathologic study of 558 women with vulvar cancer, two significant risk factors were identified that predispose for recurrence in the vulva: tumor size >4 cm and capillary lymphatic space involvement.44 If either of these factors was present, the risk of local recurrence after radical vulvectomy was 20.7% (30 of 184), but if neither factor was present, the risk of local recurrence was only 9.2% (37 of 404). In this study the depth of invasion did not predict for vulvar failure.
In an analysis of formalin-fixed tissue specimens, Heaps et al.51 demonstrated a sharp rise in the incidence of local recurrence for tumors with microscopic, surgical margins <8 mm. They suggested that this would correspond to a minimum margin of 1 cm in fresh, unfixed tissue. Although the frequency of local recurrences correlates with the adequacy of the margins of the surgical resection, when dealing with larger or thicker tumors or when they involve midline structures, adequate surgical margins may be difficult to obtain.
Lymph node extracapsular tumor extension has been noted in several series and it is known to have a negative effect on prognosis. Origoni et al.52 evaluated the significance of the size of the metastases in the lymph nodes, the number of positive lymph nodes, and extracapsular extension of the disease and found that the presence of any one of these factors worsened the prognosis. Extracapsular tumor extension as an independent adverse prognostic factor on survival was also described by van der Velden et al.53
INITIAL EVALUATION
A thorough examination of the genitourinary system is warranted in all women with vulvar cancer because the disease may be multifocal. Examination of the vagina, cervix, perianal skin, and anal canal is of particular importance in order to delineate the extent of disease and to identify synchronous lesions. Special attention as well is paid to the inguinofemoral basins for clinical detection of lymphatic spread.
Imaging studies may not be necessary in early lesions that may be approached with surgery as the first treatment modality. However, imaging in women with locally advanced disease or with clinically suspicious lymph nodes may aid the clinician in selecting the most appropriate treatment. Computed tomography (CT) scans may identify concerning lymphadenopathy in the inguinofemoral chains, pelvis, or para-aortic regions.54 Contrast-enhanced magnetic resonance imaging (MRI) may also aid in the delineation of the primary lesion, as well as with the evaluation of inguinal lymph nodes, with a sensitivity of 80% and a specificity of 88%.55 Although clinically or radiographically detected inguinal nodes may be quickly evaluated with ultrasound-guided fine-needle aspiration, a negative result does not rule out involvement.56 Fluorodeoxyglucose-positron emission tomography has been used to evaluate the groin prior to surgical evaluation, with a sensitivity of 67% and a specificity of 95%.57 It should be noted that the sensitivity of all imaging modalities available are insufficient to omit surgical evaluation in women with a high risk of nodal involvement.
TABLE 74.2 VULVAR CANCER: 2009 AMERICAN JOINT COMMITTEE ON CANCER (AJCC) STAGING AND CORRESPONDING INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING
STAGING
The staging system first adopted in 1983 was based on clinical findings. The system was modified in 1988 to give the clinical status of the nodes more importance. In 1997 the staging was revised again to create a separate category for minimally invasive lesions, stage IA, emphasizing the need for histologic assessment of the inguinal nodes in all patients presenting with primary tumors with >1 mm depth of invasion.
The most recent Federation of Gynecology and Obstetrics staging revision was performed in 2009 and contains significant changes from the 1988 framework (Table 74.2).58,59 Stage IB now includes primary lesions >2 cm in size (previously stage II), and stage II includes lesions with involvement of adjacent perineal structures (previously stage III). Stage III is now divided into three substages, reflecting the importance of the number and size of inguinal nodes involved and the prognostic significance of extracapsular extension. Presence of pelvic nodal metastases remains stage IVB disease.
GENERAL MANAGEMENT
The treatment of carcinoma of the vulva is challenging for multiple reasons. In general patients with this disease are older and have comorbidities. The tumor, by virtue of its location, can easily involve adjacent organs such as the bladder and the rectum, and the frequency of nodal involvement is high. Because of its relatively low incidence, most published reports include rather small and heterogeneous groups of patients. Management of carcinoma of the vulva is further complicated by the major psychosexual impact that the treatment can have on patients. For the aforementioned reasons it has been difficult to study this disease and to develop treatment guidelines.
The management of vulvar carcinoma has undergone very significant changes in the last few decades. En bloc resection of the primary tumor and inguinal node dissection, which used to be the standard of care, have been replaced by multimodality therapy, with the surgery being more tailored to the extent of the disease. This change follows the recognition of the morbidity associated with radical surgery, the improved results achieved with multimodality therapy, and the recognition of the negative impact that radical surgery can have on sexual function and body image.6,60,61 Although radical surgery retains a very important place in the management of vulvar cancer, it is no longer the mainstay of the treatment. The likelihood of controlling the primary tumor with surgery largely depends on the adequacy of the margins of resection, and it is not necessary to remove the entire vulva. A clear margin of about 1 cm in all directions is sufficient to achieve a high rate of local control of the primary tumor.51
There have been refinements in the surgical technique that have made the procedures more tolerable. Examples of such improvements include primary closure of the perineal wound, the use of the sartorius muscle to close the surgical defect in the inguinal area, and the use of separate incisions for the resection of the primary tumor and the inguinal nodes. These developments have resulted in a decrease in operative mortality and morbidity.
