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Gynecology_Novak

Gynecology_Novak. The modern approach to patients with vulvar cancer is multidisciplinary and individualized. Management of the primary lesion and groin nodes is determined separately. Most T1,T2, and early T3 lesions can be managed with radical local excision. Large T3 and T4 primary tumors are best treated with chemoradiation followed by more limited surgical resection. When groin dissection is indicated, it should be a thorough inguinofemoral lymphadenectomy. The potential role of the sentinel lymph node procedure to eliminate the need of a complete inguinofemoral lymphadenectomy is being investigated. The single most important prognostic factor is lymph node status: 5-year survival without groin node metastases is greater than 90%; with groin node metastases 5-year survival is 50%. Postoperative radiation decreases the risk of groin recurrence in patients with multiple positive inguinofemoral lymph nodes. Recurrence in the groin is almost universally fatal.


Gynecology_Novak

Gynecology_Novak. Postoperative radiation decreases the risk of groin recurrence in patients with multiple positive inguinofemoral lymph nodes. Recurrence in the groin is almost universally fatal. With 4,340 new cases and 940 deaths annually in the United States, vulvar cancer is uncommon, representing about 4% of malignancies of the female genital tract and 0.6% of all cancers in women (1,2). Squamous cell carcinomas account for about 90% of all primary vulvar malignancies, whereas melanomas, adenocarcinomas, basal cell carcinomas, and sarcomas are less common. The incidence of in situ vulvar cancer is increasing worldwide, primarily because of the increasing occurrence in young women, who account for 75% of the cases. The overall rate of invasive vulvar carcinoma is increasing, but at a much lower rate (3,4). In women younger than 50 years, there is a striking increase in the incidence of in situ and invasive squamous cell carcinoma of the vulva (5).


Gynecology_Novak

Gynecology_Novak. Following the reports of Taussig in the United States and Way in Great Britain, radical vulvectomy and en bloc groin dissection, with or without pelvic lymphadenectomy, was standard treatment for all patients with operable disease (6,7). Postoperative morbidity was high and prolonged hospitalization common. During the past 25 years, there were significant advances in the management of vulvar cancer, reﬂecting a paradigm shift toward a more conservative surgical approach without compromised survival and with markedly decreased physical and psychological morbidity: 1. Individualization of treatment for all patients with invasive disease. 2. Vulvar conservation for patients with unifocal tumors and an otherwise normal vulva. 3. Omission of the groin dissection for patients with microinvasive tumors (T1a, ≤2 cm diameter and ≤1 mm of stromal invasion). 4. Elimination of routine pelvic lymphadenectomy. 5.


Gynecology_Novak

Gynecology_Novak. 3. Omission of the groin dissection for patients with microinvasive tumors (T1a, ≤2 cm diameter and ≤1 mm of stromal invasion). 4. Elimination of routine pelvic lymphadenectomy. 5. Investigation of the role of the sentinel lymph node procedure to eliminate requirement for complete inguinofemoral lymphadenectomy. 6. The use of separate incisions for the groin dissection to improve wound healing. 7. Omission of the contralateral groin dissection in patients with lateral T1 lesions and negative ipsilateral nodes. 8. The use of preoperative radiation therapy to obviate the need for exenteration in patients with advanced disease. 9. The use of postoperative radiation therapy to decrease the incidence of groin recurrence in patients with multiple positive groin nodes.


Gynecology_Novak

Gynecology_Novak. 9. The use of postoperative radiation therapy to decrease the incidence of groin recurrence in patients with multiple positive groin nodes. The etiology of vulvar cancer is only partially elucidated and likely to be multifactorial. Reported risk factors for vulvar cancer include human papillomavirus (HPV) infection, vulvar intra-epithelial neoplasia (VIN), cervical intraepithelial neoplasia (CIN), lichen sclerosus, squamous hyperplasia, cigarette smoking, alcohol consumption, immunosuppression, a prior history of cervical cancer, and northern European ancestry (8,9). Based on histopathologic and environmental factors, there appear to be at least two distinct etiologic entities of squamous cell carcinoma of the vulva: 1. Basaloid or warty types, which tend to be multifocal, occur generally in younger patients and are related to HPV infection, VIN, and cigarette smoking. 2.


Gynecology_Novak

Gynecology_Novak. Basaloid or warty types, which tend to be multifocal, occur generally in younger patients and are related to HPV infection, VIN, and cigarette smoking. 2. Keratinizing, differentiated, or simplex types, which tend to be unifocal, occur predominantly in older patients, are not related to HPV, and often are found in areas adjacent to lichen sclerosus and squamous hyperplasia.


Gynecology_Novak

Gynecology_Novak. High-grade vulvar intraepithelial neoplasia (VIN 3) was closely studied as a potential precancerous lesion. The direct progression of VIN to cancer is difficult to document, but a review of 3,322 published patients with VIN 3 reports a 9% progression rate to cancer for untreated cases (10). VIN is found adjacent to basaloid or warty vulvar squamous cell carcinomas in more than 80% of cases and 10% to 20% of vulvar carcinoma in situ lesions harbor an occult invasive component (11,12). HPV DNA is documented in 89% of patients with VIN 3, in 60% of vulvar cancers overall, and in up to 86% of warty or basaloid type carcinomas of the vulva; but it occurs in less than 10% of the keratinizing type of carcinomas of the vulva (13). HPV 16 and 33 are the prevalent subtypes, accounting for 55.5% of all HPV-related vulvar cancers (14). Epidemiologic risk factors for the basaloid or warty type squamous cell carcinoma of the vulva are similar to those for cervical cancer and include a history of


Gynecology_Novak

Gynecology_Novak. all HPV-related vulvar cancers (14). Epidemiologic risk factors for the basaloid or warty type squamous cell carcinoma of the vulva are similar to those for cervical cancer and include a history of multiple lower genital tract neoplasias, immunosuppression, and smoking (13,15).


Gynecology_Novak

Gynecology_Novak. Frequently implied as an etiologic variable for the keratinizing carcinoma is the itch–scratch cycle associated with lichen sclerosus and squamous hyperplasia, with atypical changes occurring in the repaired epithelium. Differentiated (or simplex) VIN is a precursor to squamous cell carcinoma and is associated with lichen sclerosus. In keratinizing carcinoma, associated lichen sclerosus or squamous hyperplasia is found in more than 80% of patients (16,17). Women with vulvar lichen sclerosus are at increased risk of developing invasive squamous cell


Gynecology_Novak

Gynecology_Novak. Table 38.1 Types of Vulvar Cancer cancer of the vulva, reported at 2.5% to 7.2% with a median follow-up of 4.7 to 6.2 years (18–20). Supportive evidence that some of these lesions could be precancerous comes from molecular studies that demonstrate aneuploid DNA content, p53 overexpression, high Ki67 expression, indicating high proliferation indices and monoclonal expansion of keratinocytes in lichen sclerosus and associated squamous hyperplasia (21–23). An area of active research explores whether treatment of lichen sclerosus with superpotent topical steroids can impact the malignancy risk (18–20). Some studies reported vulvar cancer to be more common in patients who are obese, have hypertension and diabetes mellitus, or are nulliparous, but a case-control study of vulvar cancer did not confirm any of these as risk factors (15,24,25). Types of Invasive Vulvar Cancer The histologic subtypes of invasive vulvar cancer are shown in Table 38.1.


Gynecology_Novak

Gynecology_Novak. Types of Invasive Vulvar Cancer The histologic subtypes of invasive vulvar cancer are shown in Table 38.1. Approximately 90% to 92% of all invasive vulvar cancers are of the squamous cell type. Squamous carcinomas of the vulva can be divided into distinct histologic subtypes designated as basaloid carcinoma, warty carcinoma, and keratinizing squamous carcinoma (16). Mitoses are noted in these malignancies, but atypical keratinization is the histologic hallmark of invasive vulvar cancer (26). Most vulvar squamous carcinomas reveal keratinization (Fig. 38.1). Histologic features that correlate with the occurrence of inguinal lymph node metastasis are lymph–vascular space invasion, tumor thickness, depth of stromal invasion, histologic pattern of invasion (spray and stellate versus broad and pushing), and increased amount of keratin (27–30).


