The giant steps in surgical downsizing toward a personalized treatment of vulvar cancer

Surgical management

Early-stage VC includes FIGO Stages I and II, with tumor size ≤4 cm and stromal invasion ≤1 mm. Nodal spread is absent. Stages IA, IB, and II ≤4 cm are treated surgically. For tumors >1 mm invasion and dimensions up to 4 cm, surgical approach consists in a modified radical vulvectomy, with surgical lymph node assessment. This surgical technique includes superficial and deep fascia lata, including separate incisions for tumor and groin node dissection18; in this way, radical vulvectomy approach with en bloc bilateral inguinal-femoral lymphadenectomy has been overcome, sparing several complications (Figures 1 and 2). In fact, the postoperative management of the traditional surgical approach was very difficult because of the onset of many complications and surgical sequelae (infection, necrosis, pain, functional and esthetic distortion, deterioration of sexual life and psychological health)14 Di Saia and Hacker developed the concept of minimal resections margins, limited to the tumor.20-23 These results have been confirmed by a large study conducted by the Gynecologic Oncology Group.24 Safe margins are considered and are maintained from 1 to 2 cm (according to Heaps' study).25 The resection of primary vulvar tumor aims to save organs, such as the urethra, clitoris, and anal sphincter, while maintaining an adequate surgical radicality for the patient; the site of incision depends on tumor location.18, 21 For substage VC IA ≤1 mm treatment consists of a wide local excision, adequate if margins are negative. The term “wide local excision” or “simple vulvectomy” (synonymous of wide local excision) is referred to a type of excision without the inclusion of deep fascia but limited to subcutaneous tissue; tumor margin is 1 or 2 cm above the primary vulvar tumor.20, 21

image En bloc Way–Taussing radical vulvectomy showing butterfly skin incision19 image Triple incision: A skin bridge is left between the vulval and the groin incisions19

There are situations where close margins are more common (proximity to the clitoris, urethra, or vulva), but the National Comprehensive Cancer Network (NCCN) Guidelines recommend re-excision of positive margins or those classified as close (<8 mm).26 If smaller margins are safe is subject of studies.27

Moreover, postoperative reconstruction, based on patients' characteristics, after demolitive surgeries has improved esthetic result and psychological acceptance of this pathology, representing an important step for personalized treatment. Two types of flaps were identified: Advancement Flap (V-Y Gluteal Fold Flap; Medial Thigh Flap) and Transpositional Flap (Lotus Petal Flap; Gluteal Thigh Flap; Gluteal Fold Flap and Anterolateral Thigh Flap).28, 29

Resection margins

The safety of the size of resection margin is debated. Non-pathological margins must be greater than 8 mm25 Chan et al. suggested that no local recurrence has been registered after at least 8 mm margins distant.30 The study of Woelber showed that the recurrence rate is the same for lesions with margins of less than 8 mm and at least 8 mm, demonstrating no impact of margins distance on progression free survival (PFS).31 Arvas et al., assessing the margin status in 61 patients affected by vulvar cancer, analyzed those women with pathological margins ≤2 mm had an high risk of recurrence, compared with the group with >2 mm. The intermediate margins value (2–8 mm) was not a predictor of local recurrence.32, 33 The use of re-excision or adjuvant radiotherapy on the basis of close surgical margins alone (2–8 mm) should be carefully considered.27 Höckel et al. proposed a novel approach for patients with vulvar cancer based on compartmental tumor spread and based on ontogenetic anatomy: in this prospective trial patients were treated with vulvar field resection and anatomical reconstruction, considering anatomy from embryonic development. The extent of deep vulvar resection is not defined with conventional surgical margins and this approach allows to preserve tissue for esthetic reconstruction.23

However, current recommendations suggest surgical margins of 2 cm and final pathological margin of at least 1 cm.

Sentinel lymph node (SLN) and groin treatment

Surgical assessment of nodes can be achieved with bilateral SLN biopsy or inguinofemoral lymphadenectomy [IFLND]). Node's evaluation is necessary because the risk of occult nodal metastases is up to 30%.34 Utilization of SLN represents one of the biggest steps for surgical treatment of vulvar cancer, avoiding complications of routine bilateral lymphadenectomy (risk for lower-extremity lymphedema (approximately 30%–70%).35-39 This routine approach was changed by Gynecologic Oncology Group (GOG) study in 1987, avoiding groin node dissection in microinvasive VC, with a low risk of nodal metastases and in 199336 Homesley assessed that VC localized >2 cm from the midline, drains to ipsilateral groin nodes, and did not metastasize to contralateral part; in this way bilateral groin dissection became not mandatory. The advent of SLN biopsy provides new opportunities for patients, reducing lymphedema or lymphocists, out increasing the risk of groin recurrence.40, 41

SLN is the first lymph node that drains from tumor; GOG 173 and GROINSS-V–1 were the two multicenter observational studies that have analyzed the safety and feasibility of SLN as valid alternative to IFLND.35, 42 For midline vulvar tumors, bilateral SLN should be performed; whereas for lesions that are located ≥2 cm from the midline, unilateral node dissection is sufficient.20 Currently SLN biopsy has become the standard care for surgical treatment of VC with size ≤4 cm and clinically and/or radiological negative inguinofemoral lymph node. In case of positive SLN, the postoperative management is debated: alternatives include completion lymphadenectomy or external beam radiation therapy (EBRT). The ongoing prospective trial (GOG 270/Groningen International Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V-II) is evaluating if radiation therapy is safe in patients with SLN micrometastes (Table 1).43-49