In recent decades there have been also significant advances in all aspects of radiation therapy that apply to the treatment of carcinoma of the vulva. The technical resources available now make it possible to deliver effective doses of radiation to the vulvovaginal and inguinal regions with less acute and late morbidity. With high-photon-energy units, well-collimated fields, multileaf collimators, electron beams of different energies, and intensity-modulated radiation therapy (IMRT), radiation is now delivered to the primary disease and lymph nodes with precise account of the differences in contour, tissue thickness, and extent of the disease. It is possible to tailor the treatment to the specified treatment volume while keeping the dose to the normal tissues within acceptable limits of tolerance. Brachytherapy may also be used as primary treatment in very selected cases or in combination with external beam to bring the dose higher to limited volumes.
Perhaps the most significant advance of recent decades in the management of cancer patients is the use of more than one treatment modality concurrently or sequentially. Chemotherapy, radiation, and surgery in sequence and/or in combination lessen the impact of any one modality and can achieve functional organ preservation with at least comparable or improved local tumor control and survival (Fig. 74.5).
Early Invasive Disease
Surgery
In the past even patients with early stage IB disease were considered to have diffuse disease, and a radical vulvectomy was considered the standard of care, yielding 90% survival rates but with considerable physical and emotional sequelae.51,62 Now, small, favorable lesions, ≤2 cm in diameter and ≤5 mm in depth, are managed with wide, local excision rather than a radical vulvectomy, with very satisfactory outcomes in every respect. The local recurrence and disease survival rates are similar with either procedure, ranging from 6% to 7% and 98% to 99%, respectively.63 However, anterior lesions close to the clitoris may not be amenable to wide local excision and may require a radical vulvectomy to obtain satisfactory margins.
Small, well-lateralized, T1 lesions with negative ipsilateral groin nodes have <1% risk of contralateral groin involvement, and treatment of the contralateral groin is not necessary.63 Poorly differentiated tumors, with >5-mm invasion and vascular space involvement, are at higher risk for inguinal node metastasis, and both groins must be evaluated and managed as needed.39 Centrally located lesions, within 1 cm of the introitus, are considered midline lesions and may be treated with local excision, if possible, but both groins are at risk. A deep node dissection is recommended if the superficial nodes are involved. Traditionally, primary tumors >2 cm have been treated with radical vulvectomy and bilateral groin dissection because of the high risk of nodal involvement. The indications and extent of surgery for the inguinal nodes are under re-evaluation and are the subject of further discussion later in this chapter.
FIGURE 74.5. Treatment algorithm.
Radiation Therapy
In the setting of early invasive disease treated with wide local excision, radiation to the tumor bed may be advised to prevent local recurrence. As noted previously, pathologic features associated with higher risk of local recurrence at the primary site include lymphatic-vascular invasion (LVI), depth of invasion >5 mm, margins <8 mm, and microscopically positive margins.51 Faul et al.64 reported a retrospective study of 62 patients with close (≤ 8 mm) or positive surgical margins that found that local recurrence was significantly reduced from 58% with observation to 16% with postoperative radiation. Although postoperative radiation reduces the incidence of local recurrences, some recurrences may be salvaged with surgery, resulting in equivalent survival. However, in the absence of randomized trials, women with positive margins, margins <8 mm, deep invasion, and/or LVI should also be considered for adjuvant radiation. Definitive, preoperative, and postoperative radiation, with or without chemotherapy, are treatment options in patients with tumors close to the urethra, clitoris, or anal sphincter because it can be difficult to obtain an adequate margin.
The role of radiation in the management of inguinal and pelvic nodes was evaluated in a GOG trial reported in 1986.47 In this trial patients underwent bilateral inguinal lymphadenectomy, and those with positive groin nodes were randomized to either pelvic lymphadenectomy or radiation to the pelvis and bilateral groins. The radiation group had significantly lower groin recurrence rate, 5.1% (3 of 59), compared to 23.6% (13 of 55) for the group that did not receive radiation. This translated into a 2-year significant survival benefit of 68% versus 54% (p = .03) in favor of the group that received postoperative radiation. Subgroup analysis of this study showed that the benefit was seen primarily in patients with more than one pathologically positive node. However, an exploratory analysis of the Surveillance, Epidemiology, and End Results data set in patients with one node positive revealed a significant survival difference in patients with <12 nodes submitted, suggesting that the benefit of radiation may be greater in patients with an insufficient nodal dissection.65 Based on the entry criteria for the GOG study, adjuvant radiation to the pelvis and both groins should be considered for all those with nodal involvement. Patients with extracapsular extension (ECE) of tumor in the nodes or with residual disease in the inguinal areas should receive postoperative radiation to the pelvis, the groins, and the primary tumor bed area because ECE predisposes them for recurrence at the primary and the lymph node basins.53
Advanced Disease
Surgery alone for patients with advanced disease has yielded disappointing results, stimulating interest in multimodality treatment.66,67 Concurrent chemoradiotherapy has been used for nearly three decades in preoperative, postoperative, and definitive settings. This multimodal approach is considered the standard of care.68–77 Exenterations are now considered only for patients with advanced local recurrences after initial therapy and for whom there is no other alternative. In these highly selected patients, results can be acceptable in terms of the control of the disease.78,79–80,81 However, exenterations have a very significant psychosexual impact on patients, even when measures are taken to restore some sexual function.82
Management of Patients with Histologic Variants
Melanoma
Melanoma is the second-most-common malignancy of the vulva. The treatment should be surgical, if possible. The prognosis is poor in general, with a 5-year overall survival of approximately 35%, and is worse in patients who have one or more of the following features: deep invasion, ulceration, nodular growth pattern, epithelioid cell type, and high mitotic rate.83,84,85 The prognosis is also worse in older patients. The extent of the surgery needed to achieve local control depends on the size of the lesion and the depth of invasion, similar to melanomas in other parts of the body. Wide local excision is acceptable, as long as negative margins are obtained. In a study of 32 patients treated at the Royal Marsden Hospital in London, there was no difference in the outcome between patients treated with wide local excision and those treated with more radical surgical procedures.86 Radiation may be considered for patients with positive margins or positive lymph nodes or for palliation of symptoms. As with melanomas of other sites, the prognosis is guarded due to a propensity for distant recurrence.
