TNM categories
FIGO stages
Definition
Primary tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ (preinvasive carcinoma)
T1a
IA
Lesions 2 cm or less in size, confined to the vulva or perineum and with stromal invasion 1.0 mm or less
T1b
IB
Lesions more than 2 cm in size or any size with stromal invasion more than 1.0 mm, confined to the vulva or perineum
T2
II
Tumor of any size with extension to adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement)
T3
IVA
Tumor of any size with extension to any of the following: upper/proximal 2/3 urethra, upper/proximal 2/3 vagina, bladder mucosa, rectal mucosa, or fixed to the pelvic bone
Regional lymph nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
One or two regional lymph nodes with the following features
N1a
IIIA
One or two lymph node metastases, each 5 mm or less
N1b
IIIA
One lymph node metastasis 5 mm or greater
N2
IIIB
Regional lymph node metastasis with the following features
N2a
IIIB
Three or more lymph node metastases, each less than 5 mm
N2b
IIIB
Two or more lymph node metastases 5 mm or greater
N2c
IIIC
Lymph node metastasis with extracapsular spread
N3
IVA
Fixed or ulcerated regional lymph node metastasis
Distant metastasis (M)
M0
No distant metastasis
M1
IVB
Distant metastasis (including pelvic lymph node metastasis)
Management of the Primary Tumor
Historically, the gold standard for vulvar cancer staging and treatment was en bloc radical vulvectomy and bilateral inguinofemoral lymphadenectomy through a butterfly incision. Despite the favorable survival outcomes, this procedure was associated with remarkable morbidity, including a high rate of wound infections, lymphedema, and major problems regarding patient’s sexual function, body image, and self-assurance. Therefore, over the last decades, the excision of primary tumor and inguinofemoral lymph nodes has been accomplished through three separate incisions [8, 21]. This approach results in fewer complications, without compromising survival [22].
The technique used to resect the vulvar tumor depends on its size and extension [23]. Radical vulvectomy implies removal of the entire vulva down to the level of the deep fascia of the thigh, the periosteum of the pubis, and the inferior fascia of the urogenital diaphragm [8]. In current practice, the radical local excision and modified radical vulvectomy (also known as radical hemivulvectomy) are typically used [23]. Although data from prospective trials are lacking, the oncologic outcomes of the radical local excision, modified radical vulvectomy, and radical vulvectomy seem to be comparable [24, 25]. It should be stressed that the depth of resection is the same in all the aforementioned techniques (e.g., to the urogenital diaphragm) [26]. Importantly, T1 and T2 lesions ≤4 cm not infiltrating the urethra, vagina, or anus can be treated with wide local excision [8, 23, 26].
Independently of the selected surgical approach, every effort should be made to obtain normal tissue margins of 1–2 cm at primary surgery as a means to decrease the risk of local recurrence [23, 27]. If final pathology is consistent with closer (<8 mm) or positive surgical margins, re-excision or adjuvant radiation therapy (RT) should be offered. The decision is highly individualized and should take into account multiple parameters, including a patient’s desire and comorbidities, lymph node status, and proximity to the urethra, vagina, and anus [23]. If the lesion involves the urethra, the distal 1 cm of the urethra can be excised without affecting continence [8].
Patients with locally advanced disease (T2 tumors >4 cm or with involvement of the urethra, vagina, or anus and T3 tumors) may benefit from neoadjuvant RT with concurrent platinum-based radiosensitizing chemotherapy [23, 28]. 5-Fluouracil in combination with cisplatin or mitomycin-C has been also used in this setting [29–32]. In case of residual tumor deemed to be resectable, surgical excision is favored. If the patient is a poor surgical candidate or the tumor is unresectable, additional individualized RT and/or chemotherapy or supportive care is recommended [10, 23].
