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Abstract

Treatment for early-stage vulvar carcinoma has evolved from radical en bloc dissection to wide local incision with lymphadenectomy through separate groin incisions, to sentinel lymph node biopsy (SLNB). The morbidity of SLNB is far less than traditional inguinofemoral lymphadenectomy, with less lymphedema and sensory deficit, shorter hospital stays and fewer infections. A multidisciplinary approach is required, with success of the SLNB technique maximized when radiolabeled colloid is used, with blue dye added when further identification is needed. Frozen-section analysis, followed by ultrastaging of the nodal sample, minimizes the need for reoperations and decreases the risk of false negatives. We believe that SLNB will become the standard of care for treatment of early-stage vulvar carcinoma.

Keywords

accuracy cellulitis combined modality therapy female gynecologic surgical procedure/method humans lymph node excision lymphedema negative predictive value pathology sentinel lymph node biopsy/method treatment outcome vulvar neoplasm/surgery wound breakdown

In gynecologic oncology, vulvar carcinoma (CA) represents a challenge for clinicians, owing to its rarity and the vast number of evolving treatments that are becoming available. Vulvar CA accounts for approximately 5% of gynecologic malignancies, with squamous cell CA comprising approximately 90% of cases [1]. The incidence of vulvar cancer in North America is 1–2 per 100,000 women, with an average age of diagnosis of 70 years [2]. Staging for vulvar CA is reported using the International Federation of Gynecology and Obstetrics (FIGO) classification, which was established in 1988 and modified in 1994 [2]. Treatment for early-stage disease has evolved from en bloc radical vulvectomy with bilateral inguinal lymphadenectomy to radical wide local excision with ipsilateral or bilateral inguinal lymphadenectomy performed through separate incisions [2]. The evolution of treatment towards less aggressive dissection reflects the morbidity associated with extensive vulvar and inguinofemoral surgery [3,4]. Most recently, radical wide local excision with sentinel lymph node (SLN) biopsy (SLNB) – used successfully in breast and melanoma – has been incorporated. However, adoption of the SLNB procedure has been tempered by the need for accurate assessment of the presence or absence of groin node metastases.

The concern with more conservative management of vulvar cancer is the dismal prognosis in women with inguinofemoral recurrence when the groin area is not initially dissected, with 90% of such patients dying from the disease [2]. Furthermore, survival of patients with vulvar CA is linked to the presence of nodal metastases. The seminal work by Hacker et al. revealed that the 5-year survival for patients with negative nodes is 96%, falling to 94% with one positive node, 80% with two positive nodes, and 12% with three or more positive nodes [5]. In current practice, no effective preoperative method exists for detecting the presence of metastases within the inguinofemoral region – either via physical examination, diagnostic imaging or ultrasound-guided biopsy [6]. Since only 27% of women harbor nodal metastases, approximately 70% of women undergoing groin node dissection experience no therapeutic benefit, but 100% of women are subject to the associated surgical risk [5]. Owing to these factors, many gynecologic oncologists have shifted surgical management to incorporate the SLNB technique.

This review will address the current standard of care in vulvar CA surgery and the morbidity associated with this treatment. The SLNB procedure will then be reviewed, with a focus on the technique, pathological considerations, its accuracy and questions surrounding recurrence rates.

