Clinico-pathological and biological prognostic variables in squamous cell carcinoma of the vulva

Abstract

Several clinical–pathological parameters have been related to survival of patients with invasive squamous cell carcinoma of the vulva, whereas few studies have investigated the ability of biological variables to predict the clinical outcome of these patients. The present paper reviews the literature data on the prognostic relevance of lymph node-related parameters, primary tumor-related parameters, FIGO stage, blood variables, and tissue biological variables. Regarding these latter, the paper takes into account the analysis of DNA content, cell cycle-regulatory proteins, apoptosis-related proteins, epidermal growth factor receptor [EGFR], and proteins that are involved in tumor invasiveness, metastasis and angiogenesis. At present, the lymph node status and FIGO stage according to the new 2009 classification system are the main predictors for vulvar squamous cell carcinoma, whereas biological variables do not have yet a clinical relevance and their role is still investigational.

Introduction

Vulvar squamous cell carcinoma, which represents approximately 5% of gynecological cancers, has an age-specific incidence ranging from 0.4 per 100,000 in thirty years old women to 20 per 100,000 in women older than seventy [1], [2], [3], [4]. Epidemiological data however might have selection bias because older patients are sometimes not referred to specialized centers [5]. The Surveillance Epidemiology and End Results [SEER] database reported a total of 13,176 vulvar carcinomas from 1973 to 2000. During this period vulvar intraepithelial neoplasia [VIN] and invasive disease have increased of 411% and 20%, respectively. High-risk human papillomavirus [HPV]s have been involved in the pathogenesis of a significant proportion of vulvar squamous cell carcinomas especially in younger women, whereas in older women chronic inflammation is a critical initiating event of HPV-negative tumors [6], [7], [8], [9]. Lichen sclerosus, a chronic scarring inflammatory dermatosis, could act as both an initiator and a promoter of vulvar carcinogenesis [10], [11]. Therefore vulvar squamous cell carcinomas are usually subdivided into two types: (i) basaloid or warty neoplasms, accounting for one third of the cases, that are HPV-related, are diagnosed in younger women and are often associated with usual VIN, and (ii) differentiated keratinizing neoplasms that are HPV-unrelated, develop in older women and are frequently associated with lichen sclerosus and differentiated VIN [9], [10], [12], [13], [14], [15].

The molecular pathways involved in vulvar carcinogenesis are not yet completely understood. Epigenetic inactivation due to promoter hypermethylation of genes involved in cell signaling, cycle control, DNA repair and neoascularization, could have a role in the pathogenesis of vulvar squamous cell carcinoma associated with lichen sclerosus [16], [17]. In fact the hypermethylation of RAS association domain family [RASSF]2A gene (encoding a negative effector of RAS protein) and of methylguanine-DNA methyltransferase [MGMT] (encoding a key protein for DNA repair) have been detected exclusively in vulvar squamous cell carcinoma and in lichen sclerosus associated with squamous cell carcinoma, but not in isolated lichen sclerosus [17].

Regarding therapy, wide radical dissection or modified radical vulvectomy with triple incision technique, associated with inguino-femoral-lymphadenectomy, is the recommended surgical treatment for T1b-T2 vulvar squamous cell carcinoma [18], [19], [20], [21], [22], [23]. This type of surgery is able to achieve cure rates equivalent to those obtained with enbloc radical vulvectomy but with fewer complications and better functional results. Lymph node resection can be unilateral in patients with well lateralized T1b lesions, if the ipsilateral groin is free of disease, otherwise bilateral lymph node resection is used [24], [25], [26]. Data from the literature show that only 62–67% of patients undergo inguino-femoral lymphadenectomy, thus evidencing that a significant proportion of the cases are not properly treated [27], [28]. An adequate management of the groins is critical for the clinical outcome and only women with stromal invasion ≤ 1 mm (T1a disease) do not require inguino-femoral lymphadenectomy [29]. Sentinel lymph node mapping appears to be a safe procedure in selected early-stage cases [30], [31].

Postoperative adjuvant inguinal and pelvic irradiation is needed for patients with two or more or macroscopically involved groin lymph nodes or with extra-capsular spread of disease, and often suggested for those with negative lymph nodes but with other high-risk pathologic findings, such as lymph-vascular space involvement [LVSI] or close surgical margins [26], [32], [33], [34], [35].

Primary chemoradiation can reduce tumor size and improve operability rates in patients with locally advanced disease [35], [36]. The Cochrane Gynecological Cancer group, which analyzed five studies of neoadjuvant chemoradiation in this clinical setting, reported operability rates of 63–92% in patients who received 5-fluorouracil [5-FU] plus cisplatin or mytomycin-C versus 20% in those treated with bleomycin [36]. 5-FU-based chemoradiation followed by tailored surgery represents an attractive treatment modality for patients who could otherwise be treated with exenterative procedures.

The present paper has reviewed the literature data about the ability of different clinical–pathological parameters and biological markers to predict the clinical outcome of patients with vulvar squamous cell carcinoma.