In 2008, the first Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) showed that omission of inguinofemoral lymphadenectomy is safe in patients with early-stage vulvar cancer and a negative sentinel node and it simultaneously decreases treatment-related morbidity. An important part of the sentinel node procedure is pathologic ultrastaging of the removed sentinel nodes. Subsequently, since the introduction of this procedure in the standard care of patients with early-stage vulvar cancer, more and smaller inguinofemoral lymph node metastases have been diagnosed. The clinical consequences of these micrometastases are not clear yet. With increasing size of the sentinel node metastasis, chances of non-sentinel node metastases increase and those of survival decrease. The size of lymph node metastases is included in the latest staging system for vulvar cancer, however at this moment without clinical implications. Furthermore, a separate category for micrometastases is not incorporated yet. More research is needed to determine the clinical consequences of the size of (sentinel) lymph node metastases.
Highlights
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Sentinel node biopsy is safe in well-selected patients with early-stage vulvar cancer.
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Sentinel node biopsy enables pathologic ultrastaging of the first draining lymph node.
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Chances of survival decrease with increasing size of sentinel node metastasis.
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Staging of vulvar cancer was changed in 2009, including size of lymph node metastases.
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Clinical implications of size of metastases are not clear yet.
Vulvar cancer
With an annual incidence of two to three per 100,000 women, vulvar cancer is the fourth most common gynecological malignancy. In the last decades, the incidence of vulvar cancer has been increasing . The most common histological type is squamous cell cancer, comprising about 80% of all vulvar malignancies. Other types such as melanomas, adenocarcinomas, and basal cell cancers are much less common. In this review, we focus on the staging and treatment of vulvar cancers of squamous cell origin. The mean age at diagnosis is about 70 years, and recent studies show that the increase in incidence rate is most pronounced in the oldest patient group (>80 years) . Other studies, however, showed that the increase in incidence was especially attributable to the younger patients, and that this might be caused by an increase in premalignant human papillomavirus (HPV)-associated vulvar disease . Squamous cell cancer of the vulva spreads by three routes: the initial metastatic spread occurs usually to the inguinofemoral lymph nodes. The overall incidence of inguinofemoral lymph node metastases is approximately 30%. The presence and number of inguinofemoral lymph node metastases is the most important prognostic factor in patients with vulvar cancer . Both hematogenous spread and spread by direct extension are infrequent.
Staging
Vulvar cancer has been clinically staged until 1988. Considering that palpation of the groins is inaccurate in approximately 25% of the patients , the International Federation of Gynecology and Obstetrics (FIGO) changed the vulvar cancer staging to a surgico-pathological system in 1988. This staging system provided better discrimination of survival between stages than the 1970 FIGO staging system . In 1994, stage IA was added to the staging system as studies showed that the risk of lymph node metastases in tumors with a depth of invasion ≤1 mm was negligible . In 2009, FIGO staging and TNM classification were adjusted in order to allow for better prognostic discrimination between stages and less heterogeneity within stages. The number of lymph node metastases was shown to have a major impact on survival. In 1991, the results of a Gynecologic Oncology Group (GOG) study showed a 5-year survival of >90% for patients with negative nodes, 75% for patients with one to two positive nodes, 36% for patients with three to four positive nodes, 24% for patients with five to six positive nodes, and 0% for patients with seven or more positive nodes . In 1991, Origoni was the first to report on the impact of the size of lymph node metastases on survival. He demonstrated 5-year cancer-related survival rates of 90.9% for patients with metastases <5 mm, 41.6% for those with metastases >5 to <15 mm, and 20.0% for those with metastases >15 mm. He also demonstrated the impact of extracapsular tumor growth (85.7% vs. 25%) . These results were confirmed by others and led to the incorporation of the number and size of lymph node metastases in the most recent staging system. Finally, bilaterality of lymph node metastases has been abolished, and the former stages I and II are combined in the revised classification system . For an overview of the latest vulvar cancer TNM and FIGO classification, see Table 1 .