Current standard

While surgery remains the cornerstone of vulvar CA treatment, the type of surgery incorporated has evolved. The standard of care for early-stage squamous cell CA of the vulva (FIGO I/II) is wide local excision with unilateral or bilateral inguinofemoral lymphadenectomy, depending on the proximity of the lesion to the midline [7]. The decision to undertake inguinofemoral lymphadenectomy is based upon the depth of invasion of the tumor. Any lesion invading more than 1 mm requires inguinal lymph node sampling [8]. The primary site of drainage of vulvar neoplasms, regardless of histological subtype, is to the superficial femoral node group within the femoral triangle. The triangle, bordered by the sartorius muscle laterally, the adductor longus muscle medially and the inguinal ligament superiorly, has superficial and deep nodal groups separated by the cribiform fascia [2]. The SLNs for vulvar drainage lie within the superficial and/or the deep inguinal compartments. Unilateral versus bilateral inguinal metastases can be predicted based upon the location of the vulvar primary. Lateralized lesions are known to have ipsilateral lymph flow, whereas lesions within 1 cm of the midline, have bilateral lymph drainage [9]. FIGO recommends that groin dissection includes both the superficial and deep lymph nodes found within the femoral triangle [10]. This recommendation is reflective of the Gynecologic Oncology Group (GOG) finding that 7.4% of patients had groin recurrence when inguinofemoral dissection was limited to the superficial compartment [11]. Bilateral inguinofemoral lymphadenectomy is thus undertaken in the setting of a midline lesion, within 1 cm of the midline or in the presence of a metastatic lymph node, since 10% of such patients will have a metastasis to a contralateral groin lymph node. For lateralized lesions, ipsilateral inguinofemoral dissection is sufficient [12].

The safety of the triple-incision technique versus en bloc radical dissection has never been tested in a randomized, controlled trial. The theoretical concern with separate incisions is the possibility of recurrences in the skin bridge separating the vulvar and groin incisions. Observational studies addressing this concern were summarized in a Cochrane review, which demonstrated the risk of skin bridge recurrence to be 1% at most when a tumor-free margin of 8 mm on final pathology was achieved [13]. Considering the significant morbidity of en bloc dissection and the low recurrence observed with less extensive surgery, the triple-incision technique has become the standard of care for surgical management of vulvar CA patients.

Surgical morbidity

Early experience with en bloc radical vulvectomy demonstrated complications, including wound breakdown and impaired healing, to be as high as 85% [14]. Debilitating lymphedema is a long-term problem affecting the lower extremities; in a study by Podratz et al., this was reported to be the case in 69% of their radical vulvectomy patients [14]. Other complications reported include lymphocyst development and parasthesia over the medial thigh.

While morbidity is significantly less with the triple-incision technique compared with en bloc radical dissection, it is nonetheless still a major concern for patients. Case series reveal that wound breakdown still occurs in 17–31% of patients, with wound cellulitis present in 25–39% and lymphedema in 28–39% of patients [15 –17]. GOG-195 revealed that patients experiencing a wound infection at the lymphadenectomy site had an increased risk of developing lymphedema relative to patients who did not become infected. Furthermore, wound breakdown was more common (40 vs 13%; p = 0.0064) in patients who had the saphenous vein resected at the time of lymphadenectomy [18].

For all patients undergoing surgical treatment for vulvar CA, a discussion of morbidity should include psychological issues. Even with a triple-incision technique, the lower self-esteem observed in patients dealing with changes in body image can manifest as depression, loss of confidence and withdrawal from sexual activity. Psychological morbidity following treatment for vulvar CA was investigated by Anderson et al., who demonstrated a significant impairment of sexual functioning following treatment for vulvar CA, irrespective of the ability to participate in sexual intercourse [4]. Weijmar Schulz et al. further studied the issue in a prospective cohort of women treated for vulvar CA, concluding that psychological satisfaction with the relationship, and sexual activity within the relationship preceding treatment, were most predictive of sexual functioning post-treatment [19]. Furthermore, the presence of lymphocysts and leg edema are an ongoing reminder for patients and those around them of the reality of their disease [20]. Pereira de Godoy et al. demonstrated that the greatest reduction in quality of life was in the patients with lymphedema [21].

Morbidity of the SLNB technique

One of the advantages of SLNB is the limited dissection required, thereby minimizing complications in the groin and lower extremities. The technology has been most extensively applied in breast CA, where it has shown itself to be favorable relative to standard axillary lymphadenectomy in terms of patient morbidity. The Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial by Mansel et al. determined the relative risk of lymphedema in patients at 12 months following SLNB versus standard axillary surgery to be 0.37, with lymphedema observed in 5 versus 13% of patients (p < 0.001). Sensory deficit at 12 months was 11 versus 31% (p < 0.001) favoring the SLNB arm. Those in the SLNB arm had shorter hospital stays (4.1 vs 5.4%; p < 0.001), fewer drains (17 vs 79%; p < 0.001), fewer infections (11 vs 15%; p = 0.051) and quicker resumption of activities of daily living (p < 0.001) relative to controls who underwent standard lymph node dissections [22].