Gynecology_Novak

Gynecology_Novak. Microinvasive carcinoma of the vulva (T1a) is defined as a lesion 2 cm or less in diameter with 1 mm or less stromal invasion (31). Depth of stromal invasion is measured vertically from the epithelial–stromal junction (basement membrane) of the adjacent most superficial dermal papilla to the deepest point of tumor invasion (Fig. 38.2). When the tumor invades 1 mm or less, metastasis to the inguinal lymph nodes is extremely rare among reported series. When invasion is greater than 1 mm, there is a significant risk of inguinal lymph node metastasis. Figure 38.1 Squamous cell carcinoma of the vulva, keratinizing type. The multiple pearl formations consist of laminated keratin.


Gynecology_Novak

Gynecology_Novak. Figure 38.1 Squamous cell carcinoma of the vulva, keratinizing type. The multiple pearl formations consist of laminated keratin. Figure 38.2 Early invasive carcinoma of vulva originating from vulvar intraepithelial neoplasia. An irregular nest of malignant cells extend from the base of rete pegs. Desmoplastic stromal reaction and chronic inﬂammation are useful diagnostic signs of stromal invasion. The depth of stromal invasion is measured from the base of the most superficial dermal papilla vertically to the deepest tumor cells. Most patients are asymptomatic at the time of diagnosis. If symptoms exist, vulvar pruritus, a lump, or a mass are the most common findings. Less frequent symptoms include a bleeding or ulcerative lesion, discharge, pain, or dysuria. Occasionally, a large metastatic mass in the groin is the initial symptom.


Gynecology_Novak

Gynecology_Novak. A careful inspection of the vulva should be part of every gynecologic examination. On physical examination, vulvar carcinoma is usually raised and may be ﬂeshy, ulcerated, plaquelike or warty in appearance. It may be pigmented, red or white, and tender or painless. The lesion may be clinically indistinct, especially in the presence of VIN or vulvar dystrophies (12). Any lesion of the vulva warrants a biopsy. Most squamous carcinomas of the vulva occur on the labia majora and minora (60%), but the clitoris (15%) and perineum (10%) may be primary sites. Approximately 10% of the cases are too extensive to determine a site of origin, and about 5% of the cases are multifocal.


Gynecology_Novak

Gynecology_Novak. As part of the clinical evaluation, a careful assessment of the extent of the lesion, including whether it is unifocal or multifocal, should be performed. The groin lymph nodes should be evaluated carefully, and a complete pelvic examination should be performed. A cytologic sample should be taken from the cervix, and colposcopy of the cervix and vagina should be performed because of the common association with other squamous intraepithelial or invasive neoplasms of the lower genital tract. Diagnosis Diagnosis requires a Keys punch biopsy or wedge biopsy, which can be obtained in the office using local anesthesia. The biopsy must include sufficient underlying dermis to assess for microinvasion. Physician delay is a common problem in the diagnosis of vulvar cancer, particularly if the lesion has a warty appearance. Any large or conﬂuent warty lesion requires biopsy before medical or ablative therapy is initiated. Routes of Spread Vulvar cancer spreads by the following routes: 1.


Gynecology_Novak

Gynecology_Novak. Routes of Spread Vulvar cancer spreads by the following routes: 1. Direct extension, to involve adjacent structures such as the vagina, urethra, and anus. 2. Lymphatic embolization to the regional inguinal and femoral lymph nodes. 3. Hematogenous spread to distant sites, including the lungs, liver, and bone. Lymphatic metastases may occur early in the disease. Twelve percent of tumors 2 cm in diameter or smaller have regional metastases (32,36). Initially, spread is usually to the inguinal lymph nodes, which are located between Camper’s fascia and the fascia lata (37). From these superficial groin nodes, the disease spreads to the deep femoral nodes, which are located medial to the femoral vessels (Fig. 38.3). Cloquet’s or Rosenm¨ uller’s node, situated beneath the inguinal ligament, is the most cephalad of the femoral node group. Metastases to the femoral nodes without involvement of the inguinal nodes is reported (38–41). A study from the


Gynecology_Novak

Gynecology_Novak. M. D. Anderson Cancer Center reported a 9% groin recurrence rate in 104 patients with vulvar cancer who had negative nodes on superficial inguinal lymphadenectomy at initial surgery, and intraoperative lymphatic mapping studies found the sentinel node deep to the cribriform fascia in 5% to 16% of these cases (42–44).


Gynecology_Novak

Gynecology_Novak. From the inguinal-femoral nodes, the cancer spreads to the pelvic nodes, particularly the external iliac group. Although direct lymphatic pathways from the clitoris and Bartholin gland to the pelvic nodes were described, these channels seem to be of minimal clinical significance (45–47). The lymphatics from either side of the vulva form a rich network of anastomoses along the midline. Lymphatic drainage from the clitoris, anterior labia minora, and perineum is bilateral. Metastases to contralateral lymph nodes in the absence of ipsilateral nodal involvement is very rare (0% to 0.4%) for lateral vulvar tumors that are either 2 cm or less in diameter or with 5 mm or less invasion (36,48).


Gynecology_Novak

Gynecology_Novak. The overall incidence of inguinal-femoral lymph node metastases is reported to be about 32% (41,43,46–56) (Table 38.2). Metastases to pelvic nodes occur in about 12% of cases. Pelvic nodal metastases are rare (0.6%) in the absence of groin node involvement, but they occur in about 16% of cases with positive groin nodes (Table 38.2). The risk increases to 33% in the presence of clinically suspicious groin nodes and to 40% to 50% if there are three or more pathologically positive inguinal-femoral nodes (33,48,57–60). The incidence of lymph node Table 38.2 Incidence of Lymph Node Metastases in Squamous Cell Carcinoma of the Vulva N/A, data not available. Figure 38.3 Inguinal-femoral lymph nodes. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:541, with permission.) Table 38.3 Nodal Status in T1 Squamous Cell Carcinoma of the Vulva versus Depth of Stromal Invasion


Gynecology_Novak

Gynecology_Novak. Table 38.3 Nodal Status in T1 Squamous Cell Carcinoma of the Vulva versus Depth of Stromal Invasion From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins 2010:543, with permission. metastases correlates positively with depth of invasion, as shown in Table 38.3. Hematogenous spread usually occurs late in the course of vulvar cancer and is rare in the absence of lymph node metastases.


Gynecology_Novak

Gynecology_Novak. Staging Initially, vulvar carcinoma was staged clinically based on tumor size and location, palpable regional lymph node status, and a limited search for distant metastases. The prognostic importance of the lymph node status is significant, but clinical assessment of the lymph nodes has limited accuracy. This led the Cancer Committee of FIGO to introduce a surgical staging system for vulvar cancer in 1988, which underwent several revisions, most recently in 2009, to provide better prognostic discrimination between stages and less heterogeneity within stages (31,61,62) (Table 38.4). The main changes are: 1. While stage Ia remains unchanged as the only group of patients with a negligible risk of lymph node metastases, former stages I and II have been combined into stage Ib. 2. The new stage II segregates patients whose tumors involve the lower adjacent perineal structures from those with positive lymph nodes. 3.


Gynecology_Novak

Gynecology_Novak. 2. The new stage II segregates patients whose tumors involve the lower adjacent perineal structures from those with positive lymph nodes. 3. For stages III and IV, the number and morphology of the involved nodes are taken into account and the bilaterality of lymph nodes is discounted. The new FIGO staging system was validated in 269 patients, 42% of whom were restaged (63). The number of positive nodes negatively correlated with survival, as did the presence of extracapsular growth. This study confirmed Gynecologic Oncology Group (GOG) and SEER data indicating that in patients with negative nodes, tumor size was not predictive of survival (62). This study confirmed reports demonstrating that, when corrected for the number of positive nodes, bilaterality of nodal metastases was not predictive of survival (64–67).


Gynecology_Novak

Gynecology_Novak. Paralleling the changes to the FIGO staging, the American Joint Committee on Cancer (AJCC) significantly modified the vulvar cancer tumor-node-metastasis (TNM) classification with the release of the 2009 edition of the AJCC Cancer Staging Manual (Table 38.4) (68).


