Midline Involvement as a Risk Factor for Vulvar Cancer Recurrence

It is estimated by American Cancer Society that 4,490 women will be diagnosed with and 950 women will die of cancer of the vulva in 2012 (Howlader et al., 2012). The median age at diagnosis for cancer of the vulva is 68 years of age and median age at death for cancer of the vulva is 79 years of age (Howlader et al., 2012). Treatment for early stage vulvar cancer consists of radical excision of the tumor with ipsilateral or bilateral inguinofemoral lymphadenectomy. Most of vulvar cancer recurrences occur in inguinal region and very rarely in the primary site of tumor excision (Magrina et al., 1979; Kelley et al., 1992; Sidor et al., 2006; Hampl et al., 2009). Several studies have described inguinal lymph node recurrences in up to 2.4% of cases (Hacker et al., 1983; Bell et al., 2000; Rodolakis et al., 2000; Ate van der Zee et al., 2008). Groin lymph-node metastases have been discovered as a most signifficant prognostic factors for vulvar cancer recurrence with a 5-year survival of 70-93% in patients with negative inguinofemoral lymph-nodes compared to 25-41% in patients with lymph-node metastases (Gadducci


Introduction
It is estimated by American Cancer Society that 4,490 women will be diagnosed with and 950 women will die of cancer of the vulva in 2012 (Howlader et al., 2012). The median age at diagnosis for cancer of the vulva is 68 years of age and median age at death for cancer of the vulva is 79 years of age (Howlader et al., 2012). Treatment for early stage vulvar cancer consists of radical excision of the tumor with ipsilateral or bilateral inguinofemoral lymphadenectomy. Most of vulvar cancer recurrences occur in inguinal region and very rarely in the primary site of tumor excision (Magrina et al., 1979;Kelley et al., 1992;Sidor et al., 2006;Hampl et al., 2009). Several studies have described inguinal lymph node recurrences in up to 2.4% of cases (Hacker et al., 1983;Bell et al., 2000;Rodolakis et al., 2000;Ate van der Zee et al., 2008). Groin lymph-node metastases have been discovered as a most signifficant prognostic factors for vulvar cancer recurrence with a 5-year survival of 70-93% in patients with negative inguinofemoral lymph-nodes compared to 25-41% in patients with lymph-node metastases (Gadducci
Objective of this observational study was to identify risk factors for vulvar cancer recurrence.

Materials and Methods
In the study 107 patients with primary vulvar cancer were analyzed. Surgical treatment consisted of radical excision of the primary tumor in combination with unilateral or bilateral superficial and deep inguinofemoral lymphadenectomy through separate incisions. A unilateral tumor was defined as a lesion that does not cross the midline, with the medial margin of the tumor more than 1 cm from the midline structures. The primary tumor was excised with a margin of at least 1 cm of normal skin. Unilateral excision was performed for tumors less than 2 cm in the diameter and with a deper invasion less than 1mm, unless involvement of labia minora and positive ipsilateral lymphnodes were detected. Patients with deeper tumor invasion >1 mm or wider than 2 cm and/or groin lymphnode metastases were referred for adjuvant radiotherapy. Patients with large privary vulvar tumors received neoadjuvant radiotherapy of 30Gy with a following surgical treatment and adjuvant radiotherapy. To evaluate risk factors for vulvar cancer recurrence age, FIGO stage, tumor morphology, unilocularity or multilocularity, involvement of middline, involvement of lymphnodes, extent of surgery, radiotherapy, recurrences, distant metastases and 5 year survival rates were assessed. All analyses were performed using SPSS software, version 20.0 (SPSS Inc, Chicago, IL). Differences in the distributions of patient characteristics were analyzed with the t test. Overall survival analysis was done using Kaplan-Meier test. Cox proportional hazard ratio was assessed to estimate risk factors for vulvar cancer recurrences. Differences associated with a p<0.05 were considered significant.

Results
All patients had squamous cell carcinoma. Most of them had stage III cancer with unilocular primary leasions involving midline and having metastases in the ipsilateral, contralateral or bilateral inguinal lymphnodes (   Patients with early stage vulvar cancer had longer mean survival rates-for stage I 53.1±3.4 months, 38.4±4.4 months for stage II and 33.4±2.6 and 15.6±5.2 months for patients with stage III and stage IV vulvar cancer, respectively (Figure 2). The only signifficant prognostic factors predicting vulvar cancer recurrence was involvement of midline (Table 3).