Bartholin’s Gland Carcinoma
Carcinomas of the Bartholin’s gland comprise 5% to 7% of all primary vulvar cancers. The recommended treatment consists of wide local excision and ipsilateral lymph node dissection. Contralateral groin dissection is reserved for patients with clinically suspicious nodes or for patients with involvement of the ipsilateral nodes. Similar to other types of vulvar carcinoma, pelvic node dissections are not routinely recommended. Radiation to the pelvis is advised if involvement of the pelvic nodes is suspected. The role of radiation for Bartholin’s gland carcinoma has been studied by Copeland et al.87 and Leuchter et al.88 These two studies suggest that adjuvant radiation to the vulva and regional nodes after conservative surgery may decrease local recurrence, with 7% recurrence with radiation and 27% recurrence without it in the Copeland et al.87 study. Five-year survival of 67% was obtained by Cardosi et al.89 in patients who were found to have close margins and were treated with primary surgery and adjuvant radiation.
Verrucous Carcinoma
Verrucous carcinomas are locally invasive tumors that present as fungating, ulcerative masses. These lesions are usually treated by wide local excision. Inguinofemoral dissections are not recommended routinely due to the rarity of nodal metastases. The literature regarding vulvar verrucous carcinomas consists largely of case reports. with the exception of the series by Japaze et al.90 This study was based on 24 patients, 17 of whom were treated with surgery only and 7 of whom were treated with surgery and radiation. In the surgery group only 1 patient developed recurrence and died as a result of it. In the radiation group 4 patients developed recurrence, and all died from the disease. Although it is difficult to draw definitive conclusions from this small series, there is no convincing data to recommend the routine use of radiotherapy for this disease. In addition, there is no sufficient evidence to support the notion that radiation induces anaplastic transformation.91
SURGERY
Primary Tumor
The surgical approach to vulvar cancer has evolved from the traditional en bloc radical vulvectomy for most patients to a more individualized and less radical procedure, alone or in combination with radiation and chemotherapy. For lesions not involving anus, vagina, or urethra, a radical local excision (also referred to as wide local excision, radical wide excision, or modified radical vulvectomy) is usually performed. At surgical resection, the depth of the excision should be to the deep perineal fascia. Excision of 2-cm margins of grossly normal-appearing tissue is recommended when possible, with a goal of obtaining at least 1-cm microscopic margins following tissue processing. If the tumor involves or abuts the clitoris, preservation of this structure may not be possible.
Radical vulvectomy is reserved for patients with large or multifocal lesions in whom preservation of normal vulvar tissue is not possible or would not serve a functional or reconstructive benefit. When the anus, vagina, or urethra are involved by malignancy, extended radical vulvectomy or pelvic exenteration is required to clear disease surgically.78,92 Due to the high morbidity and operative mortality of extensive surgery, preoperative or primary chemoradiation should be considered for organ preservation.
Inguinofemoral Lymph Nodes
Attention to risk factors for nodal involvement is very important because inguinofemoral node dissection can lead to morbidity and sequelae. The main complications of groin surgery are wound breakdown and lower-extremity lymphedema. Although wound breakdown almost always heals successfully by secondary intention, chronic lower-extremity edema is very difficult to deal with and can lead to significant long-term disability. To reduce the frequency and the severity of these complications, an effort is made to identify patients in whom the extent of the node dissection can be decreased or eliminated altogether without compromising the likelihood of control of the disease.
Patients with small (<2-cm diameter) superficial squamous cell carcinomas with a depth of invasion 1 mm or less and no lymph vascular invasion have a very low risk of nodal involvement, and the groin dissection may be omitted.36,93,94 For lesions with >1-mm invasion, groin node assessment should be performed in the form of superficial inguinal lymphadenectomy or sentinel node procedure. Small (<2 cm), lateralized lesions may be treated by unilateral groin dissection, whereas for midline and clitoral lesions and for those >2 cm in diameter, bilateral groins should be assessed. For patients undergoing primary surgery, palpable inguinal nodes should be removed if present.