While no randomized, controlled trials assessing the SLNB procedure in vulvar CA exist, the largest observational study by van der Zee et al. demonstrated a decrease in both short- and long-term morbidity for patients who underwent SLNB alone versus SLNB with inguinofemoral lymphadenectomy [23]. Those patients subjected to SLNB only had less wound breakdown (11.7 vs 34%; p < 0.001), cellulitis (4.5 vs 21.3%; p < 0.001) and shorter hospital stays (8.4 vs 13.7%; p < 0.001) compared with patients subjected to SLNB with inguinofemoral lymphadenectomy [23]. Long-term complications were also observed less frequently in those undergoing SLNB only, with lymphedema (1.9 vs 25.2%; p < 0.001) and erysipelas (0.45 vs 16.2%; p < 0.001) less common in the SLNB-only group [23].

SLNB technique

In 1979, DiSaia et al. advocated for wide local excision for invasive vulvar tumors less than 1 cm in diameter, with inguinofemoral lymphadenectomy limited to the superficial lymph nodes – the nodes of first drainage from the vulva [3]. In 1992, Barton et al. attempted the first identification of the SLN in vulvar cancer with the injection of a technetium colloid [24]. Since that time, the use of radiolabeled tracers has evolved to include intraoperative detection of SLNs using a γ-probe following preoperative peritumoral injection. This multidisciplinary approach utilizes nuclear medicine to inject the vulvar tumor preoperatively with a radiolabeled tracer, followed by lymphoscintography. The groin is then inspected intraoperatively with a hand-held γ-probe to assess for the location of the SLN. The incision is made over the radioactive lymph node, and confirmation is achieved by evidence of radioactivity five-times or more the baseline reading [25]. The learning curve associated with this procedure is steep, with 10–20 groin procedures felt to be the upper limit for establishing competence [23,26]. This compares with the experience in breast CA, where a detection rate of 85%, with a false-negative rate of 6% or less, is achieved at ten patients [27].

Another technique for the identification of the SLN is injection of the tumor with blue dye, first incorporated in SLN identification in melanoma. In that application, it has been estimated that 20–30 patients represent a sufficient learning curve [28]. The first use of blue dye for SLN detection for vulvar CA was reported by Levenback et al. [29]. Follow-up reports of this experience demonstrated accurate identification of the SLN in 88% of patients [30]. This technique involves injection of blue dye around the vulvar tumor then tracing the blue dye in the groin, with the SLNs detected as either a blue-stained lymph node or the lymph node with the draining blue lymphatic channels. With this technique, difficulty may be encountered when localizing the lymph node, especially if its location is outside the incision made over the femoral triangle. Furthermore, blue staining of tissue around the SLN may make precise identification of the SLN difficult [31].

Many authors have reported the use of a combination of technetium and blue dye for the SLNB procedure in vulvar CA [25,32 –42]. Rationale behind this practice relates to the importance of identifying the SLNs intraoperatively. Combining the results of studies that incorporate similar protocols yields a detection rate per person of 84% (97/115 cases) when blue dye is used, and that this increases to 98% (488/498 cases) when a combined technique of technetium and blue dye is employed ( Table 1 ).

Table 1.

False-negative results with sentinel lymph node biopsy.

