Vulvar carcinoma is a rather rare carcinoma. Here, too, prevention is better than therapy. In the case of a conspicuous vulvar finding, the entire vulva should always be carefully examined colposcopically. Treatment is provided in a tumor center by a multidisciplinary team.
Vulvar carcinoma is a rather rare carcinoma in Switzerland with <300 new cases annually [1]. Overall, 71.9% of patients survive five years or longer. In the localized state it is 86.1%, in regional tumor seeding 57.1% and in distant metastasis 17.4%. Vulvar carcinoma is classified according to the FIGO and/or TNM classification system and is localized in 59% of cases, spread to the regional inguinofemoral lymph nodes in 31%, and already distantly metastatic in 5%. The median age of onset is 68 years, with vulvar cancers most commonly diagnosed between the ages of 75 and 84. In 15% of newly diagnosed cases, it already occurs between 45 and 54 years of age.
50% of vulvar cancers are associated with human papillomavirus (HPV), with HPV 16 being the most common type [2]. HPV-positive carcinomas occur more often in younger patients. Whether or not a carcinoma is HPV-associated also appears to play a role in prognosis, as patients with HPV-negative tumors have a worse prognosis compared with patients with an HPV-positive tumor [3,4]. HPV-negative carcinomas are frequently associated with vulvar dermatoses.
Prevention
Prevention of carcinoma is always better than its therapy. This applies not only, but also to vulvar carcinoma. There is no recognized screening procedure for the detection of precancerous vulvar lesions. However, an annual gynecological check-up must include a history of vulvar symptoms such as pruritus or burning sensation and an inspection of the entire anogenital region with vulva, perineum, perianal region and vagina.
HPV-associated vulvar carcinomas develop via precursors, like cervical carcinoma. With the therapy of these precursors, carcinoma formation can be prevented. However, less than 10% of all vulvar high-grade intraepithelial lesions progress to carcinoma [5] and there remains a lack of a marker to identify which patient is at high risk for developing carcinoma. For this reason, all high-grade intraepithelial lesions of the vulva must be treated. The immunomodulator imiquimod is now the treatment of choice, although this treatment remains an “off label use”.
As with cervical carcinoma, nicotine use and immunosuppression are important risk factors for HPV-associated vulvar carcinoma. And as with cervical cancer, HPV vaccination could prevent a large proportion of vulvar cancers.
In addition to multifocality, often with multiple dysplastic sites on the vulva, multicentricity must also be considered. To exclude dysplasia of the anus, perineum, vagina, and cervix, these must also be evaluated colposcopically and appropriate additional investigations such as cervical cytology must be performed.
In contrast, the precursors of HPV-negative vulvar carcinomas are difficult to detect because they are rapidly progressive and much more common. Vulvar carcinomas arising from vulvar dermatosis (most commonly lichen sclerosus) can be prevented by long-term maintenance therapy with moderate-strength local corticosteroids [6], as recommended in the European guidelines for lichen sclerosus.
Diagnostics
In the case of a conspicuous vulvar finding, the entire vulva should always be carefully examined colposcopically. All suspicious lesions are biopsied separately. Multifocal high-grade dysplasia is frequently found, especially in HPV-associated vulvar carcinomas. Then a so-called “vulva mapping” with skin punches must be performed on all conspicuous findings. The histology of the punch biopsy should be reported by a pathology laboratory experienced with it and should include an indication of the histologic type and the depth of invasion. Preoperative workup also includes clear documentation of the location of the lesion including size, distance from the midline, clitoris, anus, vagina, and urethra. To identify any lymphogenic extension, thorough clinical palpation and, in the absence of clinical lymph node involvement in the groin, either ultrasound, PET-CT, or MRI will help. A CT scan of the thorax/abdomen/pelvis is crucial for the diagnosis of distant metastases in order to exclude any advanced disease. A patient with vulvar cancer should be treated in a tumor center by a multidisciplinary gynecologic-oncologic team [7].
Therapy
In general, radical local excision down to the deep fascia with a tumor-free margin macroscopically 1 cm apart is the treatment of choice. To ensure this, the marking of the excisate must be done in a non-tensioned state and marked in this state at least 1 cm apart. For small lesions, direct closure can be performed. Due to the often tense skin situation, a flapplasty, e.g. a Limberg flap, is sometimes necessary in the perineal area. In this procedure, tissue is rotated into the defect from the lateral side. Another option for closure is the V-Y-plasty. This flap is particularly suitable for defects in the area of the anterior vulva, as the existing fatty tissue in the area of the mons pubis allows good defect coverage. In very large defects or in a recurrence situation, closure with a pedicled flap may be necessary, in which not only is the subcutaneous fat tissue mobilized along with its blood supply, but also part of the muscle is rotated along with its blood supply. Examples include the axial fasciocutaneous flap (e.g., from the gluteus maximus muscle) or myocutaneous flaps (e.g., tensor fasciae latae or gracilis flap). In general, the excidate should always be well marked and documented by photograph so that the pathologist can easily describe the findings, including the margins of deposition.