Gynecology_Novak

Gynecology_Novak. Prognosis and Survival Survival of patients with vulvar cancer correlates with FIGO stage (69). The prognosis for patients with early-stage disease is generally good (Table 38.5). The single most important prognostic factor is lymph node status (54–56,59,70,71). A report from the Mayo Clinic on 330 patients with primary squamous cell carcinoma of the vulva demonstrated a significant correlation between lymph node status and risk of treatment failure, especially in the first 2 years following initial therapy: 44.2% overall recurrence rate with positive versus 17.5% with negative lymph nodes. More than one-third of relapses presented 5 years or more after initial therapy (72). There is a strong negative correlation between the number of positive lymph nodes and survival (Table 38.6). Patients with negative lymph nodes have a 5-year survival rate of over 80%; for patients with positive nodes 5-year survival falls below 50%. The number of positive nodes is of critical importance: Patients


Gynecology_Novak

Gynecology_Novak. with negative lymph nodes have a 5-year survival rate of over 80%; for patients with positive nodes 5-year survival falls below 50%. The number of positive nodes is of critical importance: Patients with one microscopically positive lymph node have a prognosis similar to those with all negative lymph nodes, whereas patients with three or more positive nodes have a poor prognosis and a 2-year survival rate of 20% (73). The survival rate for patients with positive pelvic nodes is about 11% (74). In addition


Gynecology_Novak

Gynecology_Novak. Table 38.4 FIGO Staging and TNM classification for Vulvar Cancer (2008) FIGO, International Federation of Gynecology and Obstetrics; TNM, tumor node metastasis. FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obstet 2009;105:103–104 (31). American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. Chicago, Illinois: Springer New York, Inc., 2010. ∗The depth of stromal invasion is measured from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. aTNM Classification:


Gynecology_Novak

Gynecology_Novak. ∗The depth of stromal invasion is measured from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. aTNM Classification: T: Primary tumor N: Regional lymph nodes (femoral and inguinal nodes) Tx: Primary tumor cannot be assessed Nx: Regional lymph nodes cannot be assessed T0: No evidence of primary tumor N0: No regional lymph node metastases Tis: Carcinoma in situ (preinvasive carcinoma) N1: One or two regional lymph node metastases with the following T1a: Lesions ≤2 cm in size, confined to the vulva or perineum features: and with stromal invasion ≤1mm N1a: One or two lymph node metastases each <5mm T1b: Lesions >2 cm in size or any size with stromal invasion N1b: One lymph node metastasis ≥5mm >1 mm, confined to the vulva or perineum N2: Regional lymph node metastases with the following features


Gynecology_Novak

Gynecology_Novak. T2: Tumor of any size with extension to adjacent perineal N2a: ≥3 lymph node metastases, each <5 mm in diameter structures (lower 1/3 of urethra, lower of 1/3 vagina, anal N2b: ≥2 lymph node metastases ≥5mm involvement) N2c: Lymph node metastases with extracapsular spread T3: Tumor of any size with extension to any of the following: N3: Fixed or ulcerated regional lymph node metastasis upper 2/3 of urethra, upper 2/3 of vagina, bladder mucosa, M: Distant metastasis rectal mucosa, or fixed to pelvic bone M0: No distant metastasis


Gynecology_Novak

Gynecology_Novak. M1: Distant metastasis (including pelvic lymph node metastasis) to the number of nodes involved, the morphology of the positive groin nodes is of prognostic significance. As demonstrated in several studies, significant negative predictors of survival are the size of the nodal metastasis, the proportion of the node replaced by tumor cells, and the presence of any extracapsular spread (62,70,75,76). Histologic grade, tumor thickness, depth of stromal invasion, and lymph–vascular space involvement contribute to the risk of lymph node involvement but are not independent predictors of survival (73). Treatment After the pioneering work of Taussig and Way, en bloc radical vulvectomy and bilateral dissection of the groin and pelvic nodes were the standard treatment for most patients with operable vulvar cancer (6,7). When the disease involved the anus, rectovaginal septum, or proximal urethra, some type of pelvic exenteration was combined with the dissection.


Gynecology_Novak

Gynecology_Novak. Table 38.5 Five-Year Survival for Patients with Vulvar Carcinoma FIGO, International Federation of Gynecology and Obstetrics. Modified from the FIGO Annual Report on the Results of Treatment in Gynecological Cancer using 1994 FIGO staging classification (31). Although the survival rate improved markedly with this aggressive surgical approach, several factors led to modifications of this treatment plan. These factors are summarized as follows: 1. An increasing proportion of patients present with early-stage disease—up to 50% of patients in many centers have tumors 2 cm in diameter or smaller. 2. Concerns about the postoperative morbidity and associated long-term hospitalization common with the en bloc radical dissection. 3. Increasing awareness of the psychosexual consequences of radical vulvectomy.


Gynecology_Novak

Gynecology_Novak. 3. Increasing awareness of the psychosexual consequences of radical vulvectomy. To individualize the patient’s care and determine the appropriate therapy, it is necessary to independently manage the primary lesion and groin lymph nodes. Before initiation of therapy, all patients should undergo colposcopy of the cervix, vagina, and vulva. Preinvasive (and rarely invasive) lesions may be present at other sites along the lower genital tract. Management of the Primary Lesion Microinvasive Vulvar Cancer (T1a) Tumors 2 cm or less in diameter with 1 mm or less invasion are appropriately treated with a wide local excision, which is as effective as radical surgery for the prevention of vulvar recurrences for these tumors (77). The excision should go sufficiently deep into the dermis that depth of invasion is fully assessed.


Gynecology_Novak

Gynecology_Novak. Early Vulvar Cancer (T1b) The modern approach to the management of patients with T1b carcinoma of the vulva should be individualized. There is no standard approach applicable to every patient, and emphasis is on performing the most conservative operation that is consistent with cure of the disease. Radical vulvectomy was considered the standard treatment for primary vulvar lesions, but this operation is associated with significant surgical morbidity and disturbances of sexual function and body image. Psychosexual sequelae are a major long-term morbidity associated with the treatment of vulvar cancer (37). One study reported that sexual arousal was reduced to the eighth percentile and body image was reduced to the fourth percentile for women who had undergone vulvectomy when compared with healthy adult women (66). Traditionally, the concern was that without an en bloc resection of vulva and groin nodes, intervening tissue left between the primary tumor and the regional lymph nodes


Gynecology_Novak

Gynecology_Novak. healthy adult women (66). Traditionally, the concern was that without an en bloc resection of vulva and groin nodes, intervening tissue left between the primary tumor and the regional lymph nodes contained


Gynecology_Novak

Gynecology_Novak. Table 38.6 Five-year Survival for Patients with Vulvar Squamous Cell Carcinoma by Number of Lymph Node Metastases No. of Lymph Node Metastases No. of Patients 5-Year Survival (%) FIGO, International Federation of Gynecology and Obstetrics. Modified from the FIGO Annual Report on the Results of Treatment in Gynecological Cancer (31). microscopic tumor foci in draining lymphatics. Experience with a separate incision technique for node dissection confirmed that metastases rarely occur in the skin bridge in patients without clinically suspicious nodes in the groin (78).


Gynecology_Novak

Gynecology_Novak. During the past 20 years, several investigators advocated a radical local excision rather than a radical vulvectomy for the primary lesion for patients with T1b tumors (37,49,79,80). Regardless of whether a radical vulvectomy or a radical local excision is performed, the surgical margins adjacent to the tumor are the same. An analysis of the literature indicates that the incidence of local invasive recurrence after radical local excision or radical hemivulvectomy is not higher than that after radical vulvectomy (36,49,74,81–83). This finding suggests that in the presence of an otherwise normal-appearing vulva, radical local excision is a safe surgical option, regardless of the size of the tumor or the depth of invasion. Based on cumulative data of 413 patients reported in four studies, an 8 mm or greater histopathological resection margin results in a high rate of local disease control (81,84–86). Of the 252 patients whose tumors were resected with margins of 8 mm or greater, 2.4%


Gynecology_Novak

Gynecology_Novak. an 8 mm or greater histopathological resection margin results in a high rate of local disease control (81,84–86). Of the 252 patients whose tumors were resected with margins of 8 mm or greater, 2.4% experienced a local recurrence, compared to 30.3% of the 161 patients whose margins were less than 8 mm. Neither clinical tumor size nor the presence of coexisting benign vulvar pathology correlated with local recurrence. It is important to bear in mind that paraffin-embedded tissue shrinks by about 25%. At the time of radical local excision, at least a 1-cm grossly negative margin, without putting the skin under tension, should be obtained and extended down to the level of the inferior fascia of the urogenital diaphragm.