Author	Patients (n)	Detection method	Detection rate (detection [n]/total [n])	False-negative results	Ref.
Johann et al. (2008)	39	T ± BD	37/39	1	[36]
Hampl et al. (2008)	119	T ± BD	117/119	3	[35]
Nyberg et al. (2007)	40	T ± BD	40/40	0	[32]
Vidal-Sicart et al. (2007)	50	T + BD	49/50	0	[42]
Hauspy et al. (2007)	41	T + BD	39/41	0	[25]
Martinez-Palones et al. (2006)	28	T + BD	27/27	1	[38]
Terada et al. (2006)	21	T + BD	21/21	0	[49]
Louise-Sylvestre et al. (2005)	17	T ± BD	17/17	0	[37]
Merisio et al. (2005)	20	T	20/20	1	[51]
Puig-Tintore et al. (2003)	26	T + BD	25/26	0	[40]
Moore et al. (2003)	21	T + BD	21/21	0	[39]
Sliutz et al. (2002)	26	T + BD	26/26	0	[41]
Levenback et al. (2001)	52	BD	46/52	0	[30]
DeCicco et al. (2000)	37	T	37/37	0	[52]
de Hullu et al. (2000)	59	T + BD	59/59	0	[33]
Bowles et al. (1999)	6	T	6/6	0	[53]
Ansink et al. (1999)	51	BD	42/51	2	[48]
Echt et al. (1999)	12	BD	9/12	1	[54]
De Cesare et al. (1997)	10	T + BD	10/10	0	[34]
Total	675		674	9

BD: Blue dye; T: Technetium.

Pathological considerations with the SLNB technique

Sentinel lymph nodes obtained at surgery are initially sent for frozen-section analysis. Utilized in breast cancer, frozen-section analysis of SLNs has been found to have a sensitivity of 87% [43]. Extrapolating to vulvar CA, similar results can be expected, with De Hulla et al. reporting that hematoxylin and eosin staining at the time of frozen-section analysis has a sensitivity of 80% [7]. Considering the implications of failure to detect inguinal metastasis, further examination of the node via ultrastaging is performed.

The first description of ultrastaging was by Terada et al. [44]. In their series, they reported on 15 SLNs harvested from nine patients. Routine hematoxylin and eosin staining found one positive node, with the remainder submitted for further sectioning and cytokeratin staining. Of these, two out of 14 nodes were found to be positive for micrometastases following ultrastaging [44]. Agreement with these findings was found in the study by Moore et al., where the application of an ultrastaging protocol identified two micrometastases less than 0.3 mm in size. Furthermore, they found that the application of immunohistochemistry (IHC) to the ultrastaging protocol did not identify any additional lymphatic metastases [39].

By contrast, Hakim et al. found no benefit in terms of further identification of micrometastases with the application of hematoxylin and eosin stain, pancytokeratin AE1/3 (CKAE1/3) IHC and additional sectioning at 50 μm intervals to their standard pathologic examination. In their report of 40 SLNs that were initially found to be negative, no further micrometastases were identified [45]. Since then, Robison et al. has argued the advantage of SLNB versus complete inguinofemoral lymphadenectomy to be the application of ultrastaging to the nodal sample. The authors demonstrated that ultrastaging allowed for a more thorough pathologic examination of the lymph nodes after frozen-section analysis, since a smaller number of nodes are submitted for examination, allowing for better detection of smaller tumor foci [46]. In the Robison et al. study, smaller micrometastases were identified in those patients exposed to SLNB versus complete lymph node dissection (0.35 vs 1.6 mm; p = 0.02). In addition, the mean size of metastatic foci identified was smaller in SLNB versus complete lymph node dissection (2.52 vs 4.35 mm; p = 0.109) [46]. Le et al. have argued that a minimum of ten lymph nodes from a bilateral inguinofemoral lymph node dissection is the threshold for an optimal inguinal dissection – in this situation, ultrastaging is not feasible [47]. While further questions regarding the value of ultrastaging and additional IHC techniques in the processing of SLN can be put forward, the protocol outlined below reflects our interpretation of the added value of ultrastaging to the identification of lymph node metastases (see Appendix 1).

Accuracy

One method to assess the safety of the SLNB procedure is consideration of the false-negative rate. The low false-negative rates of SLNB in breast and melanoma suggest the transferability to other sites, including the vulva. Case series addressing the issue of accuracy have looked at SLNB followed by inguinofemoral lymphadenectomy. In this setting, a false negative is defined as when the SLN is negative for malignancy but a non-SLN removed at the time of lymphadenectomy is positive for malignancy. A review of the literature identified 20 studies of sufficient quality to assess feasibility of the SLNB procedure. Of a total of 674 patients undergoing the SLNB procedure by any method, only nine patients had a false-negative result ( Table 1 ). Hauspy et al. reviewed only studies where performance per side could be determined, concluding the negative predictive value to be 96% [25].

