Locally advanced squamous cell carcinoma of the vulva: A challenging question for gynecologic oncologists

Highlights

• Advanced vulvar carcinoma is based on the primary tumor (T3-T4), or on the presence of bulky, fixed or ulcerated nodes.

• Preservation of the bowel and/or urinary function without permanent stomas may require multimodality approaches.

• A personalized approach with RT with/without concurrent chemo and/or surgery may be justified to avoid permanent stomas.

• A multidisciplinary approach is warranted for patients with locally advanced vulvar carcinoma.

Abstract

Squamous cell carcinoma of the vulva is a rare female malignancy, with an incidence increasing with age. Unfortunately, one third of the patients are diagnosed with locally advanced disease, which constitutes a clinical challenge for the clinicians who treat these patients. The main challenges are represented by: 1. The primary site of the disease, which can be proximal to anatomical structures like the anal canal posteriorly, or the urethra and the bladder anteriorly, that in some circumstances cannot be spared without a bowel and/or urinary stoma; 2. The locoregional nodes that can be involved by the tumor, and they can be bulky, fixed or ulcerated; 3. The clinical condition of the patient, who may carry several comorbidities. Treatment modalities include radiation with or without chemotherapy, and surgery. In order to preserve the bowel and the urinary function without a permanent stoma, a personalized management with a multimodality approach is warranted. In this systematic review, we first clarify the different definitions of “locally advanced vulvar carcinoma”. Secondly, we evaluated the different treatment modalities described in the literature, and the impact of the different treatment strategies on prognosis and on preservation of bowel/urinary function. Finally, we offer a possible algorithm that may help the clinicians in treating patients with these uncommon and challenging situations with a multidisciplinary approach.

Introduction

Squamous cell carcinoma of the vulva is a rare disease of the female genital tract, accounting for approximately 5% of all the gynecologic tumors. The age-specific incidence ranges from 0.4:100,000 in the thirty-years' population, to 20:100,000 in women older than 70 years old [1]. In the United States, approximately 6020 women have been diagnosed with vulvar cancer during 2017, with 1150 deaths from the disease [2].

Vulvar cancer spreads through 3 different routes:

• Direct extension to the adjacent anatomical structures, such as vagina, urethra and anus

• Lymphatic dissemination, usually to the regional inguino-femoral nodes. This may occur even in the early stage of the disease

• Hematogenous dissemination to distant sites, such as lungs, liver and bone, is a rare event that may occur late in the course of the disease.

The staging system reflects these different ways of dissemination. Table 1 reports the 2009 FIGO staging classification [3]. In the 2009 FIGO classification, patients with negative nodes are considered to be at low-risk regardless of tumor size. Therefore, the 1988 stage II (>2 cm) and 1988 stage Ib (< 2 cm) were combined together [3]. In the 2009 classification, tumors of any size involving the lower urethra, lower vagina or anus with negative nodes are classified as stage II (1988 stage III) because of their relatively good clinical outcome. Tumors with positive nodes with or without extension to adjacent perineal structures are still classified as stage III. The number and the characteristics of nodal metastases are taken in account to further subdivide stage III in three subgroups with different prognosis.

Surgical management is the cornerstone of treatment for most patients with vulvar cancer, and includes radical local excision or tailored radical vulvectomy with bilateral inguinal lymphadenectomy with separate groin incisions [[4], [5], [6], [7]]. Sentinel node procedure is a safe alternative to lymphadenectomy in patients with a tumor size <4 cm, without clinically suspicious groin nodes. Due to the rarity of these tumors and the expertise that is needed for this procedure, patients should be treated by surgeons with skill in both vulvar cancer and sentinel node mapping [8].

Pelvic lymphadenectomy is not part of the surgical staging. The overall rate of positive pelvic nodes is approximately 5%, with a 15–20% rate in patients with positive groin nodes and nearly 0% in those with negative groin nodes [9]. Furthermore, the results of the Gynecologic Oncology Group [GOG] 37 demonstrated the superiority of postoperative pelvic and groin radiotherapy [RT] versus ipsilateral pelvic node dissection in patients with positive groin nodes after radical vulvectomy and bilateral inguinal lymphadenectomy [10]. The survival benefit for RT was even more significant for those patients with clinically suspected or fixed ulcerated groin nodes as well as for those with two or more histologically positive groin nodes.

Postoperative adjuvant inguinal and pelvic RT is warranted in patients with more than one intranodal metastasis or with extra-nodal tumor growth after a full inguino-femoral lymphadenectomy. Another indication for postoperative radiation is the presence of positive margins for invasive disease not amenable of re-excision [6,7]. The radiation volume is adapted to the clinical indication and usually includes the lower pelvic nodes and inguinal nodes for those with positive groin nodes at time of surgery. RT dose should be approximately 50 Gy for patients with microscopic metastases and 60 Gy for those with multiple positive nodes or extracapsular spread [7,11]. In a National Cancer Data Base [NCDB] analysis, the adjunction of adjuvant chemotherapy significantly reduced the risk of death in node-positive vulvar carcinoma patients who received adjuvant RT, with a hazard ratio [HR] of 0.62 [12].

Lymph nodal status is the strongest prognostic factor for squamous cell carcinoma of the vulva. The 5-year overall survival (OS) rates range from 70 to 98% for patients with negative nodes to 12–41% for those with metastatic nodes. Several studies have demonstrated the prognostic relevance of the number and size of groin metastases, as well as of the presence of extracapsular spread [1,13,14]. The AGO-CaRE-1 retrospective study assessed 1047 patients who underwent surgery and groin resection for vulvar cancer, of which 370 (35.3%) were found to have positive groin nodes [14]. The ratio of number of positive nodes to the number of resected nodes was an independent prognostic variable for both progression-free survival (PFS) and OS.

Tumor stage is another independent prognostic variable [1,15,16]. Podratz et al. [15] retrospectively evaluated the outcome of 224 patients treated from 1955 to 1975 at the Mayo Clinic, reporting a 5- year OS of 90%, 81%, 68% and 20%, for patients with stages I, II, III, and IV, respectively. In the FIGO Annual Report n. 26, the 5-year OS was 78.5% for patients with stage I, 58.8% for stage II, 43.3% for stage III, and 13.0% for stage IV disease [16]. In a Dutch study on 269 patients treated from 1988 to 2009, 113 (42.4%) patients were reclassified in a lower stage of disease according to the 2009 FIGO classification, and no patients were upstaged. The new staging system provided a better reflection of prognosis [17].

The laterality of nodal metastasis is no longer considered a prognostic variable in vulvar cancer. A retrospective assessment of 468 patients treated at two different Institutions (Mayo Clinic of Rochester and Medical University of Gdansk), showed that bilateral nodal disease did not impact cause-specific survival, justifying it being omitted from the 2009 staging system [18].