Gynecology_Novak

Gynecology_Novak. When vulvar cancer arises in the presence of VIN, vulvar dystrophy, or some nonneoplastic epithelial disorder, treatment is inﬂuenced by the patient’s age. Elderly patients who often had many years of chronic itching may not be disturbed by the prospect of a vulvectomy. In younger women, it is desirable to conserve as much of the vulva as possible. Radical local excision should be performed for the invasive disease, and the associated intraepithelial disease should be treated in the manner most appropriate to the patient. For example, topical steroids may be required for lichen sclerosus or squamous hyperplasia, whereas VIN may require superficial local excision with primary closure or laser ablation.


Gynecology_Novak

Gynecology_Novak. Radical local excision is most appropriate for lesions on the lateral or posterior aspects of the vulva (Fig. 38.4). Midline lesions pose special challenges because of their proximity to clitoris, urethra, or anus. For anterior lesions, conservative clitoris-sparing surgery allows for excellent local control as long as pathological margins are at least 8 mm (87). For tumors that involve the clitoris or that are in close proximity to it, any type of surgical excision will have psychosexual consequences. In addition, marked edema of the posterior vulva may occur. For young patients with periclitoral lesions, the primary lesion can be treated with a small field of radiation therapy, possibly with concomitant sensitizing chemotherapy. Small vulvar lesions should respond very well to about 5,000 cGy external radiation, and biopsy can be performed after therapy to confirm the absence of any residual disease (61).


Gynecology_Novak

Gynecology_Novak. Early T2 Vulvar Cancer The indications for vulvar conservation can be extended to selected patients with early T2 tumors. The tumor-free margin should be the same, whether or not a radical vulvectomy or a radical local excision is performed. It seems both feasible and desirable to extend the indications for vulvar conservation, particularly for younger patients. Tumors that are suitable for a conservative resection are those involving the posterior vulva and lower vagina, where preservation of the anus, clitoris, and urethra is feasible. For patients with more advanced T2 lesions, management consists of radical vulvectomy and/or chemoradiation therapy, as discussed below. When the disease involves the distal urethra or anus, partial resection of these organs is required. Alternatively, it is often preferable to give preoperative radiation therapy with chemosensitization to allow for a less radical resection (see below). Closure of Large Defects


Gynecology_Novak

Gynecology_Novak. Closure of Large Defects After radical local excision, primary closure without tension can be accomplished for smaller defects. If an extensive dissection is required to treat a large primary lesion, a number of options are available to repair the defect: 1. An area may be left open to granulate, which it will usually do over a period of 6 to 8 weeks (88). Figure 38.4 Small (T1) vulvar carcinoma at the posterior fourchette. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:547, with permission.) Advanced Disease: Large T2 and T3 Primary Tumors 2. Full-thickness skin ﬂaps may be devised (89–92). The rhomboid ﬂap is best suited to covering large defects of the posterior vulva, whereas for lateral defects, a mons pubis pedicle ﬂap is advocated (89,92). 3.


Gynecology_Novak

Gynecology_Novak. 3. Myocutaneous ﬂaps may be developed to cover the defect. Unilateral or bilateral gracilis myocutaneous grafts are useful when an extensive area from the mons pubis to the perianal area was resected. Because the graft brings a new blood supply to the area, it is particularly applicable if the vulva is poorly vascularized from prior surgical resection or radiation (93). 4. If extensive defects exist in the groin and vulva, the tensor fascia lata myocutaneous graft may be the most applicable (94).


Gynecology_Novak

Gynecology_Novak. 4. If extensive defects exist in the groin and vulva, the tensor fascia lata myocutaneous graft may be the most applicable (94). To achieve primary surgical clearance for tumors involving the upper urethra, anus, rectum, or rectovaginal septum, pelvic exenteration is needed in addition to radical vulvectomy and inguinal-femoral lymphadenectomy, which carries an extremely high physical and psychological morbidity (95,96). Reported 5-year survival rates with this approach are about 50% (97– 100). For many of these patients, a combined approach of surgery and radiation therapy offers improved survival and reduced morbidity and is the preferred treatment approach. Numerous small prospective and retrospective series report on the use of external beam radiation, often with concomitant chemotherapy to shrink the primary tumor. Reported initial response rates to chemoradiation are 80% to 90%, and operability is achieved in 63% to 92% of cases (101–108).


Gynecology_Novak

Gynecology_Novak. It is important that this chemoradiation is followed by a more limited resection of the tumor bed on an individualized basis. About one-half of the specimens will contain residual tumor, and local relapse rates are as high as 50% to 79% with external radiation alone (with or without concomitant chemotherapy), emphasizing the need for a combined approach that involves radiation and surgery (109–112).


Gynecology_Novak

Gynecology_Novak. As experience with this combination therapy evolved, it appeared that external beam therapy is appropriate for most cases, with more selective use of brachytherapy. The extensiveness of the surgery is significantly modified. A limited vulvar resection is advocated, and bulky N2 and N3 nodes are resected without full groin lymphadenectomy to avoid the leg edema associated with groin lymphadenectomy and radiation. With this combined radiation-surgical approach, 5-year survival rates as high as 76% are reported (110). With the experience accrued, preoperative radiation, with or without concurrent chemotherapy, is regarded as the first treatment of choice for patients with advanced vulvar cancer who would otherwise require some type of pelvic exenteration or stoma. Neoadjuvant therapy is not justified in patients with tumors that can be adequately treated with primary radical vulvectomy and bilateral groin node dissection. Management of the Lymph Nodes


Gynecology_Novak

Gynecology_Novak. Management of the Lymph Nodes Appropriate groin dissection is the single most important factor in decreasing the mortality from early vulvar cancer. When assessing a patient for groin dissection, the following facts should to be kept in mind: 1. The only patients with virtually no risk of lymph node metastases are those whose tumor is small and invades the stroma to 1 mm or less (T1a). 2. Patients who develop recurrent disease in an undissected groin have a greater than 90% mortality (113). 3. Based on the laterality of the vulvar lesions and the status of the ipsilateral groin, an ipsilateral or bilateral lymphadenectomy becomes necessary. Groin dissection is associated with postoperative wound infection and breakdown. Although the incidence of wound breakdown is reduced significantly when separate incisions are used for the groin dissection, lymphocyst formation and chronic leg edema remain a major problem (Fig. 38.5) (78).


Gynecology_Novak

Gynecology_Novak. All patients whose tumors demonstrate more than 1 mm of stromal invasion or whose tumors are larger than 2 cm (T1b and above) require inguinal-femoral lymphadenectomy. If there is any question regarding the need for inguinofemoral lymphadenectomy, a Keys biopsy or wedge biopsy of the primary tumor should be obtained, and the depth of invasion should be determined. If it is smaller than 1 mm on the wedge biopsy specimen, the entire lesion should be locally excised and analyzed histologically to determine the depth of invasion. If the lesion is 2 cm in diameter or smaller and there is no invasive focus larger than 1 mm, groin dissection may be omitted, provided there is no lymph–vascular space invasion and there are no clinically suspicious groin lymph nodes. An occasional patient with less than 1 mm of stromal invasion has documented groin node metastases, but the incidence is so low that it is of no practical significance (114,115).