The need to perform bilateral inguinal node dissection in patients with unilateral vulvar lesions, as well as the need to dissect the deep nodes whenever a superficial node dissection is carried out, has been re-examined in light of the additive morbidity of each procedure. When bilateral superficial and deep inguinal node dissections are performed, the potential for wound breakdown and lower-extremity lymphedema increases.37,95 When a unilateral dissection is indicated and nodes are found to be negative, a contralateral node dissection is not required due to the low likelihood of contralateral metastasis.96,97 The deep inguinal node dissection is usually omitted, based on the fact that if the superficial nodes are free of tumor, the deep nodes are rarely involved.98 However, control of the disease in the lymph nodes is of utmost importance because most patients who develop groin failure will die as a result of the recurrence.94,99
Assessment of the groin nodes may be accomplished via full superficial inguinal dissection or alternatively via a sentinel lymph node procedure alone if performed by groups experienced in this technique. In the multicenter Groningen International Study on Sentinel Nodes in Vulvar Cancer, a sentinel node procedure using radioactive tracer and blue dye was performed in 623 groins and resulted in a 2.3% groin recurrence rate following a negative sentinel node.100 This compares favorably to the 5% ipsilateral groin recurrence rate following negative full superficial inguinal dissection in a prospective GOG study of low-risk vulvar cancer.99 Patients who underwent a sentinel but not a full node dissection had significantly lower groin wound breakdown (12% vs. 34%) compared to those who went on to a full inguinal dissection following the sentinel procedure. Optimal lesions for sentinel node procedures are those with small (<4 cm), unifocal lesions, and each center must have had experience with at least 10 prior sentinel procedures followed by full dissection for confirmation of proper technique.
Intraoperative diagnosis of inguinal node metastasis necessitates further diagnostic or therapeutic procedures. Because there is no established sentinel node metastasis size cutoff below which withholding further treatment of the groin can be considered safe, all women in whom a sentinel node is found to be positive should have a full ipsilateral groin dissection and/or radiotherapy to the groin.101 In the case of non–sentinel node metastasis that is diagnosed intraoperatively, the options are to dissect the deep nodes as well as the opposite groin or to cover both groins with adjuvant radiotherapy. Standard adjuvant treatment for inguinal node metastasis consists of both inguinal and pelvic radiotherapy.47
Women with fixed or ulcerated inguinal nodes are rarely curable with surgery alone. These patients should have a biopsy to document the nodal involvement and should be treated with combined radiation and chemotherapy, followed by surgery for the primary and the nodes if the response to the therapy has been good and the nodes are resectable.74,102
Pelvic Lymph Nodes
Patients with clinically or pathologically positive groin nodes are at risk for having contralateral groin and pelvic nodal involvement. Thus, the status of the groin nodes is to be taken into consideration when determining the management of the pelvic nodes. The randomized GOG trial of pelvic node dissection versus pelvic node radiation showed that control of the disease in the pelvis could be achieved with either form of therapy.47 Radiation to the pelvic nodes is preferred over surgery because women in need of treatment to the pelvis often also require radiation to the primary and/or inguinal nodes.
RADIATION THERAPY
The standard of care for early lesions is surgical resection; however, selected patients with small central lesions may be considered for definitive radiation, particularly when the lesions are in close proximity to the urethra, clitoris, or anus. There are few published series of radiation alone used as definitive therapy for vulvar cancer.103–105 The reported series include patients with recurrent disease postsurgery and patients who are not medically suitable for surgery or have declined it. In Ellis’s103 series of 65 patients treated with brachytherapy and or external beam, the crude 5-year survival rate was 23% (15 of 65). Twelve of these patients were free of disease. The local control rate was 40%, and 9 patients developed necrosis. Slevin and Pointon105 reported on the results of 58 patients treated also with brachytherapy and/or external beam, depending on the extent of the disease. The crude 5-year survival rate was 26% (15 of 58). In this series the local control rate was also 40% (23 of 58). The survival was better in the newly diagnosed group, 39% (9 of 23), compared to 17% (6 of 35) for the group of patients treated for recurrence. Nine patients developed necrosis. These series reflect the difficulty of achieving appropriate curative doses for gross disease with radiation alone without the aid of radiosensitizing chemotherapy.
Brachytherapy has been used for inoperable vulvar cancer and as a boost to the primary tumor and/or to the lymph nodes. The efficacy of this treatment is difficult to evaluate because of the variability of the clinical situation in which this type of treatment may be employed. A high rate of necrosis was reported in up to one-third of the patients.103 A series from the Centre Alexis Vautrin Institute in France describes 34 patients, 21 with primary and 13 with recurrent disease, treated with brachytherapy only.104 The median brachytherapy dose was 60 Gy, with a range of 53 to 88 Gy. In the group of 21 patients who underwent brachytherapy as primary treatment, 3 patients developed locoregional recurrence, for a 5-year local control rate of 80% and a disease-specific survival of 70%. In the group of 13 patients who were treated for recurrence, 8 developed local recurrence, with or without disease at other sites, for a local control rate of 19%. Of the entire group of 34, 5 patients developed necrosis. This relatively low complication rate most likely reflects that extensive experience and high quality of the brachytherapy carried out in this institution. The authors of this study advocate brachytherapy for primary vulvar cancer if the patient refuses surgery or if surgery is contraindicated. Nonetheless, due to the significant risk of necrosis, use of brachytherapy should be limited to very selected cases and performed by experienced practitioners.
In most instances radiation is used in combination with surgery and/or chemotherapy. The objective of radiation varies with the target: regions with lymphatic spread or the primary tumor in the perineum. For instance, in patients with advanced, unresectable nodes but less advanced primary tumor, complete control of the primary may be obtained with the combination of chemotherapy and radiation, obviating the need for surgery to the primary while making the nodes amenable to surgery.74,106 Concurrent chemotherapy and radiation may also be used for definitive treatment. For patients with advanced primary tumors and limited nodal disease it is possible to render the primary resectable while sterilizing the lymph nodes. Radiation can also play a significant role for palliation of symptoms.