In the retrospective multicenter AGO-CaRE-1 study, 1681 patients with vulvar cancer from 29 gynecologic tumor centers were studied. There was no survival benefit with a resection distance smaller or larger than 8 mm [8,9], but there was a tendency for a higher local recurrence rate with a distance smaller than 8 mm. These results could not be confirmed with regard to an increased local recurrence rate in the multivariate analysis of the study [10].
It can be concluded that radical local excision is recommended, but may be smaller in the area of the clitoris, urethra, or anus. If the excision margin is tumor-infested, re-excision is the first choice of further treatment. Multifocal invasive disease requires either radical excision of each lesion or, in rare cases, vulvectomy. Advanced stages of vulvar cancer should be discussed in a multidisciplinary setting. The optimal treatment may also be found in terms of a combined therapy modality.
Lymphonodectomy
An inguinal lymph node examination must be performed for any vulvar carcinoma that progresses beyond a stage FIGO IA. In the case of a tumor located in the midline area, <1 cm to the midline, of the labia minora or clitoris, the inguinal lymph nodes must be examined on both sides. In all other cases, ipsilateral inguinofemoral lymphadenectomy is sufficient. Inguinofemoral lymphadenectomy always involves removal of the inguinal and superficial as well as deep femoral lymph nodes, with preservation of the great saphenous vein recommended.
Sentinel lymphonodectomy is a technique that is increasing in frequency. A radioactive or optionally a colored substance is injected perivulvarly. Subsequently, the sentinel lymph node is identified. The vulva seems to be an ideal site for so-called lymphatic mapping, since the tumor is easily accessible and the primary lymphatic drainage always leads to the groin. Advantages of sentinel lymphonodectomy also include a reduction in operative time, less blood loss, less postoperative lymphocele formation, and a lower percentage of lymphedema. However, the morbidity of lymphedema is generally dependent on the site of lymphonodectomy and is further increased by continued need for postoperative radiotherapy [11].
Van der Zee studied 403 patients with small pT1/2 tumor in the GROINSS-V trial. 259 patients had a pN0 stage according to sentinel. There were 42% of positive lymph nodes detected by ultrastaging and 2.3% of patients showed groin recurrence. However, patients had significantly lower overall morbidity in terms of wound healing disorders, infections, median hospitalization length, and lymphedema [12,13]. There are a few comparable studies, namely the GOG 173 [14], which showed a false negative detection rate of 4.4% in 403 patients, and an AGO study [15], which showed a false negative rate of 7.7% in 127 patients. Therefore, two additional GROINSS trials, the GROINSS VI and GROINSS VII trials, have been conducted to examine long-term outcome and metastasis at the time of recurrence and have so far shown no increased risk [16]. Multifocal tumors, however, were excluded in most studies.
The big dilemma in the decision to do sentinel lymphonodectomy is that, on the one hand, patients with positive but missed lymph nodes are very likely to die from their vulvar cancer. On the other hand, patients with inadequately operated groin also die in 87% of cases. The AGO-CaRE-1 multicenter study also impressively demonstrated statistically significant decreased survival in patients with affected compared with unaffected inguinal lymph nodes [17,18].
The ESGO guidelines have been adapted accordingly. Sentinel lymphonodectomy may be performed for unifocal tumors smaller than 4 cm without clinically and/or imaging suspicious inguinal lymph nodes. However, it is important here to initially check for false-negative lymph nodes, which is recommended for any center starting sentinel lymphonodectomy, i.e., performing both sentinel and inguinofemoral lymphonodectomy.
Radio and chemotherapy
Adjuvant radiotherapy is the standard of care for inguinal metastatic or extracapsular spread vulvar carcinoma. The CaRE-1 trial powerfully demonstrates that adjuvant radiotherapy leads to improved progression-free survival (p=0.004) [17]. The same trend also applies to overall survival, but here the difference is no longer statistically significant. Radiotherapy should be given as soon as possible after surgical therapy, and in any case the interval should be less than six weeks. If positive resection margins are found on pathologic examination and surgical resection does not appear feasible, postoperative radiotherapy is recommended.
Adjuvant radiotherapy for positive inguinal lymph nodes should include the ipsilateral groin and pelvic lymph nodes. The radiation field should reach the level of the bifurcation of the common iliac artery. Although not established, it could be inferred from other squamous cell carcinomas such as cervical, ENT as well as anal carcinomas that radiosensitizing chemotherapy with cisplatin in addition could have a benefit.
Neoadjuvant chemoradiation represents a new aspect in the therapy of advanced vulvar carcinomas. Data from a recent study powerfully demonstrate that overall survival after weekly cisplatin administration and radiotherapy in the neoadjuvant setting has a statistically significant difference in pathologically complete remission compared with incomplete response [19]. Thus, the response to neoadjuvant chemoradiation is a good sign of what the patient’s prognosis will be. Neoadjuvant chemoradiation is therefore a good option to avoid a possibly burdensome but ineffective exenterative procedure.