In those situations where false negatives did occur, scrutiny of the failures is important. In the experience of Ansink et al., the authors used only blue dye, and neither IHC nor ultrastaging were performed on the SLNs (consistent with early applications of the SLNB technique) [48]. In the study by Hampl et al., all false-negative SLNs were found in patients where the primary lesion was located between the clitoris and urethra [35]. In each case, ultrastaging and IHC were performed. The Hampl et al. study involved seven oncology centers, and the authors suggest that the learning curve associated with the procedure may have accounted for the false-negative rate. Sylvestre et al. reported their experience of SLNB procedure and midline lesions in 17 patients, with unilateral-only SLNs identified in 13 patients. Of these 13 patients, three were found to have metastatic lymph nodes on the side where no SLN was identified, presumably owing to complete replacement of the SLN with tumor [37]. We do not believe this accurately represents cases of false-negative lymph nodes. In the situation of a midline lesion, bilateral SLNs should be identified, and in their absence, a complete bilateral inguinofemoral lymphadenectomy should be performed.

Abstracting from the van der Zee et al. observational study, one can surmise that the efficacy for detection of lymph node metastases with the SLNB procedure is at least equivalent to complete inguinofemoral lymphadenectomy. In their study (involving patients with T1 or T2 [<4 cm] squamous cell CA of the vulva with depth of invasion >1 mm), 127 out of 403 patients (31.5%) exposed to the SLNB procedure were positive for at least one metastatic lymph node [23]. It is noteworthy to compare this to the GOG data, where the incidence of groin node metastases was 18–19% in patients in T1 lesions and 31–54% in T2 lesions. In the study series by Hauspy et al., where clinically palpable nodes were excluded, 16 out of 41 patients (39%) had lymph node metastases identified using the SLNB technique [25].

Disease recurrence following SLNB

The assessment of survival in patients undergoing SLNB is complicated by the reality that many follow-up studies include patients who underwent inguinofemoral lymphadenectomy following SLNB (assessing the accuracy of the SLNB procedure). The possibility of a therapeutic benefit of inguinofemoral lymphadenectomy cannot be excluded and, therefore, evaluation of recurrence should be considered in patients exposed solely to the SLNB procedure.

Terada et al. reported their experience with SLNB in 21 patients with T1 tumors, undergoing SLNB only [49]. No patient with a negative SLN developed a groin recurrence after a median follow-up of 4.9 years. Moore et al. performed SLNB-only in 35 patients, with 31 patients having negative SLNs (15 unilateral and 16 bilateral SNLB procedures) [50]. After a median follow-up of 29 months, two patients developed a groin recurrence (one T1 with a 20 mm tumor, the other T2 with a 30 mm tumor), resulting in a 4.3% recurrence rate per groin initially treated with SLNB. Similar recurrence rates for T1 and T2 lesions treated by superficial groin node dissections have been reported (5–7%) [11]. The best evidence to date regarding recurrence is the aforementioned van der Zee et al. prospective observational study that investigated the SLNB procedure in the absence of inguinofemoral lymphadenectomy [23]. Of the 403 patients initially enrolled, 276 underwent SLNB only, with a median follow-up of 35 months. In eight patients, groin recurrences were observed after an initially negative SLNB procedure. Of these eight patients, two had multifocal disease, two had only one SLN removed despite the fact that the lymphoscintogram identified two lymph nodes, and a further two patients were found to have micrometastases at ultrastaging that was missed. The 3-year survival rate for patients with unifocal disease and negative initial SLNB was 97%, with a groin recurrence rate of 3%. The actuarial groin recurrence rate for all patients after 2 years was 3% (95% CI: 1–6) [23].