Treatment Volume and Technique
The radiation target volume usually encompasses the vulva, both groins and the lower pelvic nodes. Use of a midline block to spare the perineum and vagina should be avoided except for highly selected situations because this may increase the risk of local recurrence.107 The following factors increase the risk of vulvoperineal recurrences: close or positive margins (<8 mm), primary tumor size >4 cm, lymphovascular space invasion, deep invasion (>9 mm), tumor thickness >1 cm, infiltrative growth pattern (or “spray” pattern), >25% keratin in the tumor, and high mitotic rate (>10 per 10 high-power fields).51 All patients found to have more than one positive inguinal node should receive postoperative radiation to the inguinal and pelvic node areas because this improves overall survival.47 The pelvis must be included in the field because patients with positive inguinal nodes have a 28% incidence of pelvic node involvement.
When planning the treatment, careful attention should be given to the location and depth at which the dose is calculated for the inguinal area. The depth of the inguinal vessels can be highly variable, ranging from 2.0 to 18.5 cm.108CT- or MR-based three-dimensional planning is essential to establish the location, extent, and depth of the inguinal nodes because underdosing of the nodes may easily occur, predisposing to local recurrence. Figure 74.6 demonstrates the distribution of inguinal nodes and can be used as a guideline for the design of an inguinofemoral treatment field.109 At the time of simulation, markers should be placed on the primary, the lymph nodes, and scars from previous surgery to document the extent of the disease.
FIGURE 74.6. Topographic distribution of inguinal lymph node metastases in patients with carcinoma of the vulva–vagina–cervix (triangles), urethra (squares), or anus–low rectum (circles). (From Wang CJ, Chin YY, Leung SW, et al. Topographic distribution of inguinal lymph nodes metastasis: significance in determination of treatment margin for elective inguinal lymph nodes irradiation of low pelvic tumors. Int J Radiat Oncol Biol Phys 1996;35:133–136; copyright 1996, with permission from Elsevier.)
FIGURE 74.7. Treatment borders demonstrating the wide anterior field (outer border) and the narrow posterior field (shaded region).
Medium- or high-energy photon beams with anteroposterior/posteroanterior (AP/PA) fields with the patient in the supine position and with the thighs straight or in the “frog-leg” position are recommended for the delivery of external beam. The frog-leg position minimizes the bolus effect from skin folds. Documentation of the primary tumor with photos, tattoos, or fiducial markers prior to therapy may be used for objective evaluation of response to the treatment and for subsequent design of reduced fields or for brachytherapy boost. The superior border of the pelvic field should extend to the middle of the sacroiliac joints to cover the external and internal iliac nodes. If a patient has internal or external iliac node involvement, the superior border should be extended to the L3/4 interspace to cover the common iliac nodes. The inferior border should cover the entire vulva and the most superficial, inferior inguinal nodes. Laterally, the pelvic field extends 2 cm laterally to the widest point of the pelvic inlet. Although there are no data regarding scar recurrences, it is common practice to include the inguinal node dissection scars in the radiation field.
Depending on whether the inguinal/femoral lymph nodes and/or pelvic lymph nodes are to be included in the radiation volume, different field configurations may be used. To reduce the dose to the femoral heads while delivering an adequate dose to the inguinal nodes, various techniques are available. One approach is to use a wide AP field that includes the pelvic and inguinal areas, with a narrow posterior field covering only the pelvis and sparing the femoral heads. The photon fields are weighted equally, and the inguinal dose is supplemented by separate anterior electron fields matched to the pelvic field (Fig. 74.7). Bolus material should be used to ensure adequate dose to the superficial portions of the groin. An alternative method consists of using a wide AP field and narrow PA field, with a partial transmission block placed in the central portion of the AP field. The desired dose at a specified depth is delivered to the inguinal nodes through the AP field.110 The degree of central anterior beam attenuation is calculated so that the midpoint of the pelvis receives equal doses from the AP and PA beams. This technique eliminates the dosimetric problems of photon/electron field matching, as well as the potential for daily setup variation, but the design of a precise partial transmission block is difficult. Another method consists in using matched AP/PA fields to include the primary and the pelvic nodes and treating the groins through separate anterior electron fields. This approach has the advantage of relatively easy setup, but the main drawback is ensuring an adequate dose at the match line, particularly when the match line is over gross disease. An example of an anteroposterior radiation field encompassing the inguinal/femoral and pelvic lymph nodes is shown in Figure 74.8.
Moran et al.111 described a modified segmental boost technique using multileaf collimators with a single isocenter technique and a wide AP field to cover the vulva, pelvis, and groins and a narrow PA field to cover the vulva and pelvis. The supplemental anterior photon groin fields are angled such that the central axis is coplanar with the divergence from the PA field. The medial blocking of the groin fields is designed to match the divergence from the PA field. This technique provides a more homogeneous dose distribution and is easier to reproduce on a daily basis.