Wound infection and breakdown are the most common complications that may follow surgery to the vulva. Their incidence ranges from 9 to 58%, while extensive surgery, increased age, obesity, diabetes, smoking, and prior RT are recognized as predisposing factors [33]. When large areas of the vulva are resected, tissue mobility is poor, or in case of neoadjuvant RT, primary closure of the vulvar defects may not be feasible. In these patients, vulvar reconstruction with fasciocutaneous or myocutaneous flaps, most commonly by plastic surgeons, may be needed [4, 8]. Urinary incontinence and vaginal prolapse are also listed among vulvar surgery complications [33]. Greater than 50% of the women who undergo vulvectomy report sexual dysfunction, including dyspareunia, decreased desire, or inability to orgasm, as well as resultant psychological issues. Conservative surgical techniques, when indicated, may result in better sexual and cosmetic outcomes [33].
Prognosis
Several factors have been reported to affect the prognosis of patients with vulvar cancer, including their age, the stage of disease, tumor size, DOI, capillary lymphatic space invasion, and lymph node status [34–37]. Among them, the presence of positive inguinofemoral lymph nodes is the single most significant determinant of disease-specific mortality [4, 8, 10, 34]. Further aspects of lymph node involvement (number, size of metastasis, and capsule infiltration) that exhibit a prognostic role are incorporated into the current staging system, presented in Table 8.1 [18, 19]. As mentioned, the adequacy of surgical margins is an important parameter that influences the risk of local recurrence. Heaps et al. found that a microscopic pathologic margin <8 mm corresponding to <1 cm in fresh tissue was associated with a 50% chance of recurrence [27]. Their results were supported by more recent studies [26, 36]. Lastly, a retrospective study published in 2016 revealed that among patients with SCC who received RT with or without surgical resection, the presence of HPV or its surrogate of p16 immunostaining was associated with better progression-free survival (PFS) and lower local recurrence rates [38]. In contrast, a series of 201 cases revealed increased risk of local relapse, either close or remote to the tumor margins, when vulvar SCC arose in a field of lichen sclerosis [39].
Follow-Up
According to the recently released National Comprehensive Cancer Network (NCCN) guidelines on SCC of the vulva, surveillance includes visits every 3–6 months for the first 2 years, followed by visits every 6–12 months until the completion of 5 years after treatment. Thereafter, the patients can be examined on an annual basis, although individual risk factors for disease recurrence may modify the schedule [23]. Of note, it was shown that relapses occur ≥5 years after the initial therapy in 35% of patients; these findings underscore the value of long-term surveillance [41, 42]. Surveillance visits should include a patient’s history and detailed physical examination, with emphasis on the vulva, skin bridge, and groins [23, 42]. Distant areas of potential cancer recurrence (e.g., supraclavicular lymph nodes, lungs, brain, bones), as well as possible sites for neoplasia (cervix, vagina, perianal area), also should be evaluated [7, 42]. Regular cervical/vaginal cytology screening should be considered. In case of symptoms or clinical findings indicative of recurrence, appropriate laboratory workup and imaging studies should be ordered [23, 42]. The assessment for possible long-term complications from vulvar cancer treatment, including sexual health issues, should be part of the follow-up visit [10, 33].
Recurrence
Most treatment failures are diagnosed within 2 years after the initial surgical therapy [41]. Vulva constitutes the most common site of recurrence. In a series of 502 patients, 53.4% of them were diagnosed with local relapse. Inguinal, pelvic, distant, and multiple recurrences were found in 18.7%, 5.7%, 7.9%, and 14.2% of the patients, respectively [37]. According to a Gynecologic Oncology Group (GOG) study on patients who had undergone conservative therapy for vulvar cancer, the median time to recurrence in the vulva and groin was 35.9 and 7.0 months, respectively. Patients with local recurrence had better prognoses; the median survival after vulvar and groin relapse was 52.4 and 9.4 months, respectively [43]. Similarly, Maggino et al. showed that patients with recurrence in the vulva had favorable survival outcomes, compared to those with regional or distant recurrence. In their report, the 5-year survival rates were 60% for local, 27% for inguinal and pelvic, 15% for distant, and 14% for recurrence at multiple sites [37]. However, local relapse at the site of the primary tumor or skin bridge confers higher risk of cancer-related death compared with other perineal areas [44].