TABLE 1. Literature review of the use of sentinel lymph nodes biopsy in vulvar cancer Authors Years Study type Patients (groins) Mapping method Median FU Groin recurrence (%) Outcome in SLN negative patients (%, 95% CI) van der Zee (GROINSS-V study)37 2008 Prospective 403 (623) R + B 35 (2–87)

6/259 (2.3) unifocal disease;

8/276 (3) including multifocal disease

3-year DSS (97) Oonk42 2010 Prospective 403 R + B 120 11 (2.7) NA Levenback (GOG 173)41 2012 Prospective 452 (772) R + B NA NA NA Woelber44 2013 Retrospective

Primary SLN group = 74/106

Secondary SLN group = 32/106

R 33 (3–118)

Primary SLN group = 4/74 (5.4);

Secondary SLN group = 0

Primary SLN group = 3-year DFS (72.5)

Secondary SLN group = 3-year DFS (92.5)

Robison45 2014 Prospective 86 R + B 58 4/86 (4.7) NA Te Grootenhuis46 2015 Prospective 377 R + B 105 (0–179) 6/253 (2.5) unifocal disease

5-year DSS (93.5)

10-year DSS (90.8)

5-year OS

Klapdor47 2017 Retrospective 772 R or B 33 (0–156) 2/69 (2.9)

3-year PFS (82.7; 72.3–92.7)

3-year OS (92.7; 85.7–99.7)

Nica48 2019 Retrospective 159 (245) R or R + B 31 6/120 (5)

1-year PFS (90)

5-year PFS (80)

Abbreviations: B, blue dye; DFS, disease-free survival; DSS, disease-specific survival; OS, overall survival; PFS, progression-free survival; R, radiotracer.

For women with diagnosis of vulvar cancer, the presence of lymph node metastases is the most important prognostic factor.50 The radical lymph node (LND) dissection was used for years, although a very high morbidity (lymphedema, nerve injury) with compromised quality of life.51 Moreover, histological analysis confirms the presence of lymph node metastases only in the 25%–35% of all patients; in this way the benefits from the LND procedure were limited SLN dissection as valid alternative to LND has been proposed to avoid overtreatment and to control complications. GROINSS-V is a prospective multicentric study: 400 patients with the same tumoral characteristics (size, stromal invasion, and negative preoperative diagnostic assessment) were treated with sentinel procedure. In patients with negative biopsy, systematic lymphadenectomy was omitted. Groin recurrence rate was only 2% after almost 3 years. No significative differences with patients with early-stage vulvar cancer treated with groin lymphadenectomy were noted.37 The number of groin recurrence in sentinel-node negative patients seems to be comparable to the other reported for early-stage vulvar cancer treated with lymphadenectomy. So, the effect seems to be the same.52

Oonk et al. demonstrated from the GROINSS-V data that even when only isolated cells are found in the sentinel node, the rate of no sentinel node metastasis is 4.1%, and in cases of metastasis of less than 5 mm, 11.7%.42, 43

GOG 173 is a prospective study in early-stage vulvar cancer, in which patients with SLN mapping followed by standard complete IFLND. The false-negative rate of an SLN biopsy in GOG 173 was 2.7% in patients whose tumors were <4 cm.41 Thanks to results of these studies, SLN was considered safe, sparing serious complications.

A systematic review and meta-analysis of the cumulative data on SLN detection reported a per-groin detection rate of 87% and a false-negative rate of 6.4% and groin recurrence rates appeared to be similar only under optimal conditions (unifocal tumors <4 cm, clinically non-suspicious nodes in the groin, appropriate techniques, and procedures).53

Recent studies checked safety and feasibility of sentinel node biopsy after vulvar surgery, confirming that this procedure after previous surgery is safe and reflects groin status.42, 54, 55 However false-negative sentinel carries a high risk of mostly fatal groin recurrences. Particularly midline tumors larger than 2 cm have to be treated carefully, because they are mostly found in cases with groin recurrences after sole SLN.56

In conclusion, patients with unifocal vulvar cancer, tumor size less than 4 cm, and clinically negative groin assessment can undergo SLN and vulvar surgery in a center with experienced team; if the sentinel node biopsy is positive, patient should undergo systematic IFLND. However, the optimal postoperative management of positive SLN is debated; in fact, adjuvant radiotherapy seems to be a valid alternative. The results of GROINSS-V-II trial show that for positive SLN with metastasis ≤2 mm radiotherapy is a valid therapeutic option instead of IFLND; toxicity is minimal. For patients with positive SLN and metastasis >2 mm, radiotherapy does not seem to be a safe alternative but systematic IFLND is the best option.42

The current standard approach for detection of SLN includes the use of lymphoscintigraphy with technetium 99 m with intraoperative blue dye (methylene blue or indigo carmine), whereas the use of blue dye alone is not recommended.53

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