Conclusion

The SLNB procedure offers patients a safe alternative to complete inguinofemoral groin node dissection. The decrease in postoperative morbidity, extrapolated from the experience in breast cancer and melanoma, and realized through case series and a large observational study in vulvar CA, offers patients the option of improved quality of life. Furthermore, the low recurrence rate observed in patients treated with SLNB only is reassuring for ongoing utilization of the technique. Protocols for adopting the procedure abound in the literature on vulvar SLNB, with most surgeons opting for complete inguinofemoral lymphadenectomy in conjunction with SLNB for the initial cohort of patients. The multidisciplinary nature requires close collaboration between nuclear medicine, pathology and gynecologic oncology. When employed according to a strict protocol, SLNB offers patients the opportunity for decreased morbidity and equivalent cure rates for vulvar CA. We believe the SLNB technique will become the standard of care in gynecologic oncology for the treatment of vulvar CA.

Executive summary

Current standard

Current standard of care for early-stage squamous cell carcinoma (CA) of the vulva is wide local excision with unilateral/bilateral inguinofemoral lymphadenectomy, based upon tumor location and depth of invasion.

Of the total number of patients experienceing early-stage CA, approximately 30% of women will harbor metastases, meaning 70% of women undergo groin dissection with no potential benefit, while experiencing 100% of the surgical risk.

Surgical morbidity

In approximately 85% of cases, en bloc radical dissection has wound breakdown and impaired healing.

Triple-incision technique has wound breakdown in 17–31% of cases, wound cellulitis in 25–39% and lymphedema in 28–39%.

The greatest reduction in quality of life is observed in patients with lymphedema.

Morbidity of the sentinel lymph node biopsy technique

Sentinel lymph node (SLN) biopsy (SLNB) in breast cancer, highlighted in the Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial, showed fewer complications and a quicker resumption to normal activities relative to standard lymphadenectomy.

No randomized, controlled trials assessing SLNB relative to the current standard of care exist, but abstracting from the van der Zee et al. trial, a marked decrease in both short- and long-term morbidity is observed in patients undergoing SLNB only.

SLNB technique

A multidisciplinary approach utilizing close collaboration between nuclear medicine, pathology and the surgical team is required for successful application of the SLNB technique.

Preoperative peritumoral injection of a radiolabeled tracer, followed by lymphoscintography, with/without intraoperative injection of blue dye, identifies the SLN.

The learning curve associated with SLNB is steep, ranging from 10 to 20 groin procedures.

Detection rate per person is 84% when blue dye is used alone, increasing to 98% when a combined technique of technetium and blue dye is employed.

Pathological considerations

Hematoxylin and eosin staining at the time of frozen-section analysis has a sensitivity of 80% in vulvar CA.

Following frozen sectioning, further ultrastaging of the node is required to detect micrometastases.

Accuracy

A false negative is defined when the SLN is negative for malignancy but a nonsentinel lymph node removed at the time of lymphadenectomy is positive for malignancy.

Of a total of 674 patients undergoing the SLNB procedure taken from validation studies, only nine had a false negative.

Factors related to false negatives include: operator inexperience, midline lesions and multifocal lesions.

The negative predictive value per groin for the SLNB procedure is 96%.

Abstraction from observational studies suggests that survival following the SLNB procedure is equivalent to complete SLN dissection.

Future perspective

SLNB will soon be recognized as the standard of care for surgical treatment of early-stage vulvar CA.

Our position is that frozen-section analysis at the time of the initial odds ratio is an important aspect of any protocol, maximizing the benefits for patients treated with the SLNB technique with a minimization of the number of reoperations for completion lymphadenectomy (limiting second surgeries to those patients whose metastases are identified through ultrastaging).

One advantage of SLNB in vulvar CA is the opportunity for pathological analysis with ultrastaging and the increased identification of micrometastases.

The prognostic significance of micrometastases identified through ultrastaging is yet to be determined.

Appropriate adjuvant treatment for patients with micrometastases needs further elucidation.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Appendix 1

Sentinel lymph node biopsy protocol

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State of the Art of Sentinel Lymph Node Biopsy in Vulvar Carcinoma

Abstract

Keywords

Current standard

Surgical morbidity

Morbidity of the SLNB technique

SLNB technique

Pathological considerations with the SLNB technique

Accuracy

Disease recurrence following SLNB

Conclusion

Footnotes

Appendix 1

References