In recurrent cases, the treatment intent (curative vs. palliative) and plan depend on the patient’s performance status, site of recurrence, and previous management. In patients not previously irradiated, recurrences confined to vulva with clinically negative lymph nodes are treated with radical re-excision. Unilateral or bilateral inguinofemoral lymphadenectomy (IFLD) is performed if neglected at the time of initial therapy [23]. Pelvic exenteration can be considered in case of local, central recurrence [23]. In this setting, PET/CT should be preoperatively ordered to rule out distant metastases [42]. Patients not previously exposed to pelvic RT can be scheduled for surgical resection if isolated pelvic lymph node recurrence is diagnosed. In case of multiple pelvic lymph node involvement, distant recurrence, or history of pelvic RT, management options include systemic chemotherapy, supportive care, or enrollment in a clinical trial [23]. The treatment recommendations for patients with groin recurrence are outlined in the relevant section of this chapter.
Management of Inguinofemoral Lymph Nodes
Inguinofemoral Lymphadenectomy (IFLD ) in Patients with SCC of the Vulva
Full or complete IFLD refers to the removal of all lymph nodes of the Scarpa’s triangle; the superficial chain lies between the superficial and femoral fascia, while the deep lymph nodes are situated within the fossa ovalis medial to the femoral vein. This procedure can be performed with the preservation of the femoral fascia [45].
Landmark studies published over the last decades determined the indications of performing IFLD in vulvar cancer patients that guide the current practice. As aforementioned, the risk of lymph node spread is <1% when DOI ≤1 mm [4, 7, 46]. In 1979, DiSaia et al. proposed that superficial IFLD could substitute for full IFLD in select patients. Their single-institution trial on women with stage I disease, DOI ≤5 mm, and negative nodes on frozen section supported this approach [21, 47]. However, the GOG-74 protocol demonstrated a disappointingly high rate of groin and/or vulva recurrence in women treated with radical local excision and ipsilateral superficial IFLD compared to historic controls having undergone radical vulvectomy and bilateral IFLD (15.6% vs. 6.7%, respectively) [48]. The GOG-88 protocol was designed to test whether groin RT was superior to and less morbid than IFLD in patients with clinically nonsuspicious nodes. The study was closed prematurely due to an unacceptably increased rate of groin recurrence in the RT group [49]. In terms of laterality, numerous studies pointed out that the risk of contralateral groin node metastasis in case of patients with early-stage, lateral disease and negative nodes after unilateral IFLD is <3% [48, 50, 51]. More recently, Gonzalez Bosquet et al. showed that in tumors located >1 cm from the midline with size ≤2 cm and DOI ≤5 mm, the risk of contralateral metastasis is zero [52].
Taken together, the NCCN recommends that IFLD can be safely omitted in patients with stage IA SCC of the vulva. In contrast, women with IB-II disease should undergo IFLD. For a tumor that is <2 cm in maximum dimension, located 2 cm or more from the vulvar midline and in the setting of clinically negative groin nodes, ipsilateral IFLD is appropriate. If positive lymph nodes are identified on pathology, contralateral IFLD or RT of the contralateral groin is recommended. Tumors closer than 2 cm from or crossing the vulvar midline should be treated with bilateral IFLD. Women with positive lymph nodes after bilateral IFLD should be offered RT with or without chemotherapy, especially when two or more lymph nodes are involved or the metastatic deposits are larger than 2 mm [23]. Homesley et al. demonstrated that for patients with positive groin nodes, adjuvant radiation is preferred over pelvic lymphadenectomy [53].
The management of bulky inguinofemoral lymph nodes in the setting of an unresectable or T3 primary vulvar tumor is more controversial. Platinum-based chemoradiation to the primary tumor, bilateral groins, and pelvis with or without prior debulking of the positive inguinofemoral lymph nodes is among the available options [23].