IMRT is now often used to treat the pelvis and inguinal nodes.112,113 Beriwal et al.112 reported 15 patients treated with IMRT using a median of seven fields. The clinical tumor volume (CTV) was defined as a 1- to 2-cm margin around bilateral external iliac, internal iliac, and inguinofemoral nodes, as well as a 1-cm margin around the entire vulvar region. Gross tumor was also expanded by 1 cm for the CTV. The planning treatment volume was defined as 1-cm margin beyond the CTV, and the prescription dose was 43 to 48 Gy for preoperative treatment and 50 Gy for postoperative treatment, delivered partly on a twice-daily schedule. This early experience yielded reasonable clinical response, with 13 of 15 patients having no evidence of disease at last follow-up. This technique also resulted in improved dose conformality and lower doses to normal structures, including rectum, bladder, small bowel, and femoral heads. A second publication by the same group expanded on the preoperative experience with 18 patients treated with concurrent cisplatin and 5-fluorouracil (5-FU), resulting in a pathologic complete response (pCR) rate of 64% and a 2-year cause-specific survival of 75%.113 However, it must be noted that careful quality assurance is required when using IMRT. Placement of thermoluminescent dosimetry chips in the inguinal and perineum areas is recommended to document the dose given to the skin and target areas (Fig. 74.9).
FIGURE 74.8. A: Portal for elective irradiation of regional lymphatics in patients with no clinical evidence of inguinal lymph node involvement. B: Portal for irradiation of pelvic and inguinofemoral lymph nodes and vulvar area. A final boost to the positive inguinal lymph nodes may be given with further field reduction. C: Simulation film of portal covering pelvic and inguinofemoral lymph nodes and vulva.
Preoperative Radiation Therapy with Concurrent Chemotherapy
As the treatment for vulvar cancer has evolved with the goal of decreasing the sequelae of radical surgery and to maximize functional outcome, multimodality therapies have become the standard of care, particularly for patients with advanced stages of the disease.74 After initial concurrent chemoradiation and healing of the reaction, the response to the therapy at the primary site and the lymph nodes is assessed. If there is complete clinical regression of the disease at the site of the primary, one option is to perform biopsies of the primary site, foregoing resection if there is a pathologic complete response.106 In general, it is recommended to carry out the inguinal node dissection whether or not there has been complete response of the lymph nodes because residual disease is often found in the lymph nodes.74 It also should be noted that whereas recurrences at the primary site following surgery or chemoradiation are potentially salvageable, nodal recurrences are not.
The preoperative radiation dose for the primary and the lymph nodes areas should be 45 to 55 Gy.67,114 The most common chemotherapeutic agents used have been 5-FU, cisplatin, and mitomycin-C. Acute mucocutaneous toxicity from combined therapy is rather severe, and a preferably short treatment break during the course of the treatment is often required.73,74,106,115 In a GOG trial for patients with advanced primary and/or nodal disease, the radiation treatment consisted of 170 cGy twice daily on days 1 to 4 and 170 cGy once a day on day 5 and days 8 to 12, for a dose of 2,380 cGy.74,106 Cisplatin, 50 mg/m2, was given on day 1, and 5-FU, 1,000 mg/m2 by a 24-h infusion, daily on days 1 to 4. The combined cycle of chemotherapy and radiation was repeated after about a 2-week break, thus delivering a total radiation dose of 4,760 cGy. In the locally advanced cohort, the pCR rate was 34%, R0 resections were possible in 77% of the patients, and 55% were alive and without disease at last follow-up. In the group of patients with advanced nodal disease, the nodes became resectable in 83%, with a pCR rate of 40% in those who underwent surgery, with 43% of the patients being alive and disease free at last follow-up.74
A follow-up GOG study was recently presented by Moore et al.102 in which T3 or T4 tumors were treated with a total dose of 5,760 cGy (180 cGy/fraction) and weekly cisplatin (40 mg/m2). In an interim report, 40 of 58 (69%) patients were able to complete the protocol per plan, 37 of 58 (64%) achieved a complete response, and 29 of 58 (50%) had a pCR on surgical biopsy. Due to these encouraging initial results, the GOG is moving forward with radiation combined with weekly cisplatin as a potential backbone for continuing study.
FIGURE 74.9. Intensity-modulated radiation therapy for vulvar cancer. This patient had a lesion of the posterior labia minora, involving the fourchette and the distal vagina. Three axial views are shown of the conformality of the 100% isodose line (yellow) and the planning treatment volume contour (shaded red volume). The central dose in the middle axial level is the superior margin for the vagina, added in this case due to the distal vaginal involvement.
TABLE 74.3 STUDIES OF CONCURRENT RADIATION AND COMBINATION CHEMOTHERAPY AS PRIMARY TREATMENT FOR ADVANCED VULVAR CANCER
Definitive Chemoradiation Therapy
Definitive chemoradiation is used for patients with advanced tumors considered unresectable at presentation or for patients who are medically inoperable (Table 74.3). This may be used when the tumor does not become resectable in the midst of preoperative intent chemoradiation or as an upfront alternative to surgically based treatment. In these patients, chemotherapy should be continued throughout the entire course of radiation for the purpose of radiosensitization of the tumor in the treatment volume and possible eradication of subclinical disease outside of the radiation field. With appropriate field reductions, the radiation dose should be brought up to 60 to 70 Gy. The total dose to certain areas is dependent upon the location and extent or bulk of the disease, the response to the therapy, and the estimated tolerance of the area requiring the high radiation dose. Often, it is the tolerance of normal tissue that limits the dose to ≤65 Gy.