Gynecology_Novak

Gynecology_Novak. Inguinal-Femoral Lymphadenectomy If groin dissection is indicated in patients with vulvar cancer, it should be a thorough inguinal-femoral lymphadenectomy. The GOG reported six groin recurrences among 121 patients with tumors 2 cm or less after a superficial (inguinal) dissection, although the removed inguinal nodes were negative, and a study from the M. D. Anderson Cancer Center reported a 9% groin recurrence rate in 104 patients with vulvar cancer and negative nodes on superficial inguinal lymphadenectomy (41,42). Whether all of these recurrences were in the femoral nodes is unclear, but both studies indicate that an incomplete groin dissection will increase the number of groin recurrences and mortality. GOG data indicate that radiation therapy cannot substitute for groin dissection followed by selective radiation as indicated, even in patients with clinically nonsuspicious lymph nodes (116). This GOG study was closed early because a significantly higher incidence of recurrences


Gynecology_Novak

Gynecology_Novak. followed by selective radiation as indicated, even in patients with clinically nonsuspicious lymph nodes (116). This GOG study was closed early because a significantly higher incidence of recurrences occurred in women who were receiving groin radiation therapy only (19% versus 0%). The dose of radiation was 5,000


Gynecology_Novak

Gynecology_Novak. Figure 38.5 Skin incision for groin dissection through a separate incision. A line is drawn 1 cm above and parallel to the groin crease, and a narrow ellipse of skin is removed. (Revised from Berek JS, Hacker NF. Practical Gynecologic Oncology. 2nd ed. Baltimore, MD: Williams & Wilkins, 1994:418, with permission.) cGy given in daily 200-cGy fractions to a depth of 3 cm below the anterior skin surface. Although the radiation regimen prescribed was criticized extensively, other uncontrolled studies give no evidence for better groin control with radiotherapy (117,118). Surgery remains the treatment of choice for the groin for women with vulvar cancer.


Gynecology_Novak

Gynecology_Novak. Unilateral versus Bilateral Groin Dissection It is not necessary to perform a bilateral groin dissection if the primary lesion is unilateral and the ipsilateral lymph nodes are negative. In a patient with a unilateral lesion and negative ipsilateral groin nodes, the risk of contralateral lymph node metastasis is very low (36,48). In a study from the Mayo Clinic, 8 of 163 patients with unilateral vulvar cancers (4.8%) had bilateral lymph node metastases and only 3 (1.8%) had isolated contralateral lymph node metastases. None of the patients with unilateral vulvar lesions that were either 2 cm or less or had 5 mm or less depth of invasion had bilateral groin node involvement at diagnosis (48). There is an increase in the risk of contralateral nodal involvement proportional to the number of positive ipsilateral inguinal nodes (60,48). It is recommended that patients with any bulky or multiple microscopically positive ipsilateral groin lymph nodes undergo contralateral inguinal-femoral


Gynecology_Novak

Gynecology_Novak. positive ipsilateral inguinal nodes (60,48). It is recommended that patients with any bulky or multiple microscopically positive ipsilateral groin lymph nodes undergo contralateral inguinal-femoral lymphadenectomy. Bilateral inguinal-femoral lymphadenectomy should be performed for midline lesions (clitoris, anterior labia minora, posterior fourchette) or those within 2 cm of the midline because of the more frequent contralateral lymph ﬂow from these regions (119).


Gynecology_Novak

Gynecology_Novak. Management of Bulky Groin Nodes All clinically or radiologically suspicious groin nodes should be resected. If nodal metastasis is confirmed by frozen section, the question arises whether a full inguinofemoral lymphadenectomy may be safely omitted to decrease morbidity without compromising survival. One small, retrospective, multi-institutional study suggests that targeted nodal debulking compared with full lymphadenectomy does not jeopardize survival when both are followed by groin and pelvic radiation (120). Patients with fixed, unresectable groin nodes should be treated with primary chemoradiation. If there is no other evidence of metastatic disease following chemoradiation, GOG data suggest that it may be appropriate to resect the residual nodes (121).


Gynecology_Novak

Gynecology_Novak. Management of Pelvic Lymph Nodes In the past, pelvic lymphadenectomy was part of the routine surgery for invasive vulvar cancer. The incidence of pelvic lymph node metastasis is rare in the absence of groin node involvement, and a more selective approach is preferred (Table 38.2). Patients most prone to pelvic lymph node metastasis are those with three or more pathologically positive groin nodes (33,45,57,122). In addition to the number of nodes involved, the morphology of the positive groin nodes is of prognostic significance. As demonstrated in several studies, significant negative predictors of survival are the number of positive nodes, the size of the nodal metastasis, the proportion of the node replaced by tumor cells, and the presence of any extracapsular spread (65,70,75,76). In these patients, the pelvis requires treatment by radiation (discussed below). If a preoperative pelvic imaging study reveals bulky pelvic lymph nodes, resection of these nodes should be performed via an


Gynecology_Novak

Gynecology_Novak. patients, the pelvis requires treatment by radiation (discussed below). If a preoperative pelvic imaging study reveals bulky pelvic lymph nodes, resection of these nodes should be performed via an extraperitoneal approach prior to radiation because of the limited ability of external beam radiation therapy to sterilize bulky positive pelvic nodes.


Gynecology_Novak

Gynecology_Novak. Sentinel Lymph Node Studies Considerable investigation was conducted regarding the use of intraoperative lymphatic mapping using lymphoscintigraphy with technetium-99mlabeled nanocolloid or isosulfan blue dye to identify a sentinel node that would predict the presence or absence of regional nodal metastases (43,123–125). A systematic review of 29 small studies of 961 groins found lymphoscintigraphy to be the most accurate technique, with a pooled sensitivity and negative likelihood ratio of 97% and 0.12, respectively (126). Studies suggested that a sentinel node could be identified in most patients (127–129). A GOG study of 403 evaluable patients in whom 697 groins were assessed demonstrated that a sentinel node was successfully identified in 78.8% (67 of 85) of patients using blue dye only and in 96.2% (306 of 318) using combination of radiolocalization and blue dye, demonstrating the superiority of the combination of blue dye and radiocolloid over blue dye alone for sentinel node


Gynecology_Novak

Gynecology_Novak. only and in 96.2% (306 of 318) using combination of radiolocalization and blue dye, demonstrating the superiority of the combination of blue dye and radiocolloid over blue dye alone for sentinel node identification (130). The sensitivity of the sentinel node assessment is enhanced by ultrastaging using serial sectioning or immunohistochemistry to detect micrometastases (129,131–133).


Gynecology_Novak

Gynecology_Novak. The strong interest in the sentinel node concept lies in the desire to reduce the significant lifelong morbidity of lymphedema associated with a thorough inguinofemoral lymphadenectomy. Reliable identification of the sentinel node and forgoing full lymphadenectomy in patients with clinically nonsuspicious groin lymph nodes and a negative sentinel node may significantly reduce the number of patients who undergo unnecessary, extensive lymphadenectomy in the absence of disease. This is contingent upon a negative sentinel lymph node reliably predicting the absence of any other nodal metastases given the greater than 90% mortality associated with a groin recurrence.


Gynecology_Novak

Gynecology_Novak. The largest study published to date on the safety of the sentinel node procedure in vulvar cancer, GROINSS-V, included 403 assessable patients with a sentinel node procedure performed in 623 groins (Table 38.2) (129). Metastatic sentinel nodes were found in 26% of patients. In eight of 276 patients (3%) groin recurrences were diagnosed at a median follow-up time of 35 months. At the time of groin recurrence these patients all underwent bilateral inguinofemoral lymphadenectomy followed by chemoradiotherapy; six of the eight patients died of disease.


Gynecology_Novak

Gynecology_Novak. False-negative sentinel nodes were reported by others, but were thought to occur with low incidence in patients with clinically nonsuspicious nodes (44,134,135). Two recent studies of sentinel nodes in vulvar cancer, one single institution study of 56 patients and one multi-institution study of 127 patients with inclusion criteria similar to those in GROINSS-V, showed an unexpectedly high false-negative rate (27% and 7.7%, respectively), some of which may be attributable to insufficient experience of low-volume providers (128,136). This highlights one of the key concerns that any wide implantation of the sentinel node procedure beyond select expert centers might carry with it an unjustifiable rise in the frequency of groin recurrences.


