Introduction
Vulvar cancer has an incidence of 1–2 per 100,000 women per year and represents 3–5 % of all gynecological malignancies [
1‐
3]. Squamous cell carcinoma (SCC) is a predominating malignancy at this site as it accounts for approximately 85–90 % of vulvar cancers [
4,
5]. Acquaintance with the factors influencing prognosis is required and is still a challenge in vulvar cancer because of rarity of this disease.
Most of the knowledge about prognostic factors comes from retrospective analyses of cases with different histological types, collected for a long period, frequently treated surgically in a different way, with pathological data assessed with diverse criteria [
6‐
14].
A new staging system for vulvar cancer was introduced in 2009 by the International Federation of Gynecology and Obstetrics (FIGO) [
15] to replace the previous FIGO staging (1988), which was successfully used for over 20 years with only one modification, for stage I, introduced in 1994 [
16].
New FIGO staging system has shifted locoregional disease to the lower urethra, vagina or anus to stage II, effectively separating these cases from lymph node positive patients. In addition, larger size, non-metastatic primary lesions were grouped with smaller lesions into stage I. The second substantial change proposed in the 2009 FIGO staging system concerns stage III. This is now reserved for metastatic cases (patients with a tumor of any size with or without extension to the adjacent perineal structures with positive inguino-femoral lymph nodes) and composed of three sub-stages based on the number of lymph nodes involved and extent of involvement of nodes. Staging systems allow accurate prognostication and compare outcomes between centers and countries.
While prognostic significance of previous FIGO stage was evaluated several times [
12‐
14], the new FIGO has not been tested yet.
The aim of this study was to assess prognostic factors in vulvar SCC (including new FIGO stages) cases by analyzing histopathological features obtained by evaluation of tissue samples in cohort planned to surgery consistently with the same algorithm.
Methods
The impact of pathological variables, type of the tumor (pT), lymph node status (pN), tumor grade, depth of invasion, FIGO stage (FIGO1994 and FIGO2009), as well as clinical features, age and recurrence, on overall survival was assessed.
Statistical analysis
In order to determine statistically significant differences between the variables, the Mann–Whitney U test was used. Correlations and differences between variables were assessed using the Spearman’s rank correlation coefficient, Chi-square and Fisher tests. The Kaplan–Meier method was used to estimate overall survival, and survival differences were analyzed by the log-rank test and F Cox test. P values of <0.05 were regarded as significant. For uni- and multivariate analysis, the Cox proportional-hazards regression model was used to explore the impact of individual variables on survival. P values of <0.05 were regarded as significant in all of the analyses.
Discussion
All histopathological data were obtained by evaluation of original tissue samples in cohort planned for surgery consistently with the same algorithm.
We believe that blind review of all samples provided by two independent pathologists improved the value of the results. Several parameters were not incorporated in the available archival diagnostic reports (e.g. differentiation grade, size and number of lymph node metastasis, presence of extracapsular spread), and depth of invasion was previously assessed using diverse criteria. The importance of proper measurement of the depth of invasion in vSCC was recently indicated by Yoder et al. [
17].
The utilized algorithm for type and extent of primary surgery was consistent with widely accepted and even obligatory rules based on available evidence between 2002 and 2006 [
18‐
21]. Suspicious pelvic lymph nodes were not excised in the analyzed cohort. Postoperative radiotherapy to the groin and pelvis was given to all patients with positive inguinal lymph nodes, unless there was only one intranodal lymph node metastasis in combination with a well-differentiated primary tumor.
Most of the available reports on prognostic factors in vSCC [
13,
14] have included the analyses of cases treated with pelvic lymphadenectomy while it has been proven that such modality has negative influence on overall survival. Advantage of radiation to the pelvis in patients with positive inguinal lymph nodes as well as clinically suspected or fixed ulcerated groin nodes was confirmed in prospective randomized trials [
22,
23]. Therefore, survival analyses provided in appropriately treated cohort (up to date) serve as more reliable results.
Study group was observed for long enough (median 51.23 months) to reveal all potential recurrences [
8‐
10,
24‐
27]. Our patients had a 5-year DFS of 66.5 % and a recurrence rate of 20 % with 35 % patients in stage III and IV. While the long-term survival was comparable to those reported in the literature [
8‐
10,
24‐
27], we notified lower recurrence rate than others [
24,
25].
While depth of invasion in metastatic (median 8.2 mm) and non-metastatic cases (median 5.6 mm) was significantly different and the probability of inguino-femoral lymph node metastasis increased with depth of invasion of primary tumor, we were not able to find any borderline depth of invasion with significant impact on overall survival in our group of patients. Nicoletto et al. [
14] found stromal invasion of over 9 mm to be one of the most dominant predictor for relapsed free survival in vSCC.
Depth of invasion could be evaluated with at least three various measurement techniques, depending on whether the tumor surface, or the ulcer base was chosen as the starting point [
28] even in one institution. To standardize this parameter, we utilized only one, most recommended technique (measuring from the most superficial dermal papilla adjacent to the tumor to the deepest focus of invasion). This as well as smaller number of cases in Italian study could explain discrepancies between the two analyses.
Thirty-five patients (35/76, 46 %) were down-staged and one case (1/76, 1 %) was up-staged using the 2009 FIGO system. The results of the overall survival according to both FIGO systems indicated that the new staging stratified survival between stages less effectively than the old FIGO system.
To the best of our knowledge, there were no previous comparative analyses of the old and revised staging systems in vulvar cancer; therefore, we had no adequate source of reference to compare our results.
Conducted multivariate analysis has shown that the growing age, histologic tumor grade and FIGO1994 stage are the independent prognostic factors for overall survival in analyzed group of vSCC patients.
This study together with several previous examinations has demonstrated that differentiation grade plays an important role in the aggressiveness of a tumor and has a considerable impact on survival [
9,
10,
13,
14,
17,
27].
The results emphasize the prognostic advantage of the 1994 FIGO staging system as it has become an independent prognostic factor in contrast to the new FIGO system.
The single paper published in 2010 reported that the proposed modifications were successful and the new FIGO staging system provides a better reflection of prognosis [
29], but it was followed by the letter to the editor suggesting inverse conclusion [
30]. Lack of prognostic significance of 2009 FIGO staging system indicated in current study should be tested in future larger cohort studies.
The role of a pathologist is to provide clinicians with a diagnosis and with as much prognostic information as possible when examining biopsy material [
28]. While the data do seem to support that there is an important prognostic role for histologic grade for vSCC [
9,
10,
13,
14,
17,
27], most pathologists have not yet incorporated this parameter into common practice schemes. Towards this end, it may be prudent to consider incorporating comments about histologic tumor grade as a routine component of the diagnostic reports of this malignancy.
This study has the traditional weaknesses of a retrospective design and results obviously represent a small cohort. Its strengths include uniformly treated cohort without the effect of treatment evolution over long periods of time and the ability to review pathologic slides to correctly assign newer sub-staging criteria as well as other pathological features.