Selected patients without clinically involved nodes and at very low risk of having nodal involvement may be treated to the vulvar area alone. The treatment may be delivered using electrons or low-energy photons. When the treatment is given with electrons only, a generous margin around the primary tumor should be used because the dose decreases toward the periphery of the field. Bolus material should be used also to avoid underdosing the surface of the tumor.
There is little in the way of comparative prospective trials for chemotherapy selection with concurrent treatment; however, a recent retrospective series from Dana-Farber/Brigham and Women’s Cancer Center and Massachusetts General Hospital does shed some light.116 In this series of 44 women, 24 of whom were treated definitively without surgery, 16 received weekly platinum-based regimens and 28 received a 5-FU–based regimen every 3 to 4 weeks. The 2-year overall survival (74% platinum, 70% 5-FU), disease-free survival (62% platinum, 56% 5-FU), and locoregional recurrence (31% platinum, 33% 5-FU) were no different. The grade 3 or higher skin toxicity was higher with weekly platinum (62% platinum, 32% 5-FU), but the nonskin toxicity was higher with 5-FU (13% platinum, 46% 5-FU). Given these data and a recent GOG report of weekly platinum in preoperative treatment, weekly platinum at 40 mg/m2 is a reasonable option for concurrent treatment.102
TABLE 74.4 CHEMOTHERAPY FOR VULVAR CANCER
Postoperative Radiation Therapy
Adjuvant postoperative radiation can be used when limited surgery has been performed for organ conservation or when the surgical specimen reveals adverse pathologic features and local recurrence is likely to occur.117 Local recurrence is a major cause of failure in all patients irrespective of the stage.118 Patients with positive or close (<8 mm) margins, LVI, and depth of tumor invasion >5 mm should undergo postoperative radiation because these are factors increase the likelihood of local recurrence.51 Patients with close margins may be considered for re-resection prior to radiation, particularly if the area in question is not in close proximity to the urethra, clitoris, or anus. Patients with more than one involved inguinal node, extracapsular extension, or gross residual nodal disease should receive adjuvant radiation to both groins and the pelvis. When the surgical margins are clear and there is no pathologic indication to treat the vulva, a midline block can be used to avoid the reaction and the sequelae of the treatment to the vulvar area, although this practice raises the probability of local recurrence.107
Adjuvant radiation to the primary site may be delivered with either photons or en face electrons with bolus. When treating a large area of the vulva and groins, AP/PA photon fields as described before are appropriate. If the area of involvement is small, a direct electron field can be used, and the groins are treated with separate fields. When it is indicated to treat the primary tumor bed area for possible residual microscopic disease, a dose of 50 Gy is recommended. If there is extracapsular extension of tumor in the lymph nodes, the dose to the groins should be carried to 50 to 60 Gy. If there is gross residual disease postsurgery, the dose to the area should be brought to 65 to 70 Gy.
CHEMOTHERAPY
The use of chemotherapy alone is usually reserved for patients having advanced, inoperable, or recurrent disease.
Single-Agent Chemotherapy
There is limited experience with single-agent chemotherapy for the treatment of vulvar cancer (Table 74.4). The single agents cisplatin, piperazinedione, mitoxantrone, and etoposide have all been evaluated prospectively by the GOG with disappointing results.119–121 Paclitaxel has moderate activity, with a 14% response rate described in a phase II trial of the European Organization for Radiation Therapy and Chemotherapy (EORTC).122 Bleomycin has been tested in older studies as a single agent in both the neoadjuvant and recurrent settings with a high initial response rate.123,124 Limited objective responses have also been reported in a small number of patients with doxorubicin.125
Multiagent Regimens
Several combination chemotherapy regimens have included bleomycin, which is also associated with considerable pulmonary toxicity.126 The Gynecological Cancer Cooperative Group of the EORTC conducted two phase II studies using a regimen of bleomycin, 5 mg intramuscularly, given on days 1 to 5, methotrexate 15 mg orally on days 1 and 4, and lomustine, 40 mg orally on days 5 to 7 in the first week, followed by bleomycin 5 mg intramuscularly and methotrexate 15 mg orally on days 1 and 4 (modified to day 1 only in the second study) for 5 additional weeks.127,128 The overall response rate was between 55% and 65%, with a complete response rate of 8% to 11%. Unfortunately the toxicity was high. Severe mucositis was noted in up to 21% of patients, 13% had severe infections, and up to 7% developed severe pulmonary toxicity, with one death in each of the two studies possibly due to pulmonary toxicity. Other severe toxicities included nausea/vomiting and hematologic, renal, and mucocutaneous reactions. A second group prospectively evaluated cisplatin, bleomycin, and methotrexate in the neoadjuvant setting and reported a 10% response rate of the primary tumor but a 67% response rate of nodal disease after two cycles of treatment.129
In other small series, combinations of cisplatin with a second agent such as vinorelbine or 5-fluorouracil showed significant activity.130,131 In a recent small report of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil, at least a partial response was observed in all 10 patients. Of interest, 3 patients were treated with cisplatin alone in the same series with no responses.131
Biologic Agents
Epidermal growth factor receptor (EGFR) is a tyrosine kinase that is overexpressed in many squamous cell carcinomas of the vulva.132 Erlotinib, an EGFR inhibitor, was reported to have significant activity in a case report,133 which resulted in development of a phase II trial of this agent for women with measurable disease in the neoadjuvant or recurrent setting. Of 19 patients on this study, 5 (26%) partial responses were reported, whereas an additional 7 (37%) had stable disease. The most common toxicities were diarrhea, fatigue, and skin changes.134 In one other case report, the EGFR inhibitor cetuximab elicited a partial response when administered in combination with cisplatin.135Further studies may elucidate the role of EGRF-targeted agents and other biologics in the treatment of this disease.