Gynecology_Novak

Gynecology_Novak. The 2008 International Sentinel Node Society’s expert panel statement stresses the importance of a well-informed patient treated by a skilled multidisciplinary team of a gynecologic oncologist, a nuclear medicine specialist, and a pathologist with expertise in the sentinel lymph node technique (137). They recommended the following eligibility criteria for the performance of the sentinel node procedure: unifocal primary tumor of 4 cm or less in diameter with greater than 1 mm invasion; and absence of any obvious metastatic disease on physical examination or imaging studies, including the absence of suspicious groin nodes. Until data from prospective randomized controlled trials document comparable survival for patients undergoing the sentinel node procedure compared to full inguinofemoral lymphadenectomy, complete inguinofemoral lymphadenectomy remains indicated in all but stage Ia disease, given the high mortality of recurrence in an undissected groin. The sentinel node technique


Gynecology_Novak

Gynecology_Novak. lymphadenectomy, complete inguinofemoral lymphadenectomy remains indicated in all but stage Ia disease, given the high mortality of recurrence in an undissected groin. The sentinel node technique should be limited to carefully selected patients in expert centers, ideally on research protocols.


Gynecology_Novak

Gynecology_Novak. Despite the age and general medical condition of many elderly patients with vulvar cancer, surgery is usually remarkably well tolerated. Patients should be able to commence eating a low-residue diet on the first postoperative day. In the past, bed rest was advised for 3 to 5 days postoperatively to allow for immobilization of the wounds and to foster healing. Because radical local excisions are being performed with increasing frequency and groin lymphadenectomy is done through separate incisions, patients begin ambulation on postoperative day 1 or 2. Pneumatic calf compression or subcutaneous heparin should be given to help prevent deep venous thrombosis, and active leg movements are to be encouraged. Frequent dressing changes are performed to keep the vulvar wound dry. Meticulous perineal hygiene is maintained. Suction drainage of each side of the groin is continued until output is minimal to help decrease the incidence of groin seromas. It is not uncommon for suction drainage to


Gynecology_Novak

Gynecology_Novak. hygiene is maintained. Suction drainage of each side of the groin is continued until output is minimal to help decrease the incidence of groin seromas. It is not uncommon for suction drainage to continue for 10 or more days. The Foley catheter is removed when the patient is ambulatory. If there is significant periurethral swelling, prolonged bladder drainage may be advisable. If there is breakdown of the vulvar wound, sitz baths or whirlpool therapy is helpful, followed by drying of the perineum with a hair dryer.


Gynecology_Novak

Gynecology_Novak. The major immediate morbidity is related to groin wound infection, necrosis, and breakdown. This complication is reported in as many as 53% to 85% of patients having an en bloc operation (32,33). With the separate-incision approach, the incidence of wound breakdown can be reduced to about 44%; major breakdown occurs in about 14% of patients (34,78,138,139). With appropriate antibiotics, debridement, and wound dressings, the area will granulate and re-epithelialize over several weeks and may be managed with home nursing. Whirlpool therapy is effective for areas of extensive breakdown. The most common complications with the separate incision approach continues to be wound infection requiring antibiotic therapy and lymphocyst formation, both reported in about 40% of cases (139). Symptomatic lymphocysts should be managed by periodic sterile aspiration.


Gynecology_Novak

Gynecology_Novak. Other early postoperative complications include urinary tract infection, seromas in the femoral triangle, deep venous thrombosis, pulmonary embolism, myocardial infarction, hemorrhage, and, rarely, osteitis pubis. Anesthesia of the anterior thigh resulting from femoral nerve injury is common and usually resolves slowly.


Gynecology_Novak

Gynecology_Novak. One major late complication is chronic lymphedema, which occurs in about 30% of patients (32–34,138–140). Recurrent lymphangitis or cellulitis of the leg develops in about 10% of patients and usually responds to oral antibiotics. Urinary stress incontinence, with or without genital prolapse, occurs in about 10% of patients after radical vulvectomy and may require corrective surgery. Introital stenosis can lead to dyspareunia and may require a vertical relaxing incision, which is sutured transversely. An uncommon late complication is femoral hernia, which can be prevented intraoperatively by closure of the femoral canal with a suture from the inguinal ligament to Cooper’s ligament. Pubic osteomyelitis and rectovaginal or rectoperineal fistulas are rare late complications.


Gynecology_Novak

Gynecology_Novak. Other major long-term treatment complications associated with the extent of vulvar surgery include depression, altered body image, and sexual dysfunction (96,97). Modifications in the radical extent of the surgical approach and appropriate preoperative and postoperative counseling may help lessen some of the psychological trauma. Role of Radiation Therapy Radiation therapy traditionally had a limited role in the management of patients with vulvar cancer. In the orthovoltage era, local tissue tolerance was poor and vulvar necrosis was common, but with megavoltage therapy, tolerance improved significantly. Radiation therapy, frequently with concurrent chemotherapy, has an increasingly important role in the management of patients with vulvar cancer. It is important to remember that, with a rare exception, radiation therapy alone has little place in the primary management of vulvar cancer. It is indicated in conjunction with surgery.


Gynecology_Novak

Gynecology_Novak. The indications for radiation therapy for patients with primary vulvar cancer are evolving. Radiation seems to be indicated in the following situations: 1. Preoperatively, in patients with advanced disease who would otherwise require pelvic exenteration or suffer loss of anal or urethral sphincteric function. 2. Preoperatively, in patients with fixed, unresectable groin nodes (141). 3. Postoperatively, to treat the pelvic lymph nodes and groins of patients with multiple microscopically positive groin nodes, one or more macrometastasis (10 mm or larger), or any evidence of extracapsular spread. Possible roles for radiation therapy include the following: 1. Postoperatively, to help prevent local recurrences in patients with involved or close surgical margins (141–143). 2.


Gynecology_Novak

Gynecology_Novak. Possible roles for radiation therapy include the following: 1. Postoperatively, to help prevent local recurrences in patients with involved or close surgical margins (141–143). 2. As primary therapy for patients with small primary tumors, particularly clitoral or periclitoral lesions in young and middle-aged women, for whom surgical resection would have significant psychological consequences (80).


Gynecology_Novak

Gynecology_Novak. No additional treatment is recommended if one microscopically positive groin node (5 mm or less tumor deposit) is found in a fully dissected groin. The prognosis for this group of patients is excellent, and only careful observation is required (57). If unilateral groin dissection was performed for a lateral lesion, there seems to be no indication for dissection of the other side, because contralateral lymph node involvement is likely only if there are multiple microscopic or any gross ipsilateral inguinal node metastases (57,60). For patients with a single groin node metastasis, a recent retrospective SEER database review suggests that adjuvant radiation may provide a therapeutic benefit, especially if the groin dissection was limited (144).


Gynecology_Novak

Gynecology_Novak. If clinically evident groin metastases, any extracapsular spread or two or more microscopically positive groin nodes are found, the patient is at increased risk of groin and pelvic recurrence and should receive postoperative groin and pelvic irradiation. In 1977, the GOG initiated a prospective trial in which patients with positive groin nodes were randomized to either ipsilateral pelvic node dissection or bilateral pelvic plus groin irradiation (60). The survival rate for the radiation group (68% at 2 years) was significantly better than the survival rate for the pelvic lymphadenectomy group (54% at 2 years) (p = 0.03). The survival advantage was limited to patients with clinically evident groin nodes or more than one microscopically positive groin node. Groin recurrence occurred in 3 of 59 patients (5%) treated with radiation, compared with 13 of 55 (23.6%) patients treated with lymphadenectomy (p = 0.02). Four patients who received radiation had a pelvic recurrence, compared with


Gynecology_Novak

Gynecology_Novak. 59 patients (5%) treated with radiation, compared with 13 of 55 (23.6%) patients treated with lymphadenectomy (p = 0.02). Four patients who received radiation had a pelvic recurrence, compared with one who had lymphadenectomy. These data indicate no benefit from pelvic irradiation compared with pelvic lymphadenectomy for the prevention of pelvic recurrence, but they do highlight the value of groin irradiation in preventing groin recurrence in patients with multiple positive groin nodes.