There is no phase III trial for chemoradiation in the adjuvant setting (level of evidence C). However, chemoradiation with radiation escalation is the treatment of choice for patients with unresectable disease. The first-line chemotherapeutic agent is not proven via a prospective randomized trial. However, for this question, there are big data from a US National Cancer Database study that compared population-based retrospective analyses of 1324 patients without chemotherapy versus 473 patients with chemotherapy. This found a statistically significant difference in survival (p<0.001) [20]. The therapeutic agent with the greatest evidence is cisplatin [21], but agents such as mitamycin/fluorouracil, carboplatin/ifosfamide, erlotinib, and bevacizumab are also under discussion [22,23]. However, it must be noted that the data regarding systemic treatment is so insufficient that guidelines do not suggest a preference.
Tumor aftercare
Optimal tumor follow-up for vulvar cancer is not scientifically proven. The 2016 ESGO guidelines recommend initial follow-up after primary surgical treatment at six to eight weeks, then three-monthly for two years, six-monthly until five years, and then annually for life, as late recurrences can occur. Clinical examination during these follow-up visits should always include the entire anogenital region with vulva, perineum, perianal region, vagina, cervix and the inguinal region on both sides.
Take-Home Messages
- Vulvar carcinoma is a rather rare carcinoma.
- 50% of vulvar cancers are associated with human papillomavirus (HPV), with HPV 16 being the most common type.
- The same applies to vulvar cancer: prevention is better than therapy.
- In the case of a conspicuous vulvar finding, the entire vulva should always be carefully examined colposcopically. All suspicious lesions are biopsied separately.
- A patient with vulvar cancer should be treated in a tumor center by a multidisciplinary gynecologic-oncologic team.
Literature:
- NICER: www.nicer.org
- Jemal A, et al: Annual report to the Nation on status of cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst 2013; 105 (3): 175-201.
- Monk BJ, et al: Prognostic significance of human papillomavirus DNA in vulvar carcinoma. Obstet Gynecol 1995; 85: 709-715.
- Rodrigues IS, et al: Epithelial-mesenchymal transition-like events in vulvar cancer and its relation with HPV. Br J Cancer 2013; 109(1): 184-194.
- Van Seters M, van Beurden M, de Craen AJ: Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol 2005; 97(2): 645-651.
- Lee A, Bradford J, Fischer G: Long-term management of adult vulvar lichen sclerosus. Jama Dermatol 2015; 151(10): 1061-1067.
- ESGO Guidelines 2016: https://guidelines.esgo.org/vulvar-cancer/
- Woelber L, et al: Clinical management of primary vulvar cancer. Eur J Cancer 2011; 47(15): 2315-2321.
- Mahner S, Wölber L: Surgery or topical therapy for vulval intraepithelial neoplasia. Lancet Oncol 2014; 15 (12): 1287-1288.
- Woelber L, et al: Role of tumor-free margin distance for loco-regional control in vulvar cancer-a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study. Eur J Cancer 2016; 69: 180-188.
- Ryan M, et al: Aetiology and prevalence of lower limb lymphoedema following treatment for gynaecological cancer. Aust NZ Obstet Gynaecol 2003; 43(2): 148-151.
- Van der Zee AG, et al: Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 2008; 26(6): 884-889.
- Oonk MH, et al: Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study. Lancet Oncol 2010; 11(7): 646-652.
- Levenbeck CF, et al: Lymphatic mapping and sentinel lymph node biopsies in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study. J Clin Oncol 2012 Nov 1; 30(31): 3786-3791.
- Hampl M, et al: New aspects of vulvar cancer: changes in localization and age of onset. Gynecol Oncol 2008; 109(3): 340-345.
- Te Grootenhuis NC, et al: Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I. Gynecol Oncol 2016; 140(1): 8-14.
- Mahner S, et al: Adjuvant therapy in lymph node-positive vulvar cancer: the AGO-CaRE-1 study. J Natl Cancer Inst 2015; 107(3): pii: dju426.
- Woelber L, et al: Prognostic role of lymph node metastases in vulvar cancer and implications for adjuvant treatment. Int J Gynecol Cancer 2012; 22(3): 503-508.
- Moore DH, et al: A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study. Gynecol Oncol 2012; 124(3): 529-533.
- Gil BS, et al: Impact of adjuvant chemotherapy with radiation for node-positive vulvar cancer: A National Cancer Data Base analysis. Gynecol Oncol 2015; 137(3): 365-372.
- Rose PG, Bundy BN, Watkins EB: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 340: 1144-1153.
- Horowitz NS, et al: Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva. Gynecol Oncol 2012; 127(1): 141-146.
- Monk BJ, et al: Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 2009; 27(7): 1069-1074.
InFo ONCOLOGY & HEMATOLOGY 2017; 5(2): 16-19.