In conclusion, paclitaxel and erlotinib are single agents showing activity against advanced vulvar cancer in phase II studies. Combination chemotherapy regimens, particularly those including cisplatin and 5-fluorouracil, yield improved response rates, but they are associated with significant toxicity. Bleomycin as single agent and in combination also appears to have activity but with risk of significant pulmonary toxicity. In the recurrent or metastatic setting, the choice of regimen requires consideration of single agents having modest activity but low toxicity versus combination regimens that carry both higher response rates and higher toxicity.
TREATMENT SEQUELAE
The adverse effects of treatment can be classified as acute or chronic and depend on the treatment modality or modalities used, as well as the intensity of the treatment. With early-stage disease and appropriately limited surgery to the primary site, the acute surgical complications are relatively minor and essentially consist of wound infection and hematomas. With more extensive surgery the frequency and degree of the complications can be far more significant. With single “longhorn” or “butterfly” incisions for bilateral inguinal lymphadenectomies and for resection of the primary, wound infection, necrosis, and breakdown occurred in as many as 50% to 85% of the cases. Since the use of separate incisions was adopted, the incidence of groin wound infection, necrosis, and breakdown has decreased dramatically to a low as 15%.35,62 Other potential complications or surgery include wound infections, seromas, hemorrhage, deep vein thrombosis, pulmonary embolism, osteitis pubis, and loss of sensory perception in the anterior aspect of the thigh secondary to femoral nerve injury.
The most significant chronic surgical complication is edema of the lower extremities. Lymphedema is related to the extent of the lymphadenectomy, and it is therefore more likely to occur with a deep inguinal node dissection. The incidence of lymphedema may be as high as 69%.62,136 Lymphedema can be progressive and very difficult to manage. Early referral for physical therapy is indicated to prevent progression and stimulate regression of symptoms. Other chronic complications reported are chronic cellulitis of the inguinal areas, stenosis of the introitus, femoral hernias, and rectovaginal or rectoperineal fistulas.
The most significant acute morbidity of radiation, alone or radiation in combination with chemotherapy, is the mucocutaneous reaction in the vulva, perineum, and inguinal folds that may develop early during the course of the treatment. The severity of the reaction depends upon the radiation fractionation schema used and the type of chemotherapy employed. Often the degree of reaction is such that a treatment interruption may be unavoidable. Topical agents, such as zinc oxide preparations, may be helpful; however, this preparation must be off the skin during radiation treatments because it can exacerbate the skin reaction. Sitz baths with sodium bicarbonate may also aid in the cleansing and soothing of the affected skin. Treatment of candidal infections with appropriate antifungal agents should be provided as required. Narcotic pain medications may also be required in the final weeks of treatment.
Acute hematologic toxicity is common and depends upon the type and intensity of the chemotherapy used. Decreased leukocytes may be managed well with colony-stimulating factors, and blood transfusions may be necessary for anemia. Chemotherapy dose adjustments or interruptions are sometimes required. Severe hematologic toxicity can lead to septicemia, with fatal consequences in some instances.74,75
The late complications of chemotherapy/radiation and surgery combined include telangiectasis and atrophy of the skin and mucosa of the vulva, dryness of the mucosa of the vagina and vulva, and narrowing of the vaginal introitus. Avascular necrosis of the femoral head is rare, even when AP/PA photon fields that include the inguinal nodes are used. In the GOG combined-modality study for patients with advanced disease, only one patient developed avascular necrosis of the femoral head.74 In this study there were two instances of injury to the femoral artery. In one patient, necrosis of the femoral artery occurred immediately following surgery and was fatal. The second patient required femoral artery angioplasty.
Besides the generally recognized complications seen with surgery, radiation, and/or chemotherapy, the treatment of carcinoma of the vulva has significant psychosexual consequences. In some instances, these consequences can be far greater than expected when considering the type and extent of the therapy given. The psychosexual impact of the treatment has been studied by some investigators, but it has not received the attention that it merits, possibly because of the difficulty in its nature and impact.82 In a study by Andersen et al.137 of 42 patients, most of whom were treated with conservative surgery, with wide local excision in 32 patients and simple vulvectomy in 10, there was a twofold to threefold increase in the frequency of sexual dysfunction from the pretreatment level. In this study, 30% of the patients were sexually inactive at follow-up. Andersen and Hacker82 also reported that vulvar surgery has a significant impact on sexual functioning and body image even when intercourse remains possible. As might be expected, after pelvic exenteration patients also experience significant sexual dysfunction, even when a neovagina is created.138 The concern for the significant impact of radical surgery on patients with carcinoma of the vulva has been the principal reason for the development of multimodality therapy. Organ preservation, maintenance of function, and improved body image with reasonable control of the disease are achieved in women with this disease, particularly when the disease is early stage.
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