Gynecology_Novak

Gynecology_Novak. Recurrent Vulvar Cancer Recurrence of vulvar cancer correlates closely with the number of positive groin nodes (57). Patients with fewer than three positive nodes, particularly if the nodes are only microscopically involved, have a low incidence of recurrence at any site, whereas patients with three or more positive nodes have a high incidence of local, regional, and systemic recurrences (57,60).


Gynecology_Novak

Gynecology_Novak. Most recurrences of vulvar cancer occur within the first 2 years from initial therapy, with groin recurrences occurring sooner (median time to recurrence 6 to 7 months) than vulvar recurrences (median time to recurrence 3 years) (72,145–147). About one-third of vulvar cancer relapses present 5 or more years after initial therapy (72). In a long-term follow-up study at the Mayo Clinic, nearly 1 in 10 patients with vulvar cancer had a late (longer than 5 years) reoccurrence of disease (72). Over 95% of those late relapses had local reoccurrences (same site recurrence or second primary vulvar site). Because of this propensity for late local reoccurrence, regular and long-term careful examinations of the vulva and groin constitute the cornerstone of posttreatment surveillance for these patients.


Gynecology_Novak

Gynecology_Novak. The published literature on the management and outcome of recurrent disease is limited. The timing and primary site of recurrence is critical to the prognosis postrecurrence. Although groin recurrences tend to occur early and are nearly always fatal, 5-year overall survival rates of 50% to 70% are reported for patients with surgically treated isolated vulvar recurrences and more than 60% of patients with local recurrence or reoccurrence were alive at 20 years in the Mayo Clinic long-term follow-up study (72,147,148).


Gynecology_Novak

Gynecology_Novak. Local Recurrence Margin status at the time of radical resection of the vulvar cancer is the most powerful predictor of local vulvar recurrence, with an almost 50% recurrence risk with margins closer than 0.8 cm (84). Margin status does not predict survival (71). Local vulvar recurrences are likely in patients with primary lesions larger than 4 cm in diameter, especially if lymph–vascular space invasion is present, and in patients with deeply invasive tumors (141,149,150). When detected early, isolated local failure is usually treatable by additional surgical therapy, often with a myocutaneous graft to cover the defect (34,41,49,78,151). Radiation therapy, particularly a combination of external beam therapy plus interstitial needles, at times combined with chemotherapy, is used to treat vulvar recurrences (152).


Gynecology_Novak

Gynecology_Novak. Three distinct patterns of local recurrence were described: remote vulvar recurrence (greater than 2 cm of the primary tumor site), primary tumor site recurrence (within 2 cm of the primary tumor site), and skin bridge recurrence (81,150). Although reported treatment rates are excellent for remote site recurrences with 3-year survival rates of 67% to 100%, the literature is controversial as to the prognostic significance of primary tumor site recurrences, with one study reporting a 3-year survival rate of only 15% and the other a 5-year survival of 93% (81,150). Patients with skin bridge recurrence have a very poor prognosis, similar to those with groin recurrence.


Gynecology_Novak

Gynecology_Novak. Regional and Distant Recurrence Regional and distant recurrences are difficult to manage and are associated with a poor prognosis (141,145,146). Radiation therapy may be used in conjunction with surgery for groin recurrence, whereas chemotherapeutic agents that have activity against squamous carcinomas may be offered for distant metastases. The literature on the use of chemotherapy for recurrent vulvar cancer consists mainly of small series. The most extensively studied regimens contain bleomycin, methotrexate, and lomustine (a nitrosourea); bleomycin and mitomycin C; or cisplatin, vinorelbine, and paclitaxel, but response rates are low and the duration of response is usually disappointing (153–157). Long-term survival is very uncommon with regional or distant recurrence. Symptom control and quality of life are important treatment goals, and early involvement of a multidisciplinary palliative care team is generally indicated.


Gynecology_Novak

Gynecology_Novak. Vulvar melanomas are rare, with an incidence of 0.1 to 0.19 per 100,000 women (158,159). They account for 4% to 10% of all cases and are the second most common form of vulvar malignancy. Most melanomas arise de novo, but they may arise from a preexisting junctional nevus (160). Vulvar melanomas occur most frequently in postmenopausal white women, but are commonly seen in individuals with darker pigmented skin. Contrary to cutaneous melanoma, based on SEER data, there are low racial differences in vulvar melanomas, the development of which appears to be determined by factors other than ultraviolet radiation exposure and the photoprotective effects of melanin seen in cutaneous melanoma (161). The incidence of cutaneous melanomas worldwide is increasing significantly, but not that of vulvar melanoma (161). Vulvar melanomas appear to behave in a manner similar to that of other truncal cutaneous melanomas (162–165).


Gynecology_Novak

Gynecology_Novak. Most patients with vulvar melanoma have no symptoms other than a pigmented lesion that may be enlarging. Some patients have itching or bleeding, and a few have a groin mass. Vulvar melanomas occur most frequently on the labia minora or the clitoris (Fig. 38.6), and extension into the urethra or vagina at discovery is not uncommon. Any pigmented lesion on the vulva should be excised or, if the lesion is large, sampled for biopsy unless it is known to have been present and unchanged for some years. Most vulvar nevi are junctional and may be precursor lesions to melanoma; any nevus of the vulva should be removed. Figure 38.6 Melanoma of the vulva involving the right labium minus. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:564, with permission.)


Gynecology_Novak

Gynecology_Novak. Figure 38.7 Vulvar melanoma. Spindle-shaped melanoma cells form interlacing bundles, and some contain melanin pigment (right upper corner). Epidermal invasion is evident in the form of Pagetoid migration (left upper corner). Table 38.7 Microstaging of Vulvar Melanoma Clark Level (168) Chung Depth of Invasion (167) Breslow Tumor Thickness (169) I Intraepithelial Intraepithelial <0.76 mm II Into papillary dermis ≤1 mm from granular layer 0.76–1.5 mm Superficial invasion III Filling dermal papillae 1.1–2.0 mm from granular layer 1.51–2.25 mm Intermediate invasion IV Into reticular dermis >2 mm from granular layer 2.26–3.0 Intermediate invasion 2. The superficial spreading melanoma tends to remain relatively superficial early in its development. 3. The nodular melanoma, which is the most aggressive, is characterized by a raised lesion that penetrates deeply and may metastasize widely.


Gynecology_Novak

Gynecology_Novak. 3. The nodular melanoma, which is the most aggressive, is characterized by a raised lesion that penetrates deeply and may metastasize widely. In one of the largest reported series, more than one-fourth of the cases of melanomas were macroscopically amelanotic (158). Vulvar melanoma tends to spread early, not only lymphatically but also hematogenously.


Gynecology_Novak

Gynecology_Novak. Staging The FIGO staging used for squamous lesions is not applicable to melanomas because the lesions are usually much smaller and the prognosis is related to the depth of tumor invasion rather than to the diameter of the lesion (162,165,166). The leveling system established by Clark et al. for cutaneous melanomas is less readily applicable to vulvar lesions because of the different skin morphology (166). The vulvar skin lacks a well-defined papillary dermis. Breslow measured the thickest portion of the melanoma from the surface of intact epithelium to the deepest point of invasion (167). This system is more adequate for the vulva. Chung et al. proposed a modified system that retained Clark’s definitions for levels I and V but arbitrarily defined levels II, III, and IV, using measurements in millimeters (165). A comparison of these systems is shown in Table 38.7.


Gynecology_Novak

Gynecology_Novak. The revised 2009 AJCC staging for cutaneous melanoma indicates that tumor thickness remains the primary determinant of the T staging, but mitotic rate was integrated to subcategorize T1 tumors in addition to the presence of ulcerations. Specific immunohistochemistry criteria for the detection of micrometastases were included. The number and volume of metastatic nodes, site(s) of distant metastatic disease, serum lactate dehydrogenase level, and sentinel node results remained part of the staging (168).