IFLD leads to significant morbidity; it is estimated that more than half of patients undergoing IFLD will experience at least one complication associated with the procedure. Lymphedema is a chronic condition that may be evident in almost 50% of these patients. It most commonly presents within 12 months of the groin dissection and may result in decreased mobility, severe limitations in daily activities, and psychological distress [33]. Obesity, a large number of lymph nodes removed, extensive surgery, postoperative infection or deep venous thrombosis (DVT), and RT to the groins are listed as risk factors for lymphedema development [33, 54, 55]. Lymphocele, a term used to describe collections of lymphatic fluid into the dead space resulting from lymph node dissection, may be diagnosed in up to 40% of patients after IFLD. Lymph leakage along with impaired lymphatic reabsorption seems to be the underlying mechanism for their formation. Importantly, lymphocele confers a higher risk for infection, edema, pain, and DVT [33]. Lastly, despite the remarkable decrease in their incidence after the implementation of the separate groin incisions, wound secondary events are common in patients undergoing IFLD. Wound infection, cellulitis, or breakdown may complicate 21–39%, 21–57%, or 17–39% of the cases, respectively [33].
Sentinel Lymph Node (SLN) Biopsy
Rationale, Diagnostic Accuracy, and Oncologic Safety
SLN mapping is an image-guided procedure used in the treatment of multiple types of cancer, primarily melanoma and breast cancers [56, 57]. This approach is based on the concept that lymph drains in an orderly pattern away from the tumor through the lymphatic system. Consequently, if the SLN is negative for metastasis, then the remaining nodes should also be negative and can be left behind [56]. The desire to limit the incidence and severity of the complications associated with complete lymphadenectomy largely accounts for SLN biopsy’s increasing popularity over the last decades [57].
Lymph node involvement will be diagnosed in only 20–30% of early-stage vulvar cancer patients. Therefore, the vast majority of these women will be exposed to the risks of IFLD without, most likely, gaining a benefit from it [51]. Given that the need to exclude lymph node metastasis in the preoperative setting cannot be reliably met by imaging studies, including US, CT, MRI, and PET, the role of SLN biopsy has been extensively studied [15]. The encouraging results from several small studies led to the design of two large prospective trials, which validated the accuracy and established the safety of the procedure: the Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) and GOG-173 [51, 58, 59].
The GROINSS-V study was a multicenter observational study of 403 women with early-stage vulvar cancer, in which full IFLD was omitted in patients with a negative SLN. Squamous cell histology, primary tumor smaller than 4 cm, DOI >1 mm, and nonsuspicious groin nodes at palpation served as the eligibility criteria. By utilizing a radioactive tracer and blue dye, the false-negative rate (FNR) was 5.9% (4.6% in patients with unifocal disease), and the false-negative predictive value was 2.9%. Among 259 patients with unifocal disease and negative SLN, a groin recurrence rate of 2.3% over a median follow-up time of 35 months and a 3-year disease-specific survival (DSS) rate of 97% were recorded [57, 58]. This rate of groin relapse was at least comparable to that reported for patients with early-stage vulvar cancer and negative lymph nodes following any type of formal IFLD [60]. In contrast, groin recurrence was diagnosed in 11.8% of patients with multifocal disease; this high rate resulted in the protocol amendment and exclusion of patients with multifocal disease. The rates of complications in patients with SLN biopsy and full IFLD, as indicated by positive SLN, were as follows: wound breakdown, 11.7% vs. 34.0%; cellulitis, 4.5% vs. 21.3%; recurrent erysipelas, 0.4% vs. 16.2%; and lymphedema, 1.9% vs. 25.2%, respectively [58]. In 2016, after a median follow-up time of 105 months, study outcomes were published. Among SLN-negative patients, the rate of isolated groin recurrence was 2.5%, and the 10-year DSS was 91% [61].