| TNM | FIGO | ||||
|---|---|---|---|---|---|
| T1 | Confined to vulva/perineum | ||||
| T1a | ≤2 cm with stromal invasion ≤1 mm | Stage IA | T1a | N0 | M0 |
| T1b | >2 cm or stromal invasion >1 mm | Stage IB | T1b | N0 | M0 |
| T2 | Lower urethra/vagina/anus involved | Stage II | T2 | N0 | M0 |
| T3 | Involvement upper urethra/vagina, bladder, rectal/mucosa, bone, fixed to the pelvic bone | Stage IIIA | T1, T2 | N1a, 1b | M0 |
| Stage IIIB | T1, T2 | N2a, 2b | M0 | ||
| Stage IIIC | T1, T2 | N3c | M0 | ||
| N0 | Node negative | Stage IVA | T1, T2 T3 | N3 Any N | M0 M0 |
| N1a | Lymph node metastases, 1–2 nodes ≤5 mm | Stage IVB | Any T | Any N | M1 |
| N1b | One node >5 mm | ||||
| N2a | 3 or more nodes <5 mm | ||||
| N2b | 2 of more nodes ≥5 mm | ||||
| N2c | Extracapsular spread | ||||
| N3 | Fixed ulcerated nodes | ||||
| M0 | No distant metastases | ||||
| M1 | Distant metastases | ||||
Staging
Vulvar cancer has been clinically staged until 1988. Considering that palpation of the groins is inaccurate in approximately 25% of the patients , the International Federation of Gynecology and Obstetrics (FIGO) changed the vulvar cancer staging to a surgico-pathological system in 1988. This staging system provided better discrimination of survival between stages than the 1970 FIGO staging system . In 1994, stage IA was added to the staging system as studies showed that the risk of lymph node metastases in tumors with a depth of invasion ≤1 mm was negligible . In 2009, FIGO staging and TNM classification were adjusted in order to allow for better prognostic discrimination between stages and less heterogeneity within stages. The number of lymph node metastases was shown to have a major impact on survival. In 1991, the results of a Gynecologic Oncology Group (GOG) study showed a 5-year survival of >90% for patients with negative nodes, 75% for patients with one to two positive nodes, 36% for patients with three to four positive nodes, 24% for patients with five to six positive nodes, and 0% for patients with seven or more positive nodes . In 1991, Origoni was the first to report on the impact of the size of lymph node metastases on survival. He demonstrated 5-year cancer-related survival rates of 90.9% for patients with metastases <5 mm, 41.6% for those with metastases >5 to <15 mm, and 20.0% for those with metastases >15 mm. He also demonstrated the impact of extracapsular tumor growth (85.7% vs. 25%) . These results were confirmed by others and led to the incorporation of the number and size of lymph node metastases in the most recent staging system. Finally, bilaterality of lymph node metastases has been abolished, and the former stages I and II are combined in the revised classification system . For an overview of the latest vulvar cancer TNM and FIGO classification, see Table 1 .
| TNM | FIGO | ||||
|---|---|---|---|---|---|
| T1 | Confined to vulva/perineum | ||||
| T1a | ≤2 cm with stromal invasion ≤1 mm | Stage IA | T1a | N0 | M0 |
| T1b | >2 cm or stromal invasion >1 mm | Stage IB | T1b | N0 | M0 |
| T2 | Lower urethra/vagina/anus involved | Stage II | T2 | N0 | M0 |
| T3 | Involvement upper urethra/vagina, bladder, rectal/mucosa, bone, fixed to the pelvic bone | Stage IIIA | T1, T2 | N1a, 1b | M0 |
| Stage IIIB | T1, T2 | N2a, 2b | M0 | ||
| Stage IIIC | T1, T2 | N3c | M0 | ||
| N0 | Node negative | Stage IVA | T1, T2 T3 | N3 Any N | M0 M0 |
| N1a | Lymph node metastases, 1–2 nodes ≤5 mm | Stage IVB | Any T | Any N | M1 |
| N1b | One node >5 mm | ||||
| N2a | 3 or more nodes <5 mm | ||||
| N2b | 2 of more nodes ≥5 mm | ||||
| N2c | Extracapsular spread | ||||
| N3 | Fixed ulcerated nodes | ||||
| M0 | No distant metastases | ||||
| M1 | Distant metastases | ||||
Treatment
The cornerstone of treatment of patients with vulvar cancer is surgery. A Canadian study on patterns of care in 978 patients with vulvar cancer showed that 85% had at least one surgical procedure, and approximately 25% received radiotherapy . The standard treatment for squamous cell cancer of the vulva has changed dramatically over the last decades. Early in the 20th century, Basset was the first to propose “en bloc” dissection of the vulva and inguinofemoral lymph nodes . Taussig and Way clinically applied the principles proposed by Basset and developed radical vulvectomy with inguinofemoral lymphadenectomy “en bloc.” The radical approach replaced simple local excision in the second half of the last century and became the standard of care for a prolonged period. The rationale for this approach was the assumption that the prognosis is better after elective inguinofemoral lymphadenectomy compared to surveillance of the groins, despite the fact that only about 30% of patients will have lymph node metastases. Although highly effective, the morbidity of this treatment modality was very high. Wound breakdown, infections, and lymphedema were of great concern and they often prolonged hospitalization. Since then, many modifications of surgery have been proposed in the treatment