Gynecology_Novak

Gynecology_Novak. Treatment With better understanding of the prognostic significance of the microstage, some individualization of treatment developed. Treatment of vulvar melanoma continues to be controversial, in part because of the lack of large prospective studies, which makes it difficult to draw conclusions regarding its behavior and best treatment. Treatments are guided by experience from cutaneous melanoma and squamous cell carcinomas of the vulva. Paralleling the trend toward more conservative surgical management of cutaneous melanoma, there is a shift toward more conservative management of vulvar melanoma (163,164,169–171).


Gynecology_Novak

Gynecology_Novak. It is accepted that lesions with less than 1 mm of invasion may be treated with radical local excision alone (165,172). With more invasive lesions, en bloc resection of the primary tumor and regional groin nodes was traditionally recommended. In the past 15 years, radical vulvectomy was performed less frequently and survival did not seem to be compromised (173). One study reported on 32 patients with vulvar melanoma who underwent local excision (n = 14), simple vulvectomy (n = 7), or radical resection (n = 11) (174). No group had a superior survival rate, although the overall survival rate at 5 years was only 25%. Another study reported on 59 patients who underwent radical vulvectomy and 19 who underwent more conservative resections (163). Survival was not improved by the more radical approach, and they recommended radical local excision for the primary tumor, with groin dissection for tumors with a thickness of more than 1 mm. A recent SEER data analysis of 644 patients with vulvar


Gynecology_Novak

Gynecology_Novak. and they recommended radical local excision for the primary tumor, with groin dissection for tumors with a thickness of more than 1 mm. A recent SEER data analysis of 644 patients with vulvar melanoma did not find a survival difference in patients with localized disease treated with more conservative versus radical surgery. Five-year disease specific survival rates for patients undergoing conservative surgery for localized disease were 75% versus 79% for those undergoing radical surgery (174). Literature on cutaneous melanoma suggests that a 1-cm margin of skin and subcutaneous tissue is sufficient for the treatment of superficial localized melanoma (Breslow tumor thickness <0.76 mm), whereas a 2-cm margin suffices for intermediate-thickness lesions (1 to 4 mm) (175,176). At least a 1-cm tumor-free deep surgical margin is recommended, irrespective of tumor thickness. Because melanomas commonly involve the clitoris and labia minora, the vaginourethral margin of resection is a common


Gynecology_Novak

Gynecology_Novak. tumor-free deep surgical margin is recommended, irrespective of tumor thickness. Because melanomas commonly involve the clitoris and labia minora, the vaginourethral margin of resection is a common site of failure, and care should be taken to obtain an adequate “inner” resection margin (177). A 10-year survival rate of 61% was shown for lateral lesions, compared with 37% for medial lesions (p = 0.027) (149).


Gynecology_Novak

Gynecology_Novak. Controversy exists as to which patients may benefit from inguinal-femoral lymphadenectomy. A prospective study by the GOG demonstrated that the risk of inguinal-femoral lymph node metastasis correlated with the Breslow microstage (165). As with cutaneous melanoma, it appears that for superficial lesions (Breslow tumor thickness <0.76 mm), the risk for nodal spread is so low that routine lymphadenectomy is not indicated as long as the nodes appear clinically free of disease. For intermediate-thickness (1 to 4 mm) cutaneous melanoma, a randomized controlled trial of elective lymph node dissection versus observation showed a 5-year survival advantage for patients who underwent elective lymph node dissection, who were younger than 60 years, and whose tumors were characterized by 1-to 2-mm thickness and no ulcerations (178). Patients with deeply invasive cutaneous melanomas (>4-mm tumor thickness) have a high risk of regional and systemic metastases and are unlikely to benefit from


Gynecology_Novak

Gynecology_Novak. thickness and no ulcerations (178). Patients with deeply invasive cutaneous melanomas (>4-mm tumor thickness) have a high risk of regional and systemic metastases and are unlikely to benefit from regional lymphadenectomy (179). Given some of the epidemiologic, histologic, and prognostic differences between vulvar and cutaneous melanoma, extrapolation of these data to the vulva should be done with caution (180). Specific to patients with vulvar melanoma, there is a small body of literature to suggest that there may be a clinical benefit in elective groin lymphadenectomy and the resection of clinically positive nodes (162,163). The role of the sentinel lymph node procedure in vulvar melanoma is under investigation. In cutaneous melanoma, sentinel lymph node biopsy replaced elective lymph node dissection in patients with clinically negative nodes, as it provides the same prognostic information with reduced morbidity. Only patients with metastatic disease undergo completion


Gynecology_Novak

Gynecology_Novak. lymph node dissection in patients with clinically negative nodes, as it provides the same prognostic information with reduced morbidity. Only patients with metastatic disease undergo completion lymphadenectomy. Results from an interim analysis of the Multicenter Selective Lymphadenectomy Trial confirmed the prognostic value of the sentinel node procedure. These data suggest that an immediate completion lymphadenectomy following detection of a positive sentinel lymph node improves survival in patients with regional nodal metastases (181). Studies on the sentinel lymph node procedure for vulvar melanoma are limited. A review of the literature estimates a false-negative rate of about 15% (182). Although the sentinel node procedure appears appropriate for select patients with vulvar melanoma, the importance of an expert team familiar with the procedure and consisting of a gynecologic oncologist, a nuclear medicine specialist, and a pathologist with expertise in microstaging cannot be


Gynecology_Novak

Gynecology_Novak. the importance of an expert team familiar with the procedure and consisting of a gynecologic oncologist, a nuclear medicine specialist, and a pathologist with expertise in microstaging cannot be overemphasized.


Gynecology_Novak

Gynecology_Novak. Pelvic node metastases do not occur in the absence of groin node metastases (177,183,184). The prognosis for patients with positive pelvic nodes is so poor that there seems to be no value in performing pelvic lymphadenectomy for this disease. Immunotherapy and chemotherapy have demonstrated modest results in cutaneous melanoma. Several randomized cooperative and Intergroup trials of high-risk melanoma patients demonstrated a small but significant improvement in disease-free and overall survival with adjuvant interferon alpha (185–187). Dacarbazine (DTIC) is considered the most active single-agent chemotherapy, with a response rate of 16%, and randomized controlled trials failed to demonstrate superiority of any multiagent regimen (188). Targeted therapy is an area of promising development as single agents, in combination, and combined with chemotherapy. A vaccine stimulating both antibody and T-cell responses against melanoma is a promising but experimental treatment that is under


Gynecology_Novak

Gynecology_Novak. as single agents, in combination, and combined with chemotherapy. A vaccine stimulating both antibody and T-cell responses against melanoma is a promising but experimental treatment that is under investigation (189). Estrogen receptors were demonstrated in human melanomas, and an occasional response to tamoxifen was reported (190,191). Traditionally, melanomas were thought to be radiation resistant. There is a growing body of literature for advanced, high-risk, lymph node–metastatic cutaneous melanoma, demonstrating improved locoregional disease control compared to surgery with therapeutic lymphadenectomy alone (192,193).


Gynecology_Novak

Gynecology_Novak. Table 38.8 Prognosis for Patients with Vulvar Melanoma Stratified by Breslow Microstaging DOD, died of disease. aAll but one of these seven deaths were reported in one study with an unusually low 5-year survival of 48% for 12 patients with superficial melanomas of Breslow thickness <0.76 mm. If these 12 cases were excluded, 5% of patients with superficial melanoma of the vulva died of disease. From references 160, 165, 174, 185, 186, 196–199.


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Gynecology_Novak. Prognosis The behavior of melanomas can be unpredictable, but the prognosis is poor. The reported 5year overall survival rate for vulvar melanoma is in the range of 50% to 60% (158,159,171). A SEER database analysis showed disease-specific survival rates for patients with localized, regional, and distant disease of 76%, 39%, and 22%, respectively (171). Localized disease, negative lymph nodes, and younger age were significant independent prognostic factors for improved survival. Because vulvar melanoma has a propensity for late recurrences, 5-year survival may not reﬂect cure. Prognosis is best predicted by microstaging. Patients with lesions invading to 1 mm or less have a good prognosis, but as depth of invasion increases, the prognosis worsens (Table 38.8). Tumor volume is reported to correlate with prognosis; patients whose lesions have a volume less than 100 mm3 have an excellent prognosis (184). Additional prognostic factors are the patient’s age, AJCC stage, presence of