The GOG protocol 173 was a multi-institutional observational study of 452 women with early-stage vulvar cancer. Eligible women should have had SCC, DOI ≥1 mm, tumor size ≥2 and ≤6 cm, as well as clinically benign lymph nodes. All patients underwent SLN biopsy, followed by full IFLD. The FNR for SLNs identified by blue dye alone, radiocolloid alone, and combination of blue dye and radiocolloid was 2.0%, 7.8%, and 1.6%, respectively. As far as the size of primary tumor was concerned, the FNR dropped from 8% in the study population to 5.6%, when the analysis was restricted to patients with tumor size <4 cm. The false-negative predictive value for SLN biopsy was 3.7%. In patients with tumors measuring <4 cm, the false-negative predictive value for SLN biopsy was 2.0%. In case of tumors measuring 4–6 cm, the false-negative predictive value for SLN biopsy climbed up to 7.4% [59].
The meta-analyses of the literature on SLN mapping in early-stage vulvar cancer patients confirmed the above findings. Hassanzade et al. found a detection rate per groin of 84.6% [62]. More recently, an FNR of 5% was reported after using the combination of radiocolloid and blue dye for detection and pathological examination with ultrastaging and immunohistochemistry [63]. Lastly, Covens and coworkers from Canada showed that the overall detection rate per groin with the combination of blue dye and radiocolloid was 86.9%. The SLN detection rate per groin with a radioactive tracer was much higher, compared to blue dye alone (85% vs. 63%). Similarly, the FNR in cases of combined technique was lower than that calculated for the use of radiocolloid or blue dye alone (6.6% vs. 10.4% vs. 9.3%, respectively). The groin recurrence rate in patients treated with SLN biopsy was estimated to be 3.4%, as opposed to 1.4% in those undergoing full IFLD [64]. It is worth mentioning that a repeat SLN procedure in patients with recurrent vulvar cancer is technically more challenging and leads to a lower SLN detection rate [65].
Selection Criteria, Technique, and Pathologic Processing
In light of the above data, NCCN guidelines incorporated SLN biopsy in the management of select patients with early-stage vulvar cancer. The candidates for this technique should have SCC, unifocal tumor measuring less than 4 cm, negative clinical groin examination and imaging, as well as no prior surgeries to the vulva that may have impacted lymphatic flow to the inguinal region [23]. The best imaging technique (e.g., US, CT, MRI, PET) for the preoperative assessment of groins has not been determined; the decision largely depends on local expertise and availability [57].
In terms of SLN technique, the combination of both radiocolloid and dye is favored as a means to increase the sensitivity of SLN detection. The radioactive tracer—most commonly technetium-99m sulfur colloid—is usually injected 2–4 h prior to the surgical procedure [23]. A preoperative lymphoscintigraphy (LSG ) may be performed to aid in anatomically locating the SLN, although this strategy is more controversial [23, 57, 64]. Importantly, according to GOG-173 results, patients with lateral tumors (>2 cm from the midline) or lesions within 2 cm from the midline without involving it and only unilateral drainage on preoperative LSG may safely undergo unilateral SLN biopsy [66]. Approximately, 3–4 cc of dye—most commonly isosulfan blue 1%—is injected intradermally at the margins of the tumor (2, 5, 7, and 10 o’clock) within 15–30 min of initiating the SLN dissection. It should be stressed that the localization of blue dye in the nodal group of interest is transient (e.g., for 30–60 min). In order for the surgeons to explore the groins in a timely fashion and preserve the lymphatic channels connecting the vulvar tumor to the inguinal lymph node basin, the NCCN recommends that the SLN procedure be performed prior to the excision of the primary tumor. The location and size of the groin incision is more accurately determined after detecting the radiocolloid in the inguinofemoral region with the use of a gamma probe [23] (Fig. 8.1). A node that has >5 times the background radioactivity should be used to identify an SLN. Once the incision is made, the surgeon should also look for blue lymphatic channels and follow their course [64] (Fig. 8.2). It has been shown that 84% of SLNs are found in the superficial inguinal chain, while the remaining ones are deep femoral [67]. If an SLN is not identified, a side-specific, complete IFLD is required [23]. Of interest, a limited number of studies on the role of near-infrared (NIR) fluorescence imaging and indocyanine green (ICG ) tracer in SLN mapping for vulvar cancer have been conducted, showing promising results [68–71] (Fig. 8.3).