Discussion
Results from the studies regarding prognostic factors for prognostic factors in vulvar cancer are contraversial and can be explained by small sample size included in the retsopective studies and heterogenous treatment approaches (Iversen et al., 1980;Burger et al., 1995;Gonzalez et al., 2005). Potential risk factors for vulvar rancer recurrences include stage, tumour size, depth of invasion, tumor free margin, lymphovascular space invasion, age and nodal involvement. Althought the importance of these risk factors is inconclusive and varies across the studies (Andreasson et al., 1985;Podratz et al., 1983;Hefler et al., 1999;Chan et al., 2007).  In this study, 107 patients with primary vulvar carcinoma were treated either with primary radical surgery following adjuvant radiotherapy or only radiotherapy in patients who were not appropriate for surgical treatment and were evaluated for risk factors of vulvar cancer recurrence.
In our study the only statistically signifficant risk factor preventing vulvar cancer recurrences was tumor involvement of middline (HR 0.46; p=0.02). This can be explained by more aggresive treatment of patients with middline involvement and thus better prognosis and less recurrences. Statistically there were no differences of vulvar cancer recurrences in patients with or without groin metastases (p=0.46), although this has been described in literature as a most signifficant risk factor predicting recurrent disease. In the study of Woelber et al. (2009) groin lymph node metastasis was the most important prognostic factor for disease-free and overall survival -patients with unilateral lymph node metastasis had a five-fold increased risk of recurrence compared to node-negative patients; in cases of bilateral lymph node involvement, this risk was 17 times higher.
Almost significant risk factors predicting vulvar cancer recurrence in our study was age over 70 years, tumor characteristics such as multilocular or unilocular and combined treatment of neoadjuvant radiotherapy following surgical treatment and adjuvant radiotherapy versus radiotherapy alone. There was a tendency for fewer vulvar cancer recurrences in patients over 70 years of age (HR 0.61; p=0.07). However, in the study of Woolderink et al. vulvar cancer recurrences more often were found in elderly patients (Woolderink et al., 2006).
Almost twice higher risk for vulvar cancer recurrence was observed in patients having multifoccal disease in contrast to patient with unilocular leasion, althought this factor didn't reach statistical signifficance (HR 1.91,p=0.08). This finding can be explained by tumor leasions that were left undiagnosed and thus led to tumor recurrence.
The last risk factor found to be very close to reach statistical signifficance was neoadjuvant radiotherapy following sugery and adjuvant radiotherapy versus radiotherapy as an only treatment option (HR 1.66; p=0.06). Such finding can be explained by larger tumors and more widespread dissemination in patients receivind pre-and postoperative radiotherapy. Although patients who are receiving radiotherapy as an only treatment are not approprite for surgical treatment because of tumor spread, part of them are referred for radiotherapy because of co-morbidities and risk of wound dehiscence and not only because of wide tumor dissemination.
In our study we didn't evaluate a number of involved groin lymphnodes and neither involvement of pelvic lymphnodes, but there are some studies not showing any association between the number of metastatic lymphnodes and the risk of recurrence, while in other analyses involvement of two or more nodes, extracapsular spread and large size of the metastases were predictive of vulvar canccer recurrence (Origoni et al., 1992;Paladini et al., 1994;Van et al., 1995;Lataifeh et al., 2004).
In the literature as a risk factors predicting vulvar cancer recurrrence have been described also intracapsular lymph-node metastasis, lymphangio invasion and large primary tumours (Burger et al., 1995;Woelber et al., 2009;Oonk et al., 2010).
To get clear conclusions of vulvar cancer prognostic factors, large multicentric, prospective trial with uniform treatment approache is needed. In conclusions, patients having midline involvement of vulvar cancer has lower recurrence risk, probably because of receiving more aggressive treatment. There is a tendency for lower vulvar cancer recurrence risk for patients over 70 years of age and patients who are receiving radiotherapy as an only treatment without surgery, but tendency for higher risk of recurrence in patients with multifocal vulvar cancer.