of patients with vulvar cancer. The aim of all modifications was to reduce the morbidity of vulvar cancer treatment without compromising survival rates. Strides were made with the introduction of inguinofemoral lymphadenectomy through separate groin incisions , replacement of radical vulvectomy by wide local excision , abandonment of bilateral lymphadenectomy in lateralized tumors <2 cm , and abandonment of inguinofemoral lymphadenectomy in microinvasive tumors (<1-mm depth of invasion) . Due to these modifications, treatment-related morbidity has decreased, but is still significant for patients undergoing inguinofemoral lymphadenectomy, with long-term lymphedema and discomfort of the legs described in up to 50% of the patients . At this moment, wide local excision with a tumor-free margin of 1–2 cm is advised for local treatment, with uni- or bilateral inguinofemoral lymphadenectomy, depending on the location of the tumor with respect to the midline. Only 20–30% of the patients with early-stage vulvar cancer will have lymph node metastases. The other 70–80% will probably not benefit from the inguinofemoral lymphadenectomy, but they are at a risk of the high morbidity associated with the procedure. Therefore, the most ideal approach would be a noninvasive procedure that is able to exclude lymph node metastases with a very high negative predictive value, resulting in about 70% of the patients who can safely be excluded from undergoing inguinofemoral lymphadenectomy. Until now, the results of imaging, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET), were not good enough to exclude lymph node metastases with a high enough negative predictive value . The introduction of the sentinel node procedure provides a minimally invasive tool to assess lymph node status.
Sentinel node biopsy
The term “sentinel node” was first described by Gould et al. in their report on parotid gland cancer . In 1977, Cabanas performed lymphangiograms in 100 cases of penile cancer and demonstrated the existence of a specific lymph node center, the so-called sentinel lymph node (SLN). He described that this appeared to be the primary site of metastases from penile cancer . The first application in vulvar cancer was reported in 1994 by Levenback et al., who used only blue dye in nine patients with vulvar cancer . In their following paper in which they extended their series to 21 patients, an identification rate of 86% was shown and intraoperative lymphatic mapping appeared to be safe and simple to perform . In 1998, De Hullu et al. published our results of a pilot study on the combined technique (blue dye and radioactive tracer) for SLN detection in 10 patients with vulvar cancer . An identification rate of 100% and no false negatives were demonstrated. Subsequently larger studies (in which the sentinel node procedure was always followed by a full lymphadenectomy) were designed in order to investigate the diagnostic accuracy of the SLN procedure in patients with early-stage vulvar cancer. In 1999, Ansink et al. published their results of the sentinel node procedure with only blue dye in 51 patients with vulvar cancer. This technique appeared to be inaccurate with only a 56% identification rate of a sentinel node and two false negatives . In 2000, de Hullu et al. presented our extended results of the combined procedure for sentinel node detection. A radioactive tracer and blue dye were used in 59 patients with vulvar cancer. With an identification rate of 100% and no false negatives, this seemed a promising technique . Subsequently, many other centers published their results on the application of the sentinel node procedure, followed by inguinofemoral lymphadenectomy. Identification rates were high, especially with the combined procedure, and false-negative rates low. In 2008, a German multicenter study that included 127 patients showed an identification rate of 98% and a false-negative rate of 7.7%. The false-negative rate was high compared with the results reported in the literature until then. One explanation might be the inclusion of patients with T1–T3 tumors on the condition that radical excision was possible. Two out of three false-negative cases occurred in patients with tumors of at least 4 cm (40 and 56 mm), indicating that larger tumors might be less suitable for sentinel node biopsy. Experience with the sentinel node procedure was not a requirement to participate in this multicenter study, which might be another explanation for the higher false-negative rate . A Polish study including patients with vulvar cancer using the same inclusion criteria as GROINSS-V (Groningen International Study on Sentinel nodes in Vulvar cancer) also showed a very high false-negative rate. They described a false-negative rate of 27%. The authors conclude that it is highly probable that the main factor responsible for the high false-negative rate was the surgeons’ experience . Table 2 shows an overview of accuracy studies on the sentinel node application in